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2.
J Bacteriol ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33753471

RESUMO

Chlamydiae are obligate intracellular pathogens that rely on secreted effector proteins to establish their intracellular niche. In this issue of the Journal of Bacteriology, Yanatori et al describe a screen for C. pneumoniae effectors, performed in C. trachomatis, which identified several new proteins that are translocated during infection (Yanatori, Miura et al. 2021). More broadly, they demonstrate how new genetic approaches in C. trachomatis can be used to characterize the virulence factors of other Chlamydia species.

3.
Aliment Pharmacol Ther ; 53(7): 830-843, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33565643

RESUMO

BACKGROUND: Cirrhosis develops in <10% of individuals homozygous for the C282Y variant in the homeostatic iron regulator (HFE) gene. Carriage of PCSK7:rs236918 is associated with an increased risk of cirrhosis in this population. AIM: To determine if genetic variants significantly associated with the risk of alcohol- and NAFLD-related cirrhosis also modulate the cirrhosis risk in C282Y homozygotes. METHODS: Variants in PCSK7, PNPLA3, TM6SF2, MBOAT7 and HSD17B13 were genotyped in 1319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis. Genotypic and allelic associations with the risk for developing cirrhosis were assessed, adjusting for age and sex. Fixed effects meta-analyses of the adjusted summary data for each country were performed. Post hoc association testing was undertaken in the 131 (76.6%) cases and 299 (26.0%) controls with available liver histology. RESULTS: Significant associations were observed between PCSK7:rs236918 (OR = 1.52 [95% CI 1.06-2.19]; P = 0.022; I2  = 0%); PNPLA3:rs738409 (OR = 1.60 [95% CI 1.22-2.11]; P = 7.37 × 10-4 ; I2  = 45.5%) and TM6SF2:rs58542926 (OR = 1.94 [95% CI 1.28-2.95]; P = 1.86 × 10-3 ; I2  = 0%) and the cirrhosis risk in C282Y homozygotes. These findings remained significant in the subpopulation with available liver histology. The population-attributable fractions were 5.6% for PCSK7:rs236918, 13.8% for PNPLA3:rs738409, 6.5% for TM6SF2:rs58542926 and 24.0% for carriage of all three variants combined. CONCLUSIONS: The risk of cirrhosis associated with carriage of PCSK7:rs236918 was confirmed in this much larger population of C282Y homozygotes. In addition, PNPLA3:rs738409 and TM6SF2:rs58542926 were established as significant additional risk factors. More detailed genetic testing of C282Y homozygotes would allow risk stratification and help guide future management.


Assuntos
Hemocromatose , Hepatopatia Gordurosa não Alcoólica , Europa (Continente) , Genótipo , Humanos , Lipase/genética , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Subtilisinas
4.
JHEP Rep ; 2(6): 100154, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32995714

RESUMO

BACKGROUND & AIMS: Iron reduction by venesection has been the cornerstone of treatment for haemochromatosis for decades, and its reported health benefits are many. Repeated phlebotomy can lead to a compensatory increase in intestinal iron absorption, reducing intestinal iron availability. Given that most gut bacteria are highly dependent on iron for survival, we postulated that, by reducing gut iron levels, venesection could alter the gut microbiota. METHODS: Clinical parameters, faecal bacterial composition and metabolomes were assessed before and during treatment in a group of patients with haemochromatosis undergoing iron reduction therapy. RESULTS: Systemic iron reduction was associated with an alteration of the gut microbiome, with changes evident in those who experienced reduced faecal iron availability with venesection. For example, levels of Faecalibacterium prausnitzii, a bacterium associated with improved colonic health, were increased in response to faecal iron reduction. Similarly, metabolomic changes were seen in association with reduced faecal iron levels. CONCLUSION: These findings highlight a significant shift in the gut microbiome of patients who experience reduced colonic iron during venesection. Targeted depletion of faecal iron could represent a novel therapy for metabolic and inflammatory diseases, meriting further investigation. LAY SUMMARY: Iron depletion by repeated venesection is the mainstay of treatment for haemochromatosis, an iron-overload disorder. Venesection has been associated with several health benefits, including improvements in liver function tests, reversal of liver scarring, and reduced risk of liver cancer. During iron depletion, iron absorption from the gastrointestinal (GI) tract increases to compensate for iron lost with treatment. Iron availability is limited in the GI tract and is crucial to the growth and function of many gut bacteria. In this study we show that reduced iron availability in the colon following venesection treatment leads to a change in the composition of the gut bacteria, a finding that, to date, has not been studied in patients with haemochromatosis.

