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1.
J Cell Sci ; 136(16)2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37589341

RESUMEN

Bioenergetic metabolism is a key regulator of cellular function and signaling, but how it can instruct the behavior of cells and their fate during embryonic development remains largely unknown. Here, we investigated the role of glucose metabolism in the development of avian trunk neural crest cells (NCCs), a migratory stