Arsenic

Fowler, Bruce A.; Chou, Chun‐Nan; Jones, Robert L.; Costa, Max; Chen, Chien-Jen

doi:10.1016/b978-0-12-822946-0.00037-4

Cited by 9 publications

(31 citation statements)

References 593 publications

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“…The identified health risk, however, was very low since it was estimated that life‐long consumption of turkey meat might result in increased lifetime risk of developing or dying from cancer of 0.00031% (Nachman et al , 2017 ). Nitarsone is the oxidized form of arsanilic acid, an organic arsenic compound, considered to be less harmful than inorganic arsenic like arsenic trioxide (ATO) (Fowler et al , 2022 ). However, a transformation in carcinogenic arsenic might be possible (Nachman et al , 2017 ) by anaerobic gut microbiota (Chen & Rosen, 2016 ) and chemical modification of the compound to prevent this transformation is difficult given its almost perfect fit to the binding pocket.…”

Section: Discussionmentioning

confidence: 99%

Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease

et al. 2023

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Synaptic dysfunction caused by soluble b-amyloid peptide (Ab) is a hallmark of early-stage Alzheimer's disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Ab suppresses the transcriptional activity of cAMP-responsive elementbinding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Ab elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons. Ab-regulated trafficking of Jacob induces transcriptional inactivation of CREB leading to impairment and loss of synapses in mouse models of AD. The small chemical compound Nitarsone selectively hinders the assembly of a Jacob/ LIM-only 4 (LMO4)/ Protein phosphatase 1 (PP1) signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest targeting Jacob protein-induced CREB shutoff as a therapeutic avenue against early synaptic dysfunction in AD.

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Section: Discussionmentioning

confidence: 99%

Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease

et al. 2023

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“…The identified health risk, however, was very low since it was estimated that life-long consumption of turkey meat might result in increased lifetime risk of developing or dying from cancer of 0.00031% (Nachman Keeve et al, 2017). Nitarsone is the oxidized form of arsanilic acid, an organic arsenic compound, considered to be less harmful than inorganic arsenic like arsenic trioxide (ATO) (Fowler et al, 2022). However, a transformation in carcinogenic arsenic might be possible (Nachman et al, 2017) by anaerobic gut microbiota (Chen & Rosen, 2016) and chemical modification of the compound to prevent this transformation might be difficult given its almost perfect fit to the binding pocket.…”

Section: Discussionmentioning

confidence: 99%

Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer’s Disease

Kaushik

et al. 2020

Preprint

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Disruption of transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression, is a hallmark of neurodegenerative diseases. CREB shut-off results in synaptic dysfunction and neuronal cell death and is elicited in Alzheimer's disease (AD) by amyloid-βinduced activation of extrasynaptic N-methyl-D-aspartate-receptors (NMDAR).Following long-distance transport from NMDAR to the nucleus the protein messenger Jacob docks a signalosome to CREB that encodes the synaptic or extrasynaptic origin of the NMDAR signal. In previous work we found that in response to cell survival/plasticity related synaptic NMDAR stimulation macromolecular transport of Jacob docks the MAP-kinase ERK to the CREB complex which results in sustained CREB phosphorylation. Here we show that in case of disease-related activation of extrasynaptic NMDAR by amyloid-β, Jacob associates with protein phosphatase-1γ (PP1γ) and induces dephosphorylation and transcriptional inactivation of CREB.Binding of the adaptor protein LIM domain only 4 (LMO4) to Jacob distinguishes extrasynaptic from synaptic NMDAR signaling and determines the affinity for the association with PP1γ. This mechanism contributes to transcriptional inactivation of CREB in response to extrasynaptic NMDAR signaling in the context of early synaptic dysfunction and cell loss in AD. Accordingly, Jacob protein knockdown attenuates CREB shut-off and cellular deterioration in response to amyloid-β signaling and Jacob gene knock out is neuroprotective in a transgenic mouse model of AD.

