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1.
Antioxidants (Basel) ; 11(9)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36139888

RESUMO

Road-deposited dust (RD) is a pervasive form of particulate pollution identified (typically via epidemiological or mathematical modelling) as hazardous to human health. Finer RD particle sizes, the most abundant (by number, not mass), may pose greater risk as they can access all major organs. Here, the first in vitro exposure of human lung epithelial (Calu-3) cells to 0−300 µg/mL of the ultrafine (<220 nm) fraction of road dust (UF-RDPs) from three contrasting cities (Lancaster and Birmingham, UK, and Mexico City, Mexico) resulted in differential oxidative, cytotoxic, and inflammatory responses. Except for Cd, Na, and Pb, analysed metals were most abundant in Mexico City UF-RDPs, which were most cytotoxic. Birmingham UF-RDPs provoked greatest ROS release (only at 300 µg/mL) and greatest increase in pro-inflammatory cytokine release. Lancaster UF-RDPs increased cell viability. All three UF-RDP samples stimulated ROS production and pro-inflammatory cytokine release. Mass-based PM limits seem inappropriate given the location-specific PM compositions and health impacts evidenced here. A combination of new, biologically relevant metrics and localised regulations appears critical to mitigating the global pandemic of health impacts of particulate air pollution and road-deposited dust.

2.
PLoS One ; 17(1): e0255715, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35025874

RESUMO

The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer's disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by ß- and γ-secretases in the 'amyloidogenic' proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the 'non-amyloidogenic' pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting ß-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the ß-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, ß- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Dicloroacético/farmacologia , Proteólise/efeitos dos fármacos , Proteínas ADAM/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo
3.
Sci Rep ; 11(1): 9363, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931662

RESUMO

The presence of magnetic nanoparticles (MNPs) in the human brain was attributed until recently to endogenous formation; associated with a putative navigational sense, or with pathological mishandling of brain iron within senile plaques. Conversely, an exogenous, high-temperature source of brain MNPs has been newly identified, based on their variable sizes/concentrations, rounded shapes/surface crystallites, and co-association with non-physiological metals (e.g., platinum, cobalt). Here, we examined the concentration and regional distribution of brain magnetite/maghemite, by magnetic remanence measurements of 147 samples of fresh/frozen tissues, from Alzheimer's disease (AD) and pathologically-unremarkable brains (80-98 years at death) from the Manchester Brain Bank (MBB), UK. The magnetite/maghemite concentrations varied between individual cases, and different brain regions, with no significant difference between the AD and non-AD cases. Similarly, all the elderly MBB brains contain varying concentrations of non-physiological metals (e.g. lead, cerium), suggesting universal incursion of environmentally-sourced particles, likely across the geriatric blood-brain barrier (BBB). Cerebellar Manchester samples contained significantly lower (~ 9×) ferrimagnetic content compared with those from a young (29 years ave.), neurologically-damaged Mexico City cohort. Investigation of younger, variably-exposed cohorts, prior to loss of BBB integrity, seems essential to understand early brain impacts of exposure to exogenous magnetite/maghemite and other metal-rich pollution particles.


Assuntos
Poluentes Atmosféricos/análise , Doença de Alzheimer/epidemiologia , Encéfalo/patologia , Nanopartículas de Magnetita/análise , Metais/análise , Idoso de 80 Anos ou mais , Poluentes Atmosféricos/efeitos adversos , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Nanopartículas de Magnetita/efeitos adversos , Masculino , Metais/efeitos adversos , Reino Unido/epidemiologia
4.
Environ Res ; 191: 110139, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32888951

RESUMO

Fine particulate air pollution (PM2.5) exposures are linked with Alzheimer's and Parkinson's diseases (AD,PD). AD and PD neuropathological hallmarks are documented in children and young adults exposed lifelong to Metropolitan Mexico City air pollution; together with high frontal metal concentrations (especially iron)-rich nanoparticles (NP), matching air pollution combustion- and friction-derived particles. Here, we identify aberrant hyperphosphorylated tau, ɑ synuclein and TDP-43 in the brainstem of 186 Mexico City 27.29 ± 11.8y old residents. Critically, substantia nigrae (SN) pathology seen in mitochondria, endoplasmic reticulum and neuromelanin (NM) is co-associated with the abundant presence of exogenous, Fe-, Al- and Ti-rich NPs.The SN exhibits early and progressive neurovascular unit damage and mitochondria and NM are associated with metal-rich NPs including exogenous engineered Ti-rich nanorods, also identified in neuroenteric neurons. Such reactive, cytotoxic and magnetic NPs may act as catalysts for reactive oxygen species formation, altered cell signaling, and protein misfolding, aggregation and fibril formation. Hence, pervasive, airborne and environmental, metal-rich and magnetic nanoparticles may be a common denominator for quadruple misfolded protein neurodegenerative pathologies affecting urbanites from earliest childhood. The substantia nigrae is a very early target and the gastrointestinal tract (and the neuroenteric system) key brainstem portals. The ultimate neural damage and neuropathology (Alzheimer's, Parkinson's and TDP-43 pathology included) could depend on NP characteristics and the differential access and targets achieved via their portals of entry. Thus where you live, what air pollutants you are exposed to, what you are inhaling and swallowing from the air you breathe,what you eat, how you travel, and your occupational longlife history are key. Control of NP sources becomes critical.


Assuntos
Doença de Alzheimer , Nanopartículas de Magnetita , Nanotubos , Tronco Encefálico , Criança , Cidades , Trato Gastrointestinal , Humanos , México , Agregados Proteicos , Titânio/toxicidade , Adulto Jovem , alfa-Sinucleína
5.
Bioethics ; 24(4): 160-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20394109

RESUMO

Currently our assessment of whether someone is a good parent depends on the environmental inputs (or lack of such inputs) they give their children. But new genetic intervention technologies, to which we may soon have access, mean that how good a parent is will depend also on the genetic inputs they give their children. Each new piece of available technology threatens to open up another way that we can neglect our children. Our obligations to our children and our susceptibilities to corresponding legal and moral sanctions may be about to explosively increase. In this paper I argue that we should treat conventional neglect and 'genetic neglect' - failing to use genetic intervention technologies to prevent serious diseases and disabilities - morally consistently. I conclude that in a range of cases parents will have a moral obligation to use genetic treatments to prevent serious disabilities in their children. My particular focus is on prenatal interventions and their impact of the bodily integrity of expectant mothers. I conclude that although bodily integrity constrains moral obligations, it is outweighed in a range of cases.


Assuntos
Maus-Tratos Infantis/ética , Terapias Fetais/ética , Doenças Genéticas Inatas/prevenção & controle , Engenharia Genética/ética , Obrigações Morais , Pessoas com Deficiência , Feminino , Direitos Humanos , Humanos , Lactente , Pessoalidade , Gravidez
6.
Mol Endocrinol ; 18(10): 2570-82, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15243131

RESUMO

The ERK1/2 MAPK pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation, and cell survival. Studies have shown that this pathway is constitutively active in several human malignancies and may be involved in the pathogenesis of these tumors. In the present study we examined the ERK1/2 pathway in cell lines derived from epithelial and granulosa cell tumors, two distinct forms of ovarian cancer. We show that ERK1 and ERK2 are constitutively active and that this activation results from both MAPK kinase-dependent and independent mechanisms and is correlated with elevated BRAF expression. MAPK phosphatase 1 (MKP-1) expression, which is involved in ERK1/2 deactivation, is down-regulated in the cancer cells, thus further contributing to ERK hyperactivity in these cells. Treatment of these cancer cell lines with the proteasome inhibitor ZLLF-CHO increased MKP-1 but not MKP-2 expression and decreased ERK1/2 phosphorylation. More importantly, silencing of ERK1/2 protein expression using RNA interference led to the complete suppression of tumor cell proliferation. These results provide evidence that the ERK pathway plays a major role in ovarian cancer pathogenesis and that down-regulation of this master signaling pathway is highly effective for the inhibition of ovarian tumor growth.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Divisão Celular , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/genética , Interferência de RNA
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