Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
1.
Nature ; 593(7858): 275-281, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33789339

RESUMEN

Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.


Asunto(s)
Enfermedad de Crohn/metabolismo , Receptor gp130 de Citocinas/metabolismo , Células Mieloides/citología , Proteína Adaptadora de Señalización NOD2/metabolismo , Células del Estroma/citología , Alelos , Animales , Colágeno/metabolismo , Receptor gp130 de Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Ileítis/metabolismo , Indoles/farmacología , Interleucina-11/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Masculino , Células Mieloides/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Transcripción STAT3/metabolismo , Células del Estroma/metabolismo , Proteínas WT1/metabolismo , Pez Cebra , Proteínas de Pez Cebra/metabolismo
2.
Hepatology ; 70(6): 2107-2122, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31016744

RESUMEN

The growing burden of liver fibrosis and lack of effective antifibrotic therapies highlight the need for identification of pathways and complementary model systems of hepatic fibrosis. A rare, monogenic disorder in which children with mutations in mannose phosphate isomerase (MPI) develop liver fibrosis led us to explore the function of MPI and mannose metabolism in liver development and adult liver diseases. Herein, analyses of transcriptomic data from three human liver cohorts demonstrate that MPI gene expression is down-regulated proportionate to fibrosis in chronic liver diseases, including nonalcoholic fatty liver disease and hepatitis B virus. Depletion of MPI in zebrafish liver in vivo and in human hepatic stellate cell (HSC) lines in culture activates fibrotic responses, indicating that loss of MPI promotes HSC activation. We further demonstrate that mannose supplementation can attenuate HSC activation, leading to reduced fibrogenic activation in zebrafish, culture-activated HSCs, and in ethanol-activated HSCs. Conclusion: These data indicate the prospect that modulation of mannose metabolism pathways could reduce HSC activation and improve hepatic fibrosis.


Asunto(s)
Células Estrelladas Hepáticas/fisiología , Cirrosis Hepática/etiología , Manosa-6-Fosfato Isomerasa/fisiología , Manosa/farmacología , Animales , Células Cultivadas , Glicosilación , Humanos , Masculino , Factor de Crecimiento Derivado de Plaquetas/fisiología , Transducción de Señal/fisiología , Pez Cebra
3.
BMC Psychiatry ; 20(1): 320, 2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32560678

RESUMEN

BACKGROUND: Depression is the greatest contributor to worldwide disability. The purpose of this study was to understand the influence of antidepressant and psychotherapy treatment adherence on future work leaves for patients with major depressive disorder. METHODS: Patients with a newly diagnosed major depressive disorder (n = 26,256) were identified in IBM® Watson™ MarketScan® medical and disability claims databases. Antidepressant and psychotherapy adherence metrics were evaluated in the acute phase of treatment, defined as the 114 days following the depression diagnosis. Multiple variable Cox proportional hazards regression models evaluated the influence of antidepressant and/or psychotherapy adherence on future injury or illness work leaves. RESULTS: The majority of work leaves in the 2-year follow-up period occurred in the acute phase of treatment (71.2%). Among patients without a work leave in the acute phase and who received antidepressants and/or psychotherapy (n = 19,994), those who were adherent to antidepressant or psychotherapy treatment in the acute phase had a 16% (HR = 0.84, 95% CI = 0.77-0.91) reduced risk of a future work leave compared to treatment non-adherent patients. Patients who were non-adherent or adherent to antidepressant treatment had a 22% (HR = 1.22, 95% CI = 1.11-1.35) and 13% (HR = 1.13, 95% CI = 1.01-1.27) greater risk of a future work leave, respectively, than patients not receiving antidepressant treatment. Conversely, patients who were non-adherent or adherent to psychotherapy treatment had a 9% (HR = 0.91, 95% CI = 0.81-1.02) and 28% (HR = 0.72, 95% CI = 0.64-0.82) reduced risk of a future work leave, respectively, than patients not receiving psychotherapy treatment. CONCLUSIONS: This analysis suggests that treatment adherence may reduce the likelihood of a future work leave for patients with newly diagnosed major depressive disorder. Psychotherapy appears more effective than antidepressants in reducing the risk of a future work leave.


