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1.
Immunity ; 51(1): 50-63.e5, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31174991

RESUMEN

Chronic inflammatory diseases are associated with altered hematopoiesis that could result in neutrophilia and anemia. Here we report that genetic or chemical manipulation of different inflammasome components altered the differentiation of hematopoietic stem and progenitor cells (HSPC) in zebrafish. Although the inflammasome was dispensable for the emergence of HSPC, it was intrinsically required for their myeloid differentiation. In addition, Gata1 transcript and protein amounts increased in inflammasome-deficient larvae, enforcing erythropoiesis and inhibiting myelopoiesis. This mechanism is evolutionarily conserved, since pharmacological inhibition of the inflammasome altered erythroid differentiation of human erythroleukemic K562 cells. In addition, caspase-1 inhibition rapidly upregulated GATA1 protein in mouse HSPC promoting their erythroid differentiation. Importantly, pharmacological inhibition of the inflammasome rescued zebrafish disease models of neutrophilic inflammation and anemia. These results indicate that the inflammasome plays a major role in the pathogenesis of neutrophilia and anemia of chronic diseases and reveal druggable targets for therapeutic interventions.


Asunto(s)
Anemia/inmunología , Enfermedades de los Peces/inmunología , Factor de Transcripción GATA1/metabolismo , Inflamasomas/metabolismo , Inflamación/inmunología , Neutrófilos/inmunología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/fisiología , Animales , Animales Modificados Genéticamente , Caspasa 1/genética , Caspasa 1/metabolismo , Diferenciación Celular , Células Eritroides/citología , Factor de Transcripción GATA1/genética , Regulación del Desarrollo de la Expresión Génica , Hematopoyesis , Humanos , Inflamasomas/genética , Células K562 , Masculino , Ratones , Ratones Endogámicos C57BL , Proteolisis , Proteínas de Pez Cebra/genética
2.
Blood ; 141(9): 1047-1059, 2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36455198

RESUMEN

Venetoclax combination therapies are becoming the standard of care in acute myeloid leukemia (AML). However, the therapeutic benefit of these drugs in older/unfit patients is limited to only a few months, highlighting the need for more effective therapies. Protein phosphatase 2A (PP2A) is a tumor suppressor phosphatase with pleiotropic functions that becomes inactivated in ∼70% of AML cases. PP2A promotes cancer cell death by modulating the phosphorylation state in a variety of proteins along the mitochondrial apoptotic pathway. We therefore hypothesized that pharmacological PP2A reactivation could increase BCL2 dependency in AML cells and, thus, potentiate venetoclax-induced cell death. Here, by using 3 structurally distinct PP2A-activating drugs, we show that PP2A reactivation synergistically enhances venetoclax activity in AML cell lines, primary cells, and xenograft models. Through the use of gene editing tools and pharmacological approaches, we demonstrate that the observed therapeutic synergy relies on PP2A complexes containing the B56α regulatory subunit, of which expression dictates response to the combination therapy. Mechanistically, PP2A reactivation enhances venetoclax-driven apoptosis through simultaneous inhibition of antiapoptotic BCL2 and extracellular signal-regulated kinase signaling, with the latter decreasing MCL1 protein stability. Finally, PP2A targeting increases the efficacy of the clinically approved venetoclax and azacitidine combination in vitro, in primary cells, and in an AML patient-derived xenograft model. These preclinical results provide a scientific rationale for testing PP2A-activating drugs with venetoclax combinations in AML.


