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1.
Environ Sci Technol ; 58(20): 8792-8802, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38719742

RESUMO

Per- and polyfluoroalkyl substances (PFASs) from aqueous film forming foams (AFFFs) can hinder bioremediation of co-contaminants such as trichloroethene (TCE) and benzene, toluene, ethylbenzene, and xylene (BTEX). Anaerobic dechlorination can require bioaugmentation of Dehalococcoides, and for BTEX, oxygen is often sparged to stimulate in situ aerobic biodegradation. We tested PFAS inhibition to TCE and BTEX bioremediation by exposing an anaerobic TCE-dechlorinating coculture, an aerobic BTEX-degrading enrichment culture, and an anaerobic toluene-degrading enrichment culture to n-dimethyl perfluorohexane sulfonamido amine (AmPr-FHxSA), perfluorohexane sulfonamide (FHxSA), perfluorohexanesulfonic acid (PFHxS), or nonfluorinated surfactant sodium dodecyl sulfate (SDS). The anaerobic TCE-dechlorinating coculture was resistant to individual PFAS exposures but was inhibited by >1000× diluted AFFF. FHxSA and AmPr-FHxSA inhibited the aerobic BTEX-degrading enrichment. The anaerobic toluene-degrading enrichment was not inhibited by AFFF or individual PFASs. Increases in amino acids in the anaerobic TCE-dechlorinating coculture compared to the control indicated stress response, whereas the BTEX culture exhibited lower concentrations of all amino acids upon exposure to most surfactants (both fluorinated and nonfluorinated) compared to the control. These data suggest the main mechanisms of microbial toxicity are related to interactions with cell membrane synthesis as well as protein stress signaling.


Assuntos
Biodegradação Ambiental , Hidrocarbonetos Aromáticos , Hidrocarbonetos Aromáticos/metabolismo , Tricloroetileno/metabolismo , Sulfonamidas/metabolismo
2.
Environ Sci Technol Lett ; 10(4): 337-342, 2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-37064824

RESUMO

Fungi and laccase mediator systems (LMSs) have a proven track record of oxidizing recalcitrant organic compounds. There has been considerable interest in applying LMSs to the treatment of perfluoroalkyl acids (PFAAs), a class of ubiquitous and persistent environmental contaminants. Some laboratory experiments have indicated modest losses of PFAAs over extended periods, but there have been no clear demonstrations of a transformation mechanism or the kinetics that would be needed for remediation applications. We set out to determine if this was a question of identifying and optimizing a rate-limiting step but discovered that observed losses of PFAAs were experimental artifacts. While unable to replicate the oxidation of PFAAs, we show that interactions of the PFAA compounds with laccase and laccase mediator mixtures could cause an artifact that mimics transformation (≲60%) of PFAAs. Furthermore, we employed a surrogate compound, carbamazepine (CBZ), and electron paramagnetic resonance spectroscopy to probe the formation of the radical species that had been proposed to be responsible for contaminant oxidation. We confirmed that under conditions where sufficient radical concentrations were produced to oxidize CBZ, no PFAA removal took place.

3.
Environ Sci Technol ; 56(22): 15478-15488, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36257682

RESUMO

Sites impacted by aqueous film-forming foam (AFFF) contain co-contaminants that can stimulate biotransformation of polyfluoroalkyl substances. Here, we compare how microbial enrichments from AFFF-impacted soil amended with diethyl glycol monobutyl ether (found in AFFF), aromatic hydrocarbons (present in co-released fuels), acetate, and methane (substrates used or formed during bioremediation) impact the aerobic biotransformation of an AFFF-derived six-carbon electrochemical fluorination (ECF) precursor N-dimethyl ammonio propyl perfluorohexane sulfonamide (AmPr-FHxSA). We found that methane- and acetate-oxidizing cultures resulted in the highest yields of identifiable products (38 and 30%, respectively), including perfluorohexane sulfonamide (FHxSA) and perfluorohexane sulfonic acid (PFHxS). Using these data, we propose and detail a transformation pathway. Additionally, we examined chemical oxidation products of AmPr-FHxSA and FHxSA to provide insights on remediation strategies for AmPr-FHxSA. We demonstrate mineralization of these compounds using the sulfate radical and test their transformation during the total oxidizable precursor (TOP) assay. While perfluorohexanoic acid accounted for over 95% of the products formed, we demonstrate here for the first time two ECF-based precursors, AmPr-FHxSA and FHxSA, that produce PFHxS during the TOP assay. These findings have implications for monitoring poly- and perfluoroalkyl substances during site remediation and application of the TOP assay at sites impacted by ECF-based precursors.


Assuntos
Fluorocarbonos , Poluentes Químicos da Água , Fluorocarbonos/análise , Carbono , Poluentes Químicos da Água/análise , Água , Sulfanilamida , Sulfonamidas , Metano
4.
Environ Sci Process Impacts ; 24(3): 439-446, 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35113105

RESUMO

Aqueous film-forming foams (AFFFs) are important sources of per- and polyfluoroalkyl substances (PFASs) in soil, groundwater, and surface water. Soil microorganisms can convert polyfluorinated substances into persistent perfluoroalkyl acids, but the understanding of co-contaminant stimulation or inhibition of PFASs biotransformation is limited. In this study, we investigate how aerobic biotransformation of polyfluorinated substances was affected by common AFFF co-contaminants, such as gasoline aromatics: benzene, toluene, ethylbenzene, and o-xylene (BTEX). We performed aerobic microcosm studies by inoculating AFFF-impacted soil with medium containing 6:2 fluorotelomer thioether amido sulfonate (FtTAoS) and either diethyl glycol monobutyl ether (DGBE), a common AFFF ingredient, or BTEX compounds as the main carbon and energy source. BTEX-amended microcosms produced 4.3-5.3 fold more perfluoroalkyl carboxylates (PFCAs) than DGBE-amended ones, even though both organic carbon sources induced similar 6:2 FtTAoS biotransformation rates. In enrichments of AFFF-impacted solids selecting for BTEX biodegradation, we detected the presence of genes encoding toluene dioxygenase as well as larger abundances of transformation products from thioether oxidation that complement larger quantities of terminal transformation products. Our findings indicate that enrichment of BTEX-degrading microorganisms in the AFFF-impacted soil enhanced the conversion of 6:2 FtTAoS to PFCAs. These results provide insights into the high ratio of PFAAs to precursors at AFFF-impacted sites with history of BTEX bioremediation.


Assuntos
Fluorocarbonos , Poluentes Químicos da Água , Biodegradação Ambiental , Biotransformação , Ácidos Carboxílicos , Fluorocarbonos/análise , Sulfetos , Tensoativos , Poluentes Químicos da Água/análise
5.
Sci Rep ; 11(1): 19414, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593829

RESUMO

In humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1-2% of patients with autism spectrum disorders-a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.


Assuntos
Síndrome de Angelman/metabolismo , Hipocampo , Aprendizagem , Ubiquitina-Proteína Ligases/fisiologia , Animais , Células Cultivadas , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios
6.
Cell Chem Biol ; 28(7): 903-917, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33905676

RESUMO

Proteasomes are multisubunit complexes that catalyze the majority of protein degradation in mammalian cells to maintain protein homeostasis and influence the regulation of most cellular processes. The proteasome, a multicatalytic protease complex, is a ring-like structure with a narrow pore that exhibits regulated gating, enabling the selective degradation of target proteins into peptide fragments. This process of removing proteins is essential for eliminating proteins that are no longer wanted, such as unfolded or aggregated proteins. This is important for preserving cellular function relevant to brain health and disease. Recently, in the nervous system, specialized proteasomes have been shown to generate peptides with important cellular functions. These discoveries challenge the prevailing notion that proteasomes primarily operate to eliminate proteins and identify signaling-competent proteasomes. This review focuses on the structure, function, and regulation of proteasomes and sheds light on emerging areas of investigation regarding the role of proteasomes in the nervous system.


Assuntos
Sistema Nervoso/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Humanos
8.
Cell Rep ; 25(9): 2470-2483.e8, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30485813

RESUMO

Protein kinase C (PKC)-dependent mechanisms promote synaptic function in the mature brain. However, the roles of PKC signaling during synapse development remain largely unknown. Investigating each brain-enriched PKC isoform in early neuronal development, we show that PKCε acutely and specifically reduces the number of dendritic spines, sites of eventual synapse formation on developing dendrites. This PKCε-mediated spine suppression is temporally restricted to immature neurons and mediated through the phosphorylation and activation of Ephexin5, a RhoA guanine nucleotide exchange factor (GEF) and inhibitor of hippocampal synapse formation. Our data suggest that PKCε acts as an early developmental inhibitor of dendritic spine formation, in contrast to its emerging pro-synaptic roles in mature brain function. Moreover, we identify a substrate of PKCε, Ephexin5, whose early-elevated expression in developing neurons may in part explain the mechanism by which PKCε plays seemingly opposing roles that depend on neuronal maturity.


Assuntos
Espinhas Dendríticas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteína Quinase C-épsilon/metabolismo , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Diferenciação Celular , Ativação Enzimática , Células HEK293 , Hipocampo/metabolismo , Humanos , Isoenzimas/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-épsilon/química , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
9.
J Lipid Res ; 59(3): 550-563, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29358305

RESUMO

Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of ß-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses.


Assuntos
Diferenciação Celular , Córtex Cerebral/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Neurônios/patologia , Organoides/patologia , Doença de Sandhoff/patologia , Proliferação de Células , Células Cultivadas , Humanos , Lisossomos/metabolismo , beta-N-Acetil-Hexosaminidases/deficiência , beta-N-Acetil-Hexosaminidases/metabolismo
10.
J Biol Chem ; 291(23): 12029-38, 2016 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-27059959

RESUMO

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases (SPPases), 1 and 2, which are encoded by the Sgpp1 and Sgpp2 genes, respectively. SPPase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. SPPase 1 is important for skin homeostasis, but little is known about the functional role of SPPase 2. To identify the functions of SPPase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1(-/-) mice, Sgpp2(-/-) mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2(-/-) mice had normal pancreatic islet size; however, they exhibited defective adaptive ß-cell proliferation that was demonstrated after treatment with either a high-fat diet or the ß-cell-specific toxin, streptozotocin. Importantly, ß-cells from untreated Sgpp2(-/-) mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with ß-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes ß-cell endoplasmic reticulum stress, which is a known cause of ß-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.


Assuntos
Proliferação de Células/genética , Estresse do Retículo Endoplasmático/genética , Células Secretoras de Insulina/metabolismo , Proteínas de Membrana/genética , Monoéster Fosfórico Hidrolases/genética , Animais , Dieta Hiperlipídica , Chaperona BiP do Retículo Endoplasmático , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Células HEK293 , Proteínas de Choque Térmico , Humanos , Imuno-Histoquímica , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/enzimologia , Ilhotas Pancreáticas/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monoéster Fosfórico Hidrolases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esfingolipídeos/metabolismo , Estreptozocina/farmacologia
11.
Vet Med (Auckl) ; 7: 123-131, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-30050845

RESUMO

Investigation into the pharmacokinetic profile of esomeprazole was conducted using eight healthy dogs after intravenous (IV) and oral (po) administration in a two-part randomized crossover study. The dogs were fasted for a minimum of 12 hours and then received esomeprazole either intravenously (dose range 0.93-1.48 mg/kg) or orally using an enteric-coated formulation (dose range 0.95-1.50 mg/kg). After a 1-week washout period, the dogs received an alternative treatment. Serial blood samples were collected at predetermined time points, and plasma esomeprazole concentrations were determined by using ultra-high-performance liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Then, the area under the plasma concentration/time curve (AUC) and maximal plasma concentration (Cmax) values were normalized to a 1.0 mg/kg dose of esomeprazole, that is, AUC/dose. Median (range) dose-normalized peak plasma concentration (Cmax) values for the IV and po formulations were 4.06 µg/mL (2.47-4.57 µg/mL) and 1.04 µg/mL (0.31-1.91 µg/mL), respectively. The median (range) time-to-peak concentration (Tmax) for the po formulation was 105 minutes (45-360 minutes). Median (range) plasma terminal half-life (t½) was 45.56 minutes (39.43-64.20 minutes) for the IV formulation and 63.97 minutes (44.02-109.94 minutes) for the enteric-coated po formulation. The median (range) po bioavailability was 63.33% (32.26%-79.77%). Clinically, both po and IV formulations were well tolerated with minimal side effects observed.

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