Seleno- and Telluro-xylofuranosides attenuate Mn-induced toxicity in C. elegans via the DAF-16/FOXO pathway

Wollenhaupt, Suzi; Soares, Ana Thalita Gonçalves; Salgueiro, Willian G.; Noremberg, Simone; Reis, Gabriel Moraes; Viana, Carine; Gubert, Priscila; Soares, Félix Antunes; Affeldt, Ricardo F.; Lüdtke, Diogo S.; Santos, Francielli Weber; Denardin, Cristiane Casagrande; Aschner, Michael; Ávila, Daiana Silva

doi:10.1016/j.fct.2013.11.030

Cited by 27 publications

(16 citation statements)

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“…The antioxidant compound diethyl-2-phenyl-2-telurofenil vinyl phosphonate (DPTVP) protects against oxidative stress caused by Mn by a mechanism that involves the translocation of DAF-16 to the nucleus (Avila et al 2012a). A similar effect was obtained with the seleno-xilofuranoside compound and its tellurium analogue, noting increased SOD-3 levels and reduction in the toxic effects associated with Mn exposure in worms (Wollenhaupt et al 2014). Therefore, the absence of Akt-1/2 or SGK-1 in mutant worms may relieve the inhibition of DAF-16, and thereby increase worm resistance to Mn.…”

Section: Discussionsupporting

confidence: 55%

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity

et al. 2018

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Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson's disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.

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Section: Discussionsupporting

confidence: 55%

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity

et al. 2018

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“…Using the complementary animal model C. elegans , it was shown that these compounds could modulate the transcription factor DAF-16 (FOXO in mammals), increasing its translocation to the nucleus. In turn, the expression of antioxidant enzymes such as superoxide dismutase increased, thus protecting the worms from Mn-induced toxicity [203, 204]. An additional proposed mechanism is the anti-inflammatory action of some of these compounds, e.g.…”

Section: Main Textmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

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Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

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“…Organotellurium compounds are often described as toxic, with aryl telluroethers showing cellular toxicity below 100 µM across a range of cell lines under different assay conditions. [9][10][11][12][13][14] The IC 50 values of the reported organotellurium compounds provide promise as mass tags for activity based MC probes since the probe concentrations required in these experiments will typically be below ∼100 µM. Compounds 8, 9 and 10 are expected to show degradation over the time frame of the toxicity assay, based on our NMR stability studies, and, as such these experiments show the relative toxicities of the compounds and their resulting degradation products (Table 2).…”

Section: Cellular Toxicitymentioning

confidence: 99%

“…7,8 Tellurium has no known biological role in prokaryotic or eukaryotic cells. [9][10][11][12][13][14] The majority of this research has been based upon the ability of aryl telluroethers to mimic glutathione peroxidase activity providing, in some cases, resistance to oxidative stress, and, in other cases, disregulating redox homeostasis leading to apoptosis. Microorganisms have been found to methylate inorganic tellurium to volatile or ionic species for excretion.…”

Section: Introductionmentioning

confidence: 99%

Organotellurium scaffolds for mass cytometry reagent development

et al. 2015

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Mass cytometry (MC) is a powerful tool for studying heterogeneous cell populations. In previous work, our laboratory has developed an MC probe for hypoxia bearing a methyl telluride mass tag. The methyl telluride was unoptimized, displaying stability and toxicity limitations. Here, we investigate three classes of organotelluriums as MC mass tags: methyl tellurides, trifluoromethyl tellurides and 2-alkyl-tellurophenes. NMR was used to compare the stability of these compounds in aqueous and organic solutions and the compounds were analysed for toxicity in Jurkat cells. The methyl tellurides were moderately stable to aerobic oxidation in organic solution under dry ambient conditions. The trifluoromethyl tellurides were stable to aerobic oxidation in organic solution but decomposed in aqueous solution. The 2-alkyl-tellurophenes proved to be stable in both organic and aqueous solutions under ambient conditions and showed limited toxicity (IC50 > 200 μM) in cell based assays. The synthetic feasibility, chemically stability, and limited toxicity of tellurophenes suggests these groups will be good choices for MC reagent development.

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Seleno- and Telluro-xylofuranosides attenuate Mn-induced toxicity in C. elegans via the DAF-16/FOXO pathway

Cited by 27 publications

References 54 publications

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity

Role of Caenorhabditis elegans AKT-1/2 and SGK-1 in Manganese Toxicity

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Organotellurium scaffolds for mass cytometry reagent development

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