Asunto(s)
Leucemia Mieloide Aguda , Proteína Fosfatasa 2 , Humanos , Anciano , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-bcl-2 , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Apoptosis
3.
PLoS Biol ; 19(11): e3001455, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34748530

RESUMEN

Several studies have revealed a correlation between chronic inflammation and nicotinamide adenine dinucleotide (NAD+) metabolism, but the precise mechanism involved is unknown. Here, we report that the genetic and pharmacological inhibition of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the salvage pathway of NAD+ biosynthesis, reduced oxidative stress, inflammation, and keratinocyte DNA damage, hyperproliferation, and cell death in zebrafish models of chronic skin inflammation, while all these effects were reversed by NAD+ supplementation. Similarly, genetic and pharmacological inhibition of poly(ADP-ribose) (PAR) polymerase 1 (Parp1), overexpression of PAR glycohydrolase, inhibition of apoptosis-inducing factor 1, inhibition of NADPH oxidases, and reactive oxygen species (ROS) scavenging all phenocopied the effects of Nampt inhibition. Pharmacological inhibition of NADPH oxidases/NAMPT/PARP/AIFM1 axis decreased the expression of pathology-associated genes in human organotypic 3D skin models of psoriasis. Consistently, an aberrant induction of NAMPT and PARP activity, together with AIFM1 nuclear translocation, was observed in lesional skin from psoriasis patients. In conclusion, hyperactivation of PARP1 in response to ROS-induced DNA damage, fueled by NAMPT-derived NAD+, mediates skin inflammation through parthanatos cell death.


Asunto(s)
Inflamación/patología , NAD/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Parthanatos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piel/patología , Animales , Factor Inductor de la Apoptosis/metabolismo , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Daño del ADN , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Larva/metabolismo , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Parthanatos/efectos de los fármacos , Parthanatos/genética , Poli Adenosina Difosfato Ribosa/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Proteínas Inhibidoras de Proteinasas Secretoras/deficiencia , Proteínas Inhibidoras de Proteinasas Secretoras/metabolismo , Psoriasis/genética , Psoriasis/patología , Especies Reactivas de Oxígeno/metabolismo , Pez Cebra , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/metabolismo
4.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-34353901

RESUMEN

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Here, we report that zebrafish telomerase RNA (terc) binds to specific DNA sequences of master myeloid genes and controls their expression by recruiting RNA Polymerase II (Pol II). Zebrafish terc harboring the CR4-CR5 domain mutation found in DC patients hardly interacted with Pol II and failed to regulate myeloid gene expression in vivo and to increase their transcription rates in vitro. Similarly, TERC regulated myeloid gene expression and Pol II promoter occupancy in human myeloid progenitor cells. Strikingly, induced pluripotent stem cells derived from DC patients with a TERC mutation in the CR4-CR5 domain showed impaired myelopoiesis, while those with mutated telomerase catalytic subunit differentiated normally. Our findings show that TERC acts as a transcription factor, revealing a target for therapeutic intervention in DC patients.


Asunto(s)
Disqueratosis Congénita/genética , Mielopoyesis/fisiología , ARN Polimerasa II/genética , ARN/metabolismo , Telomerasa/metabolismo , Animales , Animales Modificados Genéticamente , Sitios de Unión , Células Cultivadas , Disqueratosis Congénita/patología , Regulación de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/patología , Larva/genética , Mutación , Mielopoyesis/genética , Regiones Promotoras Genéticas , Dominios Proteicos , ARN/genética , ARN Polimerasa II/metabolismo , Telomerasa/genética , Pez Cebra/genética , Proteínas de Pez Cebra/genética
5.
Int J Mol Sci ; 25(4)2024 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-38396822

RESUMEN

Zebrafish are an emergent animal model to study human diseases due to their significant genetic similarity to humans, swift development, and genetic manipulability. Their utility extends to the exploration of the involvement of inflammation in host defense, immune responses, and tissue regeneration. Additionally, the zebrafish model system facilitates prompt screening of chemical compounds that affect inflammation. This study explored the diverse roles of inflammatory pathways in zebrafish development and aging. Serving as a crucial model, zebrafish provides insights into the intricate interplay of inflammation in both developmental and aging contexts. The evidence presented suggests that the same inflammatory signaling pathways often play instructive or beneficial roles during embryogenesis and are associated with malignancies in adults.