6.
Sex Transm Dis ; 47(5): 329-331, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32149960

RESUMO

Identifying pathogen-specific signs or symptoms of nongonococcal urethritis could improve syndromic management accuracy. We evaluated nongonococcal urethritis signs and symptoms in 220 men with single-pathogen infections (Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, or Ureaplasma urealyticum) or idiopathic urethritis. No individual sign or symptom accurately predicted the infectious etiology.


Assuntos
Mycoplasma genitalium , Uretra/microbiologia , Uretrite/diagnóstico , Adolescente , Adulto , Humanos , Indiana , Masculino , Pessoa de Meia-Idade , Infecções por Mycoplasma/diagnóstico , Mycoplasma genitalium/isolamento & purificação , Ureaplasma urealyticum/isolamento & purificação , Uretrite/microbiologia , Adulto Jovem
8.
Frontline Gastroenterol ; 10(4): 337-346, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31682643

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a globally prevalent health problem, associated in its more severe forms with increased liver-related and cardiovascular-related morbidity and mortality. We established a multidisciplinary metabolic hepatology clinic in 2014 and have analysed the clinical data to evaluate the effectiveness of this service. Patients with NAFLD (n=165) who had attended two or more appointments were included. Prespecified clinical data were collected prospectively at clinic appointments and analysed retrospectively. Interventions offered included lifestyle advice, signposting to weight loss services and pharmacological treatment of diabetes and cardiovascular risk factors. Median follow-up was 13 months (range: 2-34). 59% (n=97) of patients had type 2 diabetes mellitus (T2DM). 53% (n=87) underwent liver biopsy of whom 18% (n=16) had cirrhosis. Median alanine aminotransferase (ALT) reduced by 11 IU/L (p<0.0001), median weight reduced by 3.3 kg (p=0.0005). There were significant reductions in HbA1c, total cholesterol and liver stiffness. Specifically, in patients with T2DM, HbA1c decreased by 4 mmol/mol (p=0.01) with significant reductions in ALT, weight and total cholesterol. Relative cardiovascular risk assessed by the QRISK3 score reduced in the whole cohort and in those with T2DM. Health economic modelling suggested the clinic intervention among those patients with poorly controlled T2DM was cost-effective. In conclusion, a multidisciplinary approach to the management of patients with NAFLD in this observational cohort study was associated with improvements in liver-related and cardio-metabolic related health parameters and with evidence of cost-effectiveness in patients with poorly controlled T2DM.

9.
EBioMedicine ; 40: 67-76, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30639417

RESUMO

BACKGROUND: Bariatric surgery leads to early and long-lasting remission of type 2 diabetes (T2D). However, the mechanisms behind this phenomenon remain unclear. Among several factors, gut hormones are thought to be crucial mediators of this effect. Unlike GLP-1, the role of the hormone peptide tyrosine tyrosine (PYY) in bariatric surgery in humans has been limited to appetite regulation and its impact on pancreatic islet secretory function and glucose metabolism remains under-studied. METHODS: Changes in PYY concentrations were examined in obese patients after bariatric surgery and compared to healthy controls. Human pancreatic islet function was tested upon treatment with sera from patients before and after the surgery, in presence or absence of PYY. Alterations in intra-islet PYY release and insulin secretion were analysed after stimulation with short chain fatty acids (SCFAs), bile acids and the cytokine IL-22. FINDINGS: We demonstrate that PYY is a key effector of the early recovery of impaired glucose-mediated insulin and glucagon secretion in bariatric surgery. We establish that the short chain fatty acid propionate and bile acids, which are elevated after surgery, can trigger PYY release not only from enteroendocrine cells but also from human pancreatic islets. In addition, we identify IL-22 as a new factor which is modulated by bariatric surgery in humans and which directly regulates PYY expression and release. INTERPRETATION: This study shows that some major metabolic benefits of bariatric surgery can be emulated ex vivo. Our findings are expected to have a direct impact on the development of new non-surgical therapy for T2D correction.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Peptídeo YY/metabolismo , Animais , Cirurgia Bariátrica , Biomarcadores , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/terapia , Células Enteroendócrinas/metabolismo , Feminino , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Interleucinas/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Peptídeo YY/sangue , Peptídeo YY/genética , Ratos
10.
Nat Microbiol ; 4(2): 339-351, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30510168

RESUMO

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.


