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1.
Parasit Vectors ; 15(1): 354, 2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36184586

RESUMO

BACKGROUND: Over the past decade, evidence has emerged of the ability of gastrointestinal (GI) helminth parasites to alter the composition of the host gut microbiome; however, the mechanism(s) underpinning such interactions remain unclear. In the current study, we (i) undertake proteomic analyses of the excretory-secretory products (ESPs), including secreted extracellular vesicles (EVs), of the 'brown stomach worm' Teladorsagia circumcincta, one of the major agents causing parasite gastroenteritis in temperate areas worldwide; (ii) conduct bioinformatic analyses to identify and characterise antimicrobial peptides (AMPs) with putative antimicrobial activity; and (iii) assess the bactericidal and/or bacteriostatic properties of T. circumcincta EVs, and whole and EV-depleted ESPs, using bacterial growth inhibition assays. METHODS: Size-exclusion chromatography was applied to the isolation of EVs from whole T. circumcincta ESPs, followed by EV characterisation via nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of EVs and EV-depleted ESPs was conducted using liquid chromatography-tandem mass spectrometry, and prediction of putative AMPs was performed using available online tools. The antimicrobial activities of T. circumcincta EVs and of whole and EV-depleted ESPs against Escherichia coli were evaluated using bacterial growth inhibition assays. RESULTS: Several molecules with putative antimicrobial activity were identified in both EVs and EV-depleted ESPs from adult T. circumcincta. Whilst exposure of E. coli to whole ESPs resulted in a significant reduction of colony-forming units over 3 h, bacterial growth was not reduced following exposure to worm EVs or EV-depleted ESPs. CONCLUSIONS: Our data points towards a bactericidal and/or bacteriostatic function of T. circumcincta ESPs, likely mediated by molecules with antimicrobial activity.


Assuntos
Anti-Infecciosos , Enteropatias Parasitárias , Animais , Anti-Infecciosos/farmacologia , Escherichia coli , Ostertagia , Proteômica , Estômago
2.
JCI Insight ; 3(20)2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30333321

RESUMO

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.


Assuntos
Antiporters/genética , Hipotireoidismo Congênito/genética , Bócio/genética , Transportadores de Sulfato/genética , Adulto , Animais , Criança , Pré-Escolar , Códon sem Sentido , Hipotireoidismo Congênito/diagnóstico , Análise Mutacional de DNA , Feminino , Bócio/congênito , Bócio/diagnóstico , Células HEK293 , Homozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Linhagem , Glândula Tireoide/patologia , Sequenciamento do Exoma
3.
Kidney Int ; 89(1): 105-112, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26398495

RESUMO

Peroxiredoxin 6 (PRDX6) is one of the six members of the PRDX family, which have peroxidase and antioxidant activity. PRDX6 is unique, containing only one conserved cysteine residue (C47) rather than the two found in other PRDXs. A yeast two-hybrid screen found PRDX6 to be a potential binding partner of the C-terminal tail of anion exchanger 1 (AE1), a Cl(-)/HCO(3)(-) exchanger basolaterally expressed in renal α-intercalated cells. PRDX6 immunostaining in human kidney was both cytoplasmic and peripheral and colocalized with AE1. Analysis of native protein showed that it was largely monomeric, whereas expressed tagged protein was more dimeric. Two methionine oxidation sites were identified. In vitro and ex vivo pull-downs and immunoprecipitation assays confirmed interaction with AE1, but mutation of the conserved cysteine resulted in loss of interaction. Prdx6 knockout mice had a baseline acidosis with a major respiratory component and greater AE1 expression than wild-type animals. After an oral acid challenge, PRDX6 expression increased in wild-type mice, with preservation of AE1. However, AE1 expression was significantly decreased in knockout animals. Kidneys from acidified mice showed widespread proximal tubular vacuolation in wild-type but not knockout animals. Knockdown of PRDX6 by siRNA in mammalian cells reduced both total and cell membrane AE1 levels. Thus, PRDX6-AE1 interaction contributes to the maintenance of AE1 during cellular stress such as during metabolic acidosis.


Assuntos
Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Rim/metabolismo , Rim/patologia , Peroxirredoxina VI/genética , Peroxirredoxina VI/metabolismo , Acidose/metabolismo , Animais , Proteína 1 de Troca de Ânion do Eritrócito/química , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Knockout , Peroxirredoxina VI/química
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