Asunto(s)
Inflamación , Pez Cebra , Animales , Humanos , Pez Cebra/genética , Modelos Animales , Envejecimiento/genética , Transducción de Señal
6.
Trends Immunol ; 41(12): 1116-1127, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33162327

RESUMEN

Hematopoiesis is a complex process through which immature bone marrow precursor cells mature into all types of blood cells. Although the association of hematopoietic lineage bias (including anemia and neutrophilia) with chronic inflammatory diseases has long been appreciated, the causes involved are obscure. Recently, cytosolic multiprotein inflammasome complexes were shown to activate inflammatory and immune responses, and directly regulate hematopoiesis in zebrafish models; this was deemed to occur via cleavage and inactivation of the master erythroid transcription factor GATA1. Herein summarized are the zebrafish models that are currently available to study this unappreciated role of inflammasome-mediated regulation of hematopoiesis. Novel putative therapeutic strategies, for the treatment of hematopoietic alterations associated with chronic inflammatory diseases in humans, are also proposed.


Asunto(s)
Hematopoyesis , Inflamasomas , Modelos Animales , Pez Cebra , Animales , Hematopoyesis/genética , Hematopoyesis/inmunología , Humanos , Inflamasomas/metabolismo , Investigación/tendencias , Pez Cebra/genética , Pez Cebra/inmunología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/inmunología
7.
Cell ; 135(4): 609-22, 2008 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-19013273

RESUMEN

Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.


Asunto(s)
Envejecimiento , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/metabolismo , Telomerasa/metabolismo , Animales , Supervivencia Celular , Epidermis/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Queratinocitos/citología , Ratones , Ratones Transgénicos , Modelos Biológicos , Células Madre/citología
8.
Int J Mol Sci ; 24(4)2023 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-36835535

RESUMEN

Functional or compositional perturbations of the microbiome can occur at different sites, of the body and this dysbiosis has been linked to various diseases. Changes in the nasopharyngeal microbiome are associated to patient's susceptibility to multiple viral infections, supporting the idea that the nasopharynx may be playing an important role in health and disease. Most studies on the nasopharyngeal microbiome have focused on a specific period in the lifespan, such as infancy or the old age, or have other limitations such as low sample size. Therefore, detailed studies analyzing the age- and sex-associated changes in the nasopharyngeal microbiome of healthy people across their whole life are essential to understand the relevance of the nasopharynx in the pathogenesis of multiple diseases, particularly viral infections. One hundred twenty nasopharyngeal samples from healthy subjects of all ages and both sexes were analyzed by 16S rRNA sequencing. Nasopharyngeal bacterial alpha diversity did not vary in any case between age or sex groups. Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes were the predominant phyla in all the age groups, with several sex-associated. Acinetobacter, Brevundimonas, Dolosigranulum, Finegoldia, Haemophilus, Leptotrichia, Moraxella, Peptoniphilus, Pseudomonas, Rothia, and Staphylococcus were the only 11 bacterial genera that presented significant age-associated differences. Other bacterial genera such as Anaerococcus, Burkholderia, Campylobacter, Delftia, Prevotella, Neisseria, Propionibacterium, Streptococcus, Ralstonia, Sphingomonas, and Corynebacterium appeared in the population with a very high frequency, suggesting that their presence might be biologically relevant. Therefore, in contrast to other anatomical areas such as the gut, bacterial diversity in the nasopharynx of healthy subjects remains stable and resistant to perturbations throughout the whole life and in both sexes. Age-associated abundance changes were observed at phylum, family, and genus levels, as well as several sex-associated changes probably due to the different levels of sex hormones present in both sexes at certain ages. Our results provide a complete and valuable dataset that will be useful for future research aiming for studying the relationship between changes in the nasopharyngeal microbiome and susceptibility to or severity of multiple diseases.