Assuntos
Ativinas/farmacologia , Antivirais/farmacologia , Proteína Morfogenética Óssea 6/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Antivirais/metabolismo , Células Cultivadas , Endopeptidases/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/metabolismo , Hepcidinas/genética , Humanos , Fatores Reguladores de Interferon/genética , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , RNA Viral/metabolismo , Transdução de Sinais/genética , Proteína Smad1/genética , Ubiquitina Tiolesterase , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos
11.
Liver Int ; 38(1): 164-173, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28679028

RESUMO

BACKGROUND AND AIMS: Elevated serum ferritin is common in NAFLD, and is associated with more advanced disease and increased mortality. Hyperferritinaemia in NAFLD is often attributed to inflammation, while in other conditions ferritin closely reflects body iron stores. The aim of this study was to clarify the underlying cause of hyperferritinaemia in NAFLD. METHODS: Ferritin levels were examined with markers of iron status, inflammation and liver injury across the clinical spectrum of NAFLD using blood, tissue and magnetic resonance (MR) imaging. A separate larger group of NAFLD patients with hepatic iron staining and quantification were used for validation. RESULTS: Serum ferritin correlated closely with the iron regulatory hormone hepcidin, and liver iron levels determined by MR. Furthermore, ferritin levels reflected lower serum adiponectin, a marker of insulin resistance, and liver fat, but not cytokine or CRP levels. Ferritin levels differed according to fibrosis stage, increasing from early to moderate disease, and declining in cirrhosis. A similar pattern was found in the validation cohort of NAFLD patients, where ferritin levels were highest in those with macrophage iron deposition. Multivariate analysis revealed liver iron and hepcidin levels as the major determinants of serum ferritin. CONCLUSIONS: While hyperferritinaemia is associated with markers of liver injury and insulin resistance, serum hepcidin and hepatic iron are the strongest predictors of ferritin levels. These findings highlight the role of disordered iron homeostasis in the pathogenesis of NAFLD, suggesting that therapies aimed at correcting iron metabolism may be beneficial.


Assuntos
Ferritinas/sangue , Distúrbios do Metabolismo do Ferro/sangue , Ferro/análise , Fígado/química , Hepatopatia Gordurosa não Alcoólica/sangue , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Hepcidinas/análise , Humanos , Resistência à Insulina , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Estudos Prospectivos , Regulação para Cima
13.
Ann Hepatol ; 16(3): 331-332, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28425401

RESUMO

MR elastography is a novel method for non-invasive fibrosis assessment, not yet sufficiently validated. In a recent study in 104 patients Park, Gastroenterology 2017; 152: 598-602), MRE was compared to transient elastography for the diagnosis of fibrosis is nonalcoholic fatty liver disease. The current viewpoint critically appraises this study.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Imageamento por Ressonância Magnética , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Humanos , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes
14.
Small ; 13(23)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28440049

RESUMO

The clinical applications of silver nanoparticles (AgNPs) remain limited due to the lack of well-established methodologies for studying their nanokinetics. Hereby, the primary goal is to adapt a suite of analytical-based methodologies for examining the in vitro absorption, distribution, metabolism, and elimination of AgNPs. Vero 76 and HEK 293 cells are exposed to ≈10-nm spherical AgNPs+ and AgNPs- at relevant concentrations (0-300 µg mL-1 ) and times (4-48 h). Absorption: Inductively coupled plasma optical emission spectroscopy (ICP-OES) demonstrates that the two AgNP formulations are not bioequivalent. For example, different bioavailabilities (Cmaximum < 20.7 ± 4% and 6.82 ± 0.4%), absorption times (Tmaximum > 48 and ≈24 h), and absorption rate laws (first- and zeroth-order at 300 µg mL-1 ) are determined in Vero 76 for AgNPs+ and AgNPs- , respectively. Distribution: Raman and CytoViva hyperspectral imaging show different cellular localizations for AgNPs+ and AgNPs- . Metabolism: Cloud point extraction (CPE)-tangential flow filtration (TFF) reveal that ≤ 11% ± 4% of the administered, sublethal AgNPs release Ag+ and contribute to the observed cytotoxicity. Elimination: ICP-OES-CPE suggests that AgNPs are cleared via exocytosis.