Asunto(s)
Antidepresivos , Trastorno Depresivo Mayor , Psicoterapia , Ausencia por Enfermedad , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Humanos , Estudios Retrospectivos
4.
Access Microbiol ; 6(7)2024.
Artículo en Inglés | MEDLINE | ID: mdl-39130737

RESUMEN

The Caliciviridae family, comprising positive-sense RNA viruses, is characterised by its non-enveloped, small virions, broad host range, and notable tendency for host switching. These viruses are primarily associated with gastroenteric disease, though they can lead to haemorrhagic or respiratory infections. Our study employed a metagenomics analysis of faecal samples from stoats (Mustela erminea), identifying two novel calicivirus species, named stoat vesivirus and stoat valovirus. Stoat vesivirus was identified in three samples (ST008, ST006, ST004), exhibiting a genome wide nucleotide identity of approximately 92 %. The complete coding sequences of these samples were 8471 (ST004) and 8322 (ST006) nucleotides in length, respectively. Each comprised three open reading frames (ORF), closely resembling the Vesivirus mink calicivirus (China/2/2016), with 70-72 % similarity in ORF1, 61-62 % in ORF2 and 71 % in ORF3. Phylogenetic analysis robustly supported stoat vesivirus as belonging within the Vesivirus genus. The second calivicirus (stoat valovirus), detected solely in sample ST008, was 6527 nucleotides in length and with complete coding sequences present. It shared highest similarity with St-Valérien swine virus and marmot norovirus HT16, showing 39.5 and 38.8 % protein identity with ORF1 and 43.3 and 42.9 % for VP1. Stoat valovirus is borderline for meeting the ICTV criteria for a new genus, demonstrating 60 % divergence in ORF1 compared to the other valovirus', however it clusters basally within the Valovirus genus, supporting leaving it included in this genus.

5.
Hepatol Commun ; 6(7): 1711-1724, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35315595

RESUMEN

The mechanisms underlying liver fibrosis are multifaceted and remain elusive with no approved antifibrotic treatments available. The adult zebrafish has been an underutilized tool to study liver fibrosis. We aimed to characterize the single-cell transcriptome of the adult zebrafish liver to determine its utility as a model for studying liver fibrosis. We used single-cell RNA sequencing (scRNA-seq) of adult zebrafish liver to study the molecular and cellular dynamics at a single-cell level. We performed a comparative analysis to scRNA-seq of human liver with a focus on hepatic stellate cells (HSCs), the driver cells in liver fibrosis. scRNA-seq reveals transcriptionally unique populations of hepatic cell types that comprise the zebrafish liver. Joint clustering with human liver scRNA-seq data demonstrates high conservation of transcriptional profiles and human marker genes in zebrafish. Human and zebrafish HSCs show conservation of transcriptional profiles, and we uncover collectin subfamily member 11 (colec11) as a novel, conserved marker for zebrafish HSCs. To demonstrate the power of scRNA-seq to study liver fibrosis using zebrafish, we performed scRNA-seq on our zebrafish model of a pediatric liver disease with mutation in mannose phosphate isomerase (MPI) and characteristic early liver fibrosis. We found fibrosis signaling pathways and upstream regulators conserved across MPI-depleted zebrafish and human HSCs. CellPhoneDB analysis of zebrafish transcriptome identified neuropilin 1 as a potential driver of liver fibrosis. Conclusion: This study establishes the first scRNA-seq atlas of the adult zebrafish liver, highlights the high degree of similarity to human liver, and strengthens its value as a model to study liver fibrosis.


Asunto(s)
Transcriptoma , Pez Cebra , Animales , Niño , Humanos , Cirrosis Hepática/genética , Manosa-6-Fosfato Isomerasa , Fenotipo , Transcriptoma/genética , Pez Cebra/genética
7.
Methods Mol Biol ; 1965: 129-138, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31069672

RESUMEN

Zebrafish (Danio rerio) larvae are a uniquely powerful model system which investigate the effects of toxicant exposure on liver development and function. Manufacturing processes and development of new synthetic compounds increased rapidly since the middle of the twentieth century, resulting in widespread exposure to environmental toxicants. This is compounded by the shift in the global burden of disease from infectious agents to chronic disease, particularly in industrialized nations, which increases the need to investigate the long-term and transgenerational effects of environmental exposures on human health. Zebrafish provide an excellent model to investigate the mechanisms of action of environmental pollutants given their large-scale embryo production and rapid development, which allow for short-term assessment of toxicity in a whole animal system. Here we describe methods for the use of zebrafish to study hepatotoxicity and liver disease induced by chemical toxicants. Many of the genetic, molecular, and cellular processes are conserved between zebrafish and mammals, enabling translation to human populations and diseases.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Exposición a Riesgos Ambientales/efectos adversos , Larva/crecimiento & desarrollo , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Larva/efectos de los fármacos , Larva/metabolismo , Análisis de Secuencia de ARN , Pez Cebra
8.
Dis Model Mech ; 12(8)2019 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-31337664

RESUMEN

Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput in vivo systems are required to rapidly evaluate therapeutic agents. We visualize, in zebrafish, the effects on epithelial barrier function and intestinal autophagy of one-course and repetitive injury. Repetitive injury induces increased mortality, impaired recovery of intestinal barrier function, failure to contain bacteria within the intestine and impaired autophagy. Prostaglandin E2 (PGE2) administration protected against injury by enhancing epithelial barrier function and limiting systemic infection. Effects of IBD therapeutic agents were defined: mesalamine showed protective features during injury, whereas 6-mercaptopurine displayed marked induction of autophagy during recovery. Given the highly conserved nature of innate defense in zebrafish, it represents an ideal model system with which to test established and new IBD therapies targeted to the epithelial barrier.This article has an associated First Person interview with the first author of the paper.


Asunto(s)
Epitelio/patología , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/patología , Intestinos/lesiones , Pez Cebra/fisiología , Ácidos/metabolismo , Animales , Autofagia , Proteínas Bacterianas/metabolismo , Sulfato de Dextran , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Enterocitos/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Intestinos/patología , Lisosomas/metabolismo , Modelos Biológicos , Mucinas/metabolismo , Moco/metabolismo
9.
Chest ; 149(5): 1197-204, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26501747

RESUMEN

BACKGROUND: Relative pulmonary arterial enlargement, defined by a pulmonary artery to aorta (PA/A) ratio > 1 on CT scanning, predicts hospitalization for acute exacerbations of COPD (AECOPD). However, it is unclear how AECOPD affect the PA/A ratio. We hypothesized that the PA/A ratio would increase at the time of AECOPD and that a ratio > 1 would be associated with worse clinical outcomes. METHODS: Patients discharged with an International Classification of Diseases, Ninth Revision, diagnosis of AECOPD from a single center over a 5-year period were identified. Patients were included who had a CT scan performed during the stable period prior to the index AECOPD episode as well as a CT scan at the time of hospitalization. A subset of patients also underwent postexacerbation CT scans. The pulmonary arterial diameter, ascending aortic diameter, and the PA/A ratio were measured on CT scans. Demographic data, comorbidities, troponin level, and hospital outcome data were analyzed. RESULTS: A total of 134 patients were included in the study. They had a mean age of 65 ± 10 years, 47% were male, and 69% were white; overall, patients had a mean FEV1 of 47% ± 19%. The PA/A ratio increased from baseline at the time of exacerbation (0.97 ± 0.15 from 0.91 ± 0.17; P < .001). Younger age and known pulmonary hypertension were independently associated with an exacerbation PA/A ratio > 1. Patients with PA/A ratio > 1 had higher troponin values. Those with a PA/A ratio > 1 and troponin levels > 0.01 ng/mL had increased acute respiratory failure, ICU admission, or inpatient mortality compared with those without both factors (P = .0028). The PA/A ratio returned to baseline values following AECOPD. CONCLUSIONS: The PA/A ratio increased at the time of severe AECOPD and a ratio > 1 predicted cardiac injury and a more severe hospital course.


Asunto(s)
Cardiopatías/sangre , Hipertensión Pulmonar/diagnóstico por imagen , Arteria Pulmonar/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Troponina/sangre , Factores de Edad , Anciano , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Cardiopatías/epidemiología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Tamaño de los Órganos , Terapia por Inhalación de Oxígeno , Arteria Pulmonar/patología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos X , Capacidad Vital
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA