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Arsenic MOA

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The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Oxidative modifications of proteins by sodium arsenite in human umbilical vein endothelial cells

Authors: Lii, C-K; Lin, A-H; Lee, S-L; Chen, H-W; Wang, T-S (In Press) Environmental Toxicology. HERO ID: 711001

[Less] Epidemiologic studies have demonstrated that chronic arsenic exposure is associated with the incidence . . . [More] Epidemiologic studies have demonstrated that chronic arsenic exposure is associated with the incidence of chronic diseases. This association is partly related to the increase in reactive oxygen species (ROS) overload and protein oxidation that result from arsenic exposure. In this study, we intended to identify proteins susceptible to oxidative carbonylation by sodium arsenite and the impact of carbonylation on the function of these proteins in human umbilical vein endothelial cells (HUVECs). The 2,4-dinitrophenylhydrazine (DNPH) dot-blot assay revealed that arsenite (0-50 muM) dose-dependently increased protein carbonylation. Consistent with these findings, the cellular ROS level as measured by 2',7'-dichlorofluorescein diacetate (DCHF-DA) assay was increased in cells exposed to arsenite. By two-dimensional gel electrophoresis and matrix assist laser desorption ionization time of flight mass spectrometry (MALDI-TOF/MS), one glycolytic enzyme, enolase-alpha, two cytoskeleton proteins, fascin (F-actin associated protein) and vimentin, and two protein quality control proteins, HSC70 (heat-shock cognate protein 70), and PDIA3 (protein disulfide isomerase family A, member 3) were identified to be arsenic-sensitive carbonlyated proteins. Accompanied by carbonylation, enolase-alpha activity was dose-dependently decreased and the F-actin filament network was disturbed. Taken together, our results suggest that arsenite exposure results in the generation of carbonylated proteins, and the resultant changes in energy metabolism and in the cytoskeletal network may partly lead to cell damage.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Reversible inhibition of Co(2) fixation by ribulose 1,5-bisphosphate carboxylase/oxygenase through the synergic effect of arsenite and a monothiol

Authors: Sudhani, HPK; García-Murria, M-J; Moreno, J (In Press) Plant, Cell and Environment. HERO ID: 1337298

[Less] The activity of the photosynthetic carbon-fixing enzyme, ribulose 1,5-bisphosphate carboxylase/oxygenase . . . [More] The activity of the photosynthetic carbon-fixing enzyme, ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco), is partially inhibited by arsenite in the millimolar concentration range. However, micromolar arsenite can fully inhibit Rubisco in the presence of a potentiating monothiol such as cysteine, cysteamine, 2-mercaptoethanol or N-acetylcysteine, but not glutathione. Arsenite reacts specifically with the vicinal Cys172-Cys192 from the large subunit of Rubisco and with the monothiol to establish a ternary complex which is suggested to be a trithioarsenical. The stability of the complex is strongly dependent on the nature of the monothiol. Enzyme activity is fully recovered through the disassembly of the complex after eliminating arsenite and/or the thiol from the medium. The synergic combination of arsenite and a monothiol acts also in vivo stopping carbon dioxide fixation in illuminated cultures of Chlamydomonas reinhardtii. Again, this effect may be reverted by washing the cells. However, in vivo inhibition does not result from the blocking of Rubisco since mutant strains carrying Rubiscos with Cys172 and/or Cys192 substitutions (which are insensitive to arsenite in vitro) are also arrested. This suggests the existence of a specific sensor controlling carbon fixation that is even more sensitive than Rubisco to the arsenite-thiol synergism.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma

Authors: Zhang, T; Cai, J; Chang, J; Yu, D; Wu, C; Yan, T; Zhai, K; Bi, X; Zhao, H; Xu, J; Tan, W; Qu, C; Lin, D (In Press) HERO ID: 1337302

[Less] APOBEC3s are a family of cytidine deaminases involved in innate cellular immunity against virus including . . . [More] APOBEC3s are a family of cytidine deaminases involved in innate cellular immunity against virus including hepatitis B virus (HBV). A germline deletion across APOBEC3A and APOBEC3B (A3B) genes results in complete removal of the A3B coding region and destroys A3B expression. To determine whether this deletion affects susceptibility to HBV infection and HBV-related hepatocellular carcinoma (HCC), A3B genotypes were analyzed in 1,124 individuals with HCC, 510 individuals with persistent HBV infection and 826 healthy controls and the association was estimated by odds ratio (OR) and 95% confidence interval (CI) computed by logistic regression. We also examined the effects of APOBEC3B on HBV genome hypermutation and replication in HCC cells. We observed a significantly higher frequency of the A3B deletion allele in persistent HBV carriers (33.3%; P=0.0015) and HCC patients (37.9%; P=1.28×10(-11)) compared with that in controls (27.5%). An increased risk for persistent HBV infection (OR=1.35, 95% CI, 1.03-1.77) and HCC development (OR=1.90, 95% CI, 1.58-2.28) was associated with at least one A3B deletion allele (+/- or -/- genotype) compared with the +/+ genotype. Transfection of A3B in HepG2 cells caused a substantial reduction of HBV RNA levels and G→A hypermutation in HBV genome. Interestingly, a cytidine deaminase null mutant of A3B (E255A) also inhibited HBV RNA production although it was unable to edit HBV. These results suggest that deletion of A3B attenuates HBV clearance, which in turn may result in persistent HBV infection and increased risk for developing HCC. Further studies are needed to verify our findings.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

F18-FDG-PET/CT thyroid incidentalomas: A wide retrospective analysis in three Italian centres on the significance of focal uptake and SUV value

Authors: Bertagna, F; Treglia, G; Piccardo, A; Giovannini, E; Bosio, G; Biasiotto, G; Bahij, EK; Maroldi, R; Giubbini, R (In Press) Endocrine. HERO ID: 1337356

[Less] Thyroid incidental uptake is defined as a thyroid uptake incidentally and newly detected by imaging . . . [More] Thyroid incidental uptake is defined as a thyroid uptake incidentally and newly detected by imaging techniques performed for an unrelated purpose and especially for non-thyroid diseases. Aim of the study was to establish the prevalence and pathological nature of focal thyroid incidentalomas detected at F18-FDG-PET/CT in patients studied for oncological purposes and not for thyroid disease. Secondary end point was to establish a possible maximum standardised uptake value cut-off over which a malignant lesion should be suspected. We have retrospectively evaluated 49519 patients who underwent F18-FDG-PET/CT for oncologic purposes in three Nuclear Medicine Centres (N.1 = 11278, N.2 = 31076, N.3 = 7165). A focal incidental thyroid uptake was diagnosed in 729 (1.5 %) patients (287-39.4 % male and 442-60.6 % female; average age: 65.26). Of 729 thyroid incidentalomas 211 (28.9 %) underwent further investigation to determine the nature of the nodule; 124/211 (58.8 %) incidentalomas were benign, 72/211 (34.1 %) malignant, 4/211 (1.9 %) non-diagnostic at cytological examination in the absence of surgery and histological evaluation and 11/211 (5.2 %) were indeterminate at cytological examination. A centre-based receiver operating curve (ROC) analysis of the patients with a definitive diagnosis was performed to identify a SUVmax cut-off useful in differentiating benign from malignant incidentalomas. In the centre N.1 it was 4.8 (sensitivity = 95.7 %, specificity = 46.4 %, area under the curve = 0.758); 5.3 in the centre N.2 (sensitivity = 76.3 %, specificity = 72.5 %, area under the curve = 0.815); 7 in the centre N.3 (sensitivity = 57.1 %, specificity = 79.3 %, area under the curve = 0.627). F18-FDG-PET/CT thyroid incidentalomas are a relevant diagnostic reality which requires further investigations and clinical management especially considering that, despite mainly benign, approximately one third of focal thyroid uptakes are malignant.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

EMT and CSC-like properties mediated by the IKKβ/IκBα/RelA signal pathway via the transcriptional regulator, Snail, are involved in the arsenite-induced neoplastic transformation of human keratinocytes

Authors: Jiang, R; Li, Y; Xu, Y; Zhou, Y; Pang, Y; Shen, L; Zhao, Y; Zhang, J; Zhou, J; Wang, X; Liu, Q (In Press) Archives of Toxicology. HERO ID: 1337675

[Less] Exposure of humans to inorganic arsenic can cause skin cancer. The epithelial-mesenchymal transition . . . [More] Exposure of humans to inorganic arsenic can cause skin cancer. The epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like properties are essential steps in the initiation of human skin cancers; however, the mechanisms of action remain obscure. We have found that, during the neoplastic transformation induced by a low concentration (1.0 μM) of arsenite in human keratinocyte HaCaT cells, the cells undergo an EMT and then acquire a malignant CSC-like phenotype. With longer times for transformation of HaCaT cells, there were increased activations of IκB kinase β (IKKβ), inhibitor nuclear factor-kappa B alpha (IκBα), and nuclear factor κB (NF-κB) RelA and increases in the level of Snail. Further, during the transformation of HaCaT cells, the activation of NF-κB RelA up-regulated Snail levels. Inhibition of NF-κB RelA blocked the arsenite-induced EMT, acquisition of a CSC-like phenotype, and neoplastic transformation. These observations show that EMT, along with acquisition of a CSC-like phenotype mediated by IKKβ/IκBα/RelA signal pathway via Snail, contributes to a low concentration of arsenite-induced tumorigenesis.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Bioreporters and biosensors for arsenic detection. Biotechnological solutions for a world-wide pollution problem

Authors: Merulla, D; Buffi, N; Beggah, S; Truffer, F; Geiser, M; Renaud, P; van der Meer, JR (In Press) Current Opinion in Biotechnology. [Review] HERO ID: 1338620