Asunto(s)
Microbiota , Virosis , Masculino , Femenino , Humanos , ARN Ribosómico 16S/genética , Genes de ARNr , Nasofaringe/microbiología , Microbiota/genética , Bacterias/genética , Envejecimiento , Virosis/genética
9.
Int J Mol Sci ; 24(9)2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37175698

RESUMEN

Atopic dermatitis (AD) is a chronic inflammatory skin disease of very high prevalence, especially in childhood, with no specific treatment or cure. As its pathogenesis is complex, multifactorial and not fully understood, further research is needed to increase knowledge and develop new targeted therapies. We have recently demonstrated the critical role of NAD+ and poly (ADP-ribose) (PAR) metabolism in oxidative stress and skin inflammation. Specifically, we found that hyperactivation of PARP1 in response to DNA damage induced by reactive oxygen species, and fueled by NAMPT-derived NAD+, mediated inflammation through parthanatos cell death in zebrafish and human organotypic 3D skin models of psoriasis. Furthermore, the aberrant induction of NAMPT and PARP activity was observed in the lesional skin of psoriasis patients, supporting the role of these signaling pathways in psoriasis and pointing to NAMPT and PARP1 as potential novel therapeutic targets in treating skin inflammatory disorders. In the present work, we report, for the first time, altered NAD+ and PAR metabolism in the skin of AD patients and a strong correlation between NAMPT and PARP1 expression and the lesional status of AD. Furthermore, using a human 3D organotypic skin model of AD, we demonstrate that the pharmacological inhibition of NAMPT and PARP reduces pathology-associated biomarkers. These results help to understand the complexity of AD and reveal new potential treatments for AD patients.


Asunto(s)
Dermatitis Atópica , Psoriasis , Animales , Humanos , Inflamación , NAD/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli Adenosina Difosfato Ribosa/metabolismo , Poli ADP Ribosilación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Psoriasis/etiología , Pez Cebra/metabolismo
10.
PLoS Biol ; 12(5): e1001855, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24802997

RESUMEN

TNFα overexpression has been associated with several chronic inflammatory diseases, including psoriasis, lichen planus, rheumatoid arthritis, and inflammatory bowel disease. Paradoxically, numerous studies have reported new-onset psoriasis and lichen planus following TNFα antagonist therapy. Here, we show that genetic inhibition of Tnfa and Tnfr2 in zebrafish results in the mobilization of neutrophils to the skin. Using combinations of fluorescent reporter transgenes, fluorescence microscopy, and flow cytometry, we identified the local production of dual oxidase 1 (Duox1)-derived H2O2 by Tnfa- and Tnfr2-deficient keratinocytes as a trigger for the activation of the master inflammation transcription factor NF-κB, which then promotes the induction of genes encoding pro-inflammatory molecules. In addition, pharmacological inhibition of Duox1 completely abrogated skin inflammation, placing Duox1-derived H2O2 upstream of this positive feedback inflammatory loop. Strikingly, DUOX1 was drastically induced in the skin lesions of psoriasis and lichen planus patients. These results reveal a crucial role for TNFα/TNFR2 axis in the protection of the skin against DUOX1-mediated oxidative stress and could establish new therapeutic targets for skin inflammatory disorders.


Asunto(s)
Liquen Plano/metabolismo , NADPH Oxidasas/metabolismo , Psoriasis/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismo , Piel/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Embrión no Mamífero , Inhibidores Enzimáticos/farmacología , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Liquen Plano/genética , Liquen Plano/patología , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Infiltración Neutrófila , Estrés Oxidativo , Psoriasis/genética , Psoriasis/patología , Receptores Tipo II del Factor de Necrosis Tumoral/genética , Transducción de Señal , Piel/patología , Factor de Necrosis Tumoral alfa/genética , Pez Cebra
11.
Sci Rep ; 14(1): 16606, 2024 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-39025936