Assuntos
Nanopartículas Metálicas/química , Prata/química , Células HEK293 , Humanos
15.
Ann Transl Med ; 5(3): 40, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28251119

RESUMO

Chronic hepatitis B virus (HBV) infection is a major cause of liver morbidity and mortality worldwide. While a proportion of the 250 million individuals chronically infected with HBV will not come to significant harm or require therapy, many others risk developing complications of the end-stage liver disease such as decompensated cirrhosis and hepatocellular carcinoma (HCC), without intervention. Due to the complex natural history of HBV infection, patients require an expert assessment to interpret biochemistry, viral serology and appropriately stage the disease, and to initiate monitoring and/or therapy where indicated. The detection and quantification of liver fibrosis is a key factor for disease management and prognostication for an individual with HBV. The reliance on invasive liver biopsy to stage disease is diminishing with the advent of robust non-invasive blood- and imaging-based algorithms which can reliably stage disease in many cases. These tests are now incorporated into International guidelines for HBV management and relied upon daily to inform clinical judgement. Both blood- and imaging-based approaches have advantages over liver biopsy, including minimal risks, lower cost, better patient acceptance and speed of results, while disadvantages include lower diagnostic accuracy in intermediate disease stages and variability with co-existing hepatic inflammation or steatosis. This review outlines the methods of fibrosis assessment in chronic HBV infection and focuses on the most commonly used blood- and imaging-based non-invasive tests, reviewing their diagnostic performance and applicability to patient care.

17.
Front Pharmacol ; 7: 159, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27378924

RESUMO

Liver fibrosis reflects sustained liver injury often from multiple, simultaneous factors. Whilst the presence of mild fibrosis on biopsy can be a reassuring finding, the identification of advanced fibrosis is critical to the management of patients with chronic liver disease. This necessity has lead to a reliance on liver biopsy which itself is an imperfect test and poorly accepted by patients. The development of robust tools to non-invasively assess liver fibrosis has dramatically enhanced clinical decision making in patients with chronic liver disease, allowing a rapid and informed judgment of disease stage and prognosis. Should a liver biopsy be required, the appropriateness is clearer and the diagnostic yield is greater with the use of these adjuncts. While a number of non-invasive liver fibrosis markers are now used in routine practice, a steady stream of innovative approaches exists. With improvement in the reliability, reproducibility and feasibility of these markers, their potential role in disease management is increasing. Moreover, their adoption into clinical trials as outcome measures reflects their validity and dynamic nature. This review will summarize and appraise the current and novel non-invasive markers of liver fibrosis, both blood and imaging based, and look at their prospective application in everyday clinical care.

19.
Mol Microbiol ; 100(6): 1039-65, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26933838

RESUMO

In ellipsoid-shaped ovococcus bacteria, such as the pathogen Streptococcus pneumoniae (pneumococcus), side-wall (peripheral) peptidoglycan (PG) synthesis emanates from midcells and is catalyzed by the essential class B penicillin-binding protein PBP2b transpeptidase (TP). We report that mutations that inactivate the pneumococcal YceG-domain protein, Spd_1346 (renamed MltG), remove the requirement for PBP2b. ΔmltG mutants in unencapsulated strains accumulate inactivation mutations of class A PBP1a, which possesses TP and transglycosylase (TG) activities. The 'synthetic viable' genetic relationship between Δpbp1a and ΔmltG mutations extends to essential ΔmreCD and ΔrodZ mutations that misregulate peripheral PG synthesis. Remarkably, the single MltG(Y488D) change suppresses the requirement for PBP2b, MreCD, RodZ and RodA. Structural modeling and comparisons, catalytic-site changes and an interspecies chimera indicate that pneumococcal MltG is the functional homologue of the recently reported MltG endo-lytic transglycosylase of Escherichia coli. Depletion of pneumococcal MltG or mltG(Y488D) increases sphericity of cells, and MltG localizes with peripheral PG synthesis proteins during division. Finally, growth of Δpbp1a ΔmltG or mltG(Y488D) mutants depends on induction of expression of the WalRK TCS regulon of PG hydrolases. These results fit a model in which MltG releases anchored PG glycan strands synthesized by PBP1a for crosslinking by a PBP2b:RodA complex in peripheral PG synthesis.


Assuntos
Aminoaciltransferases/genética , Proteínas de Ligação às Penicilinas/genética , Peptidoglicano/biossíntese , Deleção de Sequência , Streptococcus pneumoniae/genética , Aminoaciltransferases/metabolismo , Glicosiltransferases/metabolismo , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Proteínas de Ligação às Penicilinas/metabolismo , Peptidoglicano/metabolismo , Peptidil Transferases/genética , Peptidil Transferases/metabolismo , Streptococcus pneumoniae/enzimologia , Streptococcus pneumoniae/metabolismo
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