[Less] A wide variety of whole cell bioreporter and biosensor assays for arsenic detection has been developed . . . [More] A wide variety of whole cell bioreporter and biosensor assays for arsenic detection has been developed over the past decade. The assays permit flexible detection instrumentation while maintaining excellent method of detection limits in the environmentally relevant range of 10-50μg arsenite per L and below. New emerging trends focus on genetic rewiring of reporter cells and/or integration into microdevices for more optimal detection. A number of case studies have shown realistic field applicability of bioreporter assays.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast

Authors: Jacobson, T; Navarrete, C; Sharma, SK; Sideri, TC; Ibstedt, S; Priya, S; Grant, CM; Christen, P; Goloubinoff, P; Tamás, MJ (In Press) Journal of Cell Science. HERO ID: 1339148

[Less] Several metals and metalloids profoundly affect biological systems, but their impact on the proteome . . . [More] Several metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Phosphorylation of histone H3 at serine 10 has an essential role in arsenite-induced expression of FOS, EGR1 and IL8 mRNA in cultured human cell lines

Authors: Suzuki, T; Kita, K; Ochi, T (In Press) Journal of Applied Toxicology. HERO ID: 1340672

[Less] Trivalent inorganic arsenite [iAs(III)] is known to alter the expression of a number of genes associated . . . [More] Trivalent inorganic arsenite [iAs(III)] is known to alter the expression of a number of genes associated with transcription and cell proliferation, which was thought to be one of the possible mechanisms of arsenical carcinogenesis. However, the detailed mechanisms underlying iAs(III) induction of changes in gene expression are not fully understood. Here we examine the role of histone H3 phosphorylation at serine 10 (Ser(10) ) in gene regulation when the cells were treated with iAs(III). Among the 34 genes tested, iAs(III) induced mRNA expression of JUN, FOS, EGR1, HMOX1, HSPA1A, IL8, GADD45A, GADD45B and GADD153. Phosphorylation of histone H3 Ser(10) was induced by iAs(III) in interphase cells, and was effectively blocked by the ERKs pathway inhibitor (U0126). U0126 treatment significantly reduced constitutive mRNA expression of FOS and EGR1, and dramatically suppressed the induction of FOS, EGR1 and IL8 mRNA in iAs(III)-treated cells. The other genes, which were induced by iAs(III), were not affected by U0126 treatment. When the histone H3 nonphosphorylatable mutant of serine 10 (S10A) was overexpressed in cells, iAs(III) induction of FOS, EGR1and IL8 expression was significantly decreased as compared with wild-type cells. The other genes induced by iAs(III) were not changed in S10A cells nor by U0126 treatment. In addition, S10A cells were more resistant to iAs(III) cytotoxicity. These results indicated that the phosphorylation of histone H3 at Ser(10) through the ERKs pathway in interphase cells is an important regulatory event for iAs(III)-mediated gene expression. Aberrant gene expression seems to be an important cause of cytotoxicity and may have some relation to iAs(III) carcinogenicity.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

Authors: Luo, F; Xu, Y; Ling, M; Zhao, Y; Xu, W; Liang, X; Jiang, R; Wang, B; Bian, Q; Liu, Q (In Press) Toxicology and Applied Pharmacology. HERO ID: 2064223

[Less] Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant . . . [More] Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite

Authors: Hirano, S; Watanabe, T; Kobayashi, Y (In Press) Toxicology and Applied Pharmacology. HERO ID: 2088511

[Less] Inorganic arsenite (iAs(3+)) is a two-edged sword. iAs(3+) is a well-known human carcinogen; nevertheless, . . . [More] Inorganic arsenite (iAs(3+)) is a two-edged sword. iAs(3+) is a well-known human carcinogen; nevertheless, it has been used as a therapeutic drug for acute promyelocytic leukemia (APL), which is caused by a fusion protein comprising retinoic acid receptor-α and promyelocytic leukemia (PML). PML, a nuclear transcription factor, has a RING finger domain with densely positioned cysteine residues. To examine PML-modulated cellular responses to iAs(3+), CHO-K1 and HEK293 cells were each used to establish cell lines that expressed ectopic human PML. Overexpression of PML increased susceptibility to iAs(3+) in CHO-K1 cells, but not in HEK293 cells. Exposure of PML-transfected cells to iAs(3+) caused PML to change from a soluble form to less soluble forms, and this modification of PML was observable even with just 0.1μM iAs(3+) (7.5ppb). Western blot and immunofluorescent microscopic analyses revealed that the biochemical changes of PML were caused at least in part by conjugation with small ubiquitin-like modifier proteins (SUMOylation). A luciferase reporter gene was used to investigate whether modification of PML was caused by oxidative stress or activation of antioxidant response element (ARE) in CHO-K1 cells. Modification of PML protein occurred faster than activation of the ARE in response to iAs(3+), suggesting that PML was not modified as a consequence of oxidative stress-induced ARE activation.