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“…27 For many human populations, seafood has been identified as the primary source of As, since concentrations of As in many fish and shellfish vastly exceed As levels of most drinking waters and other food sources as they commonly mount into the mg/kg range. 26,28-30 Marine-derived foods present As primarily in the form of less harmful, organic As-compounds (oAs) with the non-toxic, Arsenobetaine (AsB, “fish-arsenic”) reportedly accounting for 75% - 100% of total oAS in seafood and 0.4% - 90% in freshwater fish. 28,29,31 AsB is rapidly excreted unmetabolized with a half-life of 18 hours.…”

Section: Introductionmentioning

confidence: 99%

“…The critical step in the biotransformation of absorbed inorganic arsenic is an alternate reduction followed by a sequential oxidative methylation process, which occurs primarily in the liver and to a lesser extent in kidneys and other tissues. 26,33,34 The essential co-factors of oxidative iAs methylation are S-adenosyl methionine (SAME) as methyl donor and Glutathione (GSH) and NADH as electron donors or redox-cyclers. 2,34 DMA is generally considered the primary metabolic endpoint in the human biotransformation of iAs and it accounts for the major share of iAs-derived uAs.…”

Section: Introductionmentioning

confidence: 99%

“…37,38,39 Trivalent As III and its methylated forms are much more toxic and abundant in most human tissues than As V and account for most of the biohazard from As. 26,27 Trivalent inorganic and organic arsenicals strongly bind to thiolates of closely spaced cysteine residues. Consequently, they are predominantly stored in the protein fraction of mammalian tissue, where they can impede the function of many enzymes.…”

Section: Introductionmentioning

confidence: 99%

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Variable Power Functional Dilution Adjustment of Spot Urine

Carmine¹

2023

Preprint

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Background Dilution adjustment of spot-urinary biomarkers by conventional creatinine correction (CCRC) remains controversial. Apart from unaccounted confounders like age, sex, muscle mass, or diet, the misperception of constant mass ratios between analyte and creatinine (uCR) over a wide hydration range entails deceptive creatinine correction errors (CRCE), foremost at both ends of the uCR-spectrum. Mitigating CRCE by restricting uCR-ranges to 0.3(0.4)-3 g/L generates high numbers of sample rejects and allows for misleading fluctuations within presumably tolerable uCR-ranges. Methods The CRCE for exemplary total weight Arsenic (TWuAs) was analyzed in a large set of n= 5,599 unselected spot urine samples. After confining data to 14 - 80 years, uncorrected arsenic (uAsUC) < 500 mcg/l, and uCR < 4.5g/L, the remaining 5,400 samples were partitioned, and a calculation method to standardize uAsUC to 1 g/L uCR developed based on uAsUC-stratified power functional regression analysis (PFRA). Findings The obtained standardizing method of variable power-functional creatinine correction (V-PFCRC) represents a progression of reportedly proven simple power-functional modifications of CCRC (S-PFCRC). In contrast to CCRC and S-PFCRC, standardization to 1g/L uCR by V-PFCRC yielded constant uAsN-values over the entire uCR-range in all sextiles. Residual bias was largely neutralized in all sextiles of uAsN (R2 9E-06 - 0.04), compared to uAsUC (R2 0.93 - 0.99) and CCRC (R2 0.42 - 0.89). The efficacy of CRCE compensation was confirmed by simple PFRA in both sexes and seven age bands. The strongest %CRCEs were found in samples at low concentrations of uCR (SBC -0.96) and/or uAsUC (SBC -0.11). Interpretation Standardization to 1g/L uCR by V-PFRA allows for more reliable dilution adjustment of spot urinary results than CCRC and S-PFCRC. As an easily adoptable, novel approach, the calculation method developed in this study can minimize residual dilution bias in urinary biomarkers adjusted by uCR, SG, and osmolality. While minimizing sample rejects, V-PFCRC will improve the reliability and comparability, particularly of lower concentrated urinary biomarkers in both conventional results and multiple linear regression models. Funding Self-funded.

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Arsenic

Cited by 9 publications

References 593 publications

Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease

Jacob‐induced transcriptional inactivation of CREB promotes Aβ‐induced synapse loss in Alzheimer's disease

Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer’s Disease

Variable Power Functional Dilution Adjustment of Spot Urine

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