RESUMEN

The agronomic use of compost and biochar as soil amendments may exhibit contrasting results in terms of soil fertility and plant nutrition. The effects of the biennial application of biochar, compost and a blend of compost:biochar (90:10; % dw:dw) on the agronomical performance of an organically managed and well established 25-year-old olive orchard was assessed 5 years after the initial application. The agronomical evaluation was based on the assessment of the soil physical, chemical, and biological characteristics, and the assessment of the soil fertility by both crop production and nutritional status of the orchard, and the bioassay with olive plantlets. Biochar mainly benefited the physical properties (bulk density, total porosity, aeration, water retention capacity) of soil, especially in the top 0-5 cm. Compost and its blend with biochar improved microbial activity, soil nutritional status (increasing the content of soluble organic C, N, and P) and favoured the formation of aggregates in soil. The bioassay conducted with young plantlets confirmed the enhanced soil fertility status in the three amended treatments, particularly in the case of biochar and its blend with compost. However, this effect was not significantly observed in the adult plants after 5 years of application, reflecting the slow response of adult olive trees to changes in fertilization. Based on these results, alongside the desirable long-residence time of biochar in soil and the ready availability of compost, the blend of biochar with compost assayed in this study is defined as a valid strategy for preparing high quality soil organic amendments.


Asunto(s)
Carbón Orgánico , Compostaje , Olea , Suelo , Olea/crecimiento & desarrollo , Suelo/química , Compostaje/métodos , Fertilizantes/análisis , Agricultura Orgánica/métodos
12.
Front Cell Infect Microbiol ; 14: 1396263, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38881733

RESUMEN

Introduction: Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. This disease is especially worrying in children since it can seriously alter their development. Presently, a specific diagnostic test or definitive biomarker set for confirming long COVID is lacking, relying instead on the protracted presence of symptoms post-acute infection. Methods: We measured the levels of 13 biomarkers in 105 saliva samples (49 from children with long COVID and 56 controls), and the Pearson correlation coefficient was used to analyse the correlations between the levels of the different salivary biomarkers. Multivariate logistic regression analyses were performed to determine which of the 13 analysed salivary biomarkers were useful to discriminate between children with long COVID and controls, as well as between children with mild and severe long COVID symptoms. Results: Pediatric long COVID exhibited increased oxidant biomarkers and decreased antioxidant, immune response, and stress-related biomarkers. Correlation analyses unveiled distinct patterns between biomarkers in long COVID and controls. Notably, a multivariate logistic regression pinpointed TOS, ADA2, total proteins, and AOPP as pivotal variables, culminating in a remarkably accurate predictive model distinguishing long COVID from controls. Furthermore, total proteins and ADA1 were instrumental in discerning between mild and severe long COVID symptoms. Discussion: This research sheds light on the potential clinical utility of salivary biomarkers in diagnosing and categorizing the severity of pediatric long COVID. It also lays the groundwork for future investigations aimed at unravelling the prognostic value of these biomarkers in predicting the trajectory of long COVID in affected individuals.


Asunto(s)
Biomarcadores , COVID-19 , SARS-CoV-2 , Saliva , Índice de Severidad de la Enfermedad , Humanos , COVID-19/diagnóstico , Saliva/química , Saliva/virología , Biomarcadores/análisis , Niño , Femenino , Masculino , SARS-CoV-2/aislamiento & purificación , Preescolar , Adolescente
13.
Ann Surg ; 257(5): 886-93, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23059500

RESUMEN

OBJECTIVE: The aim of this study is to identify a set of microRNAs (miRNAs) as prognostic molecular biomarkers for the progression of Barrett esophagus (BE) to esophageal adenocarcinoma (EAC) to rationalize the surveillance programs in patients with BE. BACKGROUND: Histological dysplasia is currently used as the main biomarker to identify the BE patients at high risk for developing EAC. Although miRNA expression profiles in BE and EAC have been reported, it has not been established which set of miRNAs could constitute a robust diagnostic test to predict the progression of BE to EAC. METHODS: miRNAs associated with progression of BE to EAC were identified using miRNA sequencing analysis. Further validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in 2 groups of BE patients who either developed or did not develop adenocarcinoma after at least 5 years of follow-up. RESULTS: Twenty-three miRNAs were identified by miRNA sequencing analysis in the carcinogenesis process associated with BE. qRT-PCR analysis using independent tissue samples confirmed differential expression for 19 of them (miR-let-7c, 7, 146a, 149, 153, 192, 192*, 194, 194*, 196a, 196b, 200a, 203, 205, 215, 424, 625, 625*, and 944). However, only miR-192, 194, 196a, and 196b showed a significantly higher expression in BE samples from patients with progression to EAC compared with those who did not progress to EAC. CONCLUSIONS: These findings suggest that the expression pattern of a modest number of miRNAs in metaplasia biopsies could identify the BE patients at high risk for developing EAC. Therefore, it has potential use for the control and treatment of this malignancy.


Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Lesiones Precancerosas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Esófago de Barrett/metabolismo , Esófago de Barrett/patología , Biología Computacional , Progresión de la Enfermedad , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patología , Estudios de Seguimiento , Humanos , Modelos Logísticos , Análisis Multivariante , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Curva ROC , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Transcriptoma
14.
Dev Comp Immunol ; 140: 104626, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36587712

RESUMEN

One of the most studied defense mechanisms against invading pathogens, including viruses, are Toll-like receptors (TLRs). Among them, TLR3, TLR7, TLR8 and TLR9 detect different forms of viral nucleic acids in endosomal compartments, whereas TLR2 and TLR4 recognize viral structural and nonstructural proteins outside the cell. Although many different TLRs have been shown to be involved in SARS-CoV-2 infection and detection of different structural proteins, most studies have been performed in vitro and the results obtained are rather contradictory. In this study, we report using the unique advantages of the zebrafish model for in vivo imaging and gene editing that the S1 domain of the Spike protein from the Wuhan strain (S1WT) induced hyperinflammation in zebrafish larvae via a Tlr2/Myd88 signaling pathway and independently of interleukin-1ß production. In addition, S1WT also triggered emergency myelopoiesis, but in this case through a Tlr2/Myd88-independent signaling pathway. These results shed light on the mechanisms involved in the fish host responses to viral proteins.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Receptor Toll-Like 2 , Animales , COVID-19/inmunología , Factor 88 de Diferenciación Mieloide/genética , SARS-CoV-2 , Receptor Toll-Like 2/genética , Pez Cebra/genética
15.
Waste Manag ; 158: 76-83, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36641823

RESUMEN

Different activation and N-doping treatments were used to produce biochar-based fertilizers (BBFs) with increased N concentration and slow N release. Pristine biochars were produced by pyrolysis of olive tree pruning feedstock at low and high temperatures (400 and 800 °C). These biochars were activated either by ultrasonication, or oxidation with hydrogen peroxide (H2O2) or nitric acid (HNO3) to increase their N retention potential. Subsequently biochars were enriched with N with either urea or ammonium sulfate. The activation of low-temperature biochars with HNO3 was the most effective treatment leading to new surface carboxylic groups that facilitated the later enrichment with N. When treated with urea, BBFs reached 7.0 N%, whereas the H2O2 activation only allowed an increase up to 2.0 N%. The use of urea as the external N source was the most efficient for incorporating N. Urea treated biochars had a water-soluble fraction that represented up to 14.5 % of the total N. The hydrolyzable N fraction, composed by amides and simple N heterocycles originated by the N-doping treatments, and nitro groups generated from HNO3 activation, represented up to 60 % of the total N. This study relates the N chemical forms in the new BBFs to potential N availability in soil. The presence of water-soluble, hydrolyzable and non-hydrolyzable N implied that these BBFs may supply N that would be progressively available for plants, acting as slow-release fertilizers.


Asunto(s)
Fertilizantes , Nitrógeno , Fertilizantes/análisis , Peróxido de Hidrógeno , Carbón Orgánico , Suelo , Urea , Agua
16.
FEMS Microbiol Rev ; 47(1)2023 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-36323404

RESUMEN

Although COVID-19 has only recently appeared, research studies have already developed and implemented many animal models for deciphering the secrets of the disease and provided insights into the biology of SARS-CoV-2. However, there are several major factors that complicate the study of this virus in model organisms, such as the poor infectivity of clinical isolates of SARS-CoV-2 in some model species, and the absence of persistent infection, immunopathology, severe acute respiratory distress syndrome, and, in general, all the systemic complications which characterize COVID-19 clinically. Another important limitation is that SARS-CoV-2 mainly causes severe COVID-19 in older people with comorbidities, which represents a serious problem when attempting to use young and immunologically naïve laboratory animals in COVID-19 testing. We review here the main animal models developed so far to study COVID-19 and the unique advantages of the zebrafish model that may help to contribute to understand this disease, in particular to the identification and repurposing of drugs to treat COVID-19, to reveal the mechanism of action and side-effects of Spike-based vaccines, and to decipher the high susceptibility of aged people to COVID-19.


Asunto(s)
COVID-19 , Animales , Humanos , SARS-CoV-2 , Pez Cebra , Prueba de COVID-19
17.
Nat Commun ; 14(1): 5912, 2023 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-37737237

RESUMEN

Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.


Asunto(s)
Aptámeros de Nucleótidos , Disqueratosis Congénita , Humanos , Animales , Aptámeros de Nucleótidos/genética , Mielopoyesis/genética , ARN Polimerasa II/genética , Síndrome , Pez Cebra
18.
Front Immunol ; 14: 1294766, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38077314

RESUMEN

Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing ifih1 carrying the mutation p.Arg742His (Tg(ifih1_mut)), corresponding to the human mutation p.Arg779His. RNA sequence analysis from Tg(ifih1_mut) larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters nfkb:eGFP and isg15:eGFP, respectively, making this zebrafish model suitable for future high-throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing, we have generated Tg(ifih1_mut) knocked down for mavs and ikbke, which completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA-approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISG expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.


Asunto(s)
Interferón Tipo I , Pez Cebra , Animales , Humanos , Inflamación/genética , Interferón Tipo I/genética , Poli I , Pez Cebra/genética , Helicasa Inducida por Interferón IFIH1
19.
Dev Comp Immunol ; 145: 104710, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37080369

RESUMEN

Fish are the most diverse and successful group of vertebrate animals, with about 30,000 species. The study of fish immunity is of great importance for understanding the evolution of vertebrate immunity, as they are the first animals to show both innate and adaptive immune responses. Although fish immunity is similar to that of mammals, there are obvious differences, such as their dependence of ambient temperature, their poor antibody response, and lack of antibody switching and lymph nodes. In addition, several important differences have also been found between the innate immune responses of fish and mammals. Among these, we will discuss in this review the high resistance of fish to the toxic effects of lipopolysaccharide (LPS) which can be explained by the absence of a Toll-like receptor 4 (Tlr4) ortholog in most fish species or by the inability of the Tlr4/Md2 (Myeloid differentiation 2) complex to recognize LPS, together with the presence of a negative regulator of the LPS signaling complex formed by the TLR-like molecule Rp105 (Radioprotective 105) and Md1. Taken together, these data support the idea that, although TLR4 and RP105 arose from a common ancestor to fish and tetrapods, the TLR4/MD2 receptor complex for LPS recognition arose after their divergence about 450 million years ago.


Asunto(s)
Lipopolisacáridos , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Transducción de Señal , Peces , Inmunidad Innata , Antígeno 96 de los Linfocitos , Mamíferos
20.
EMBO Mol Med ; 15(10): e18142, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37675820

RESUMEN

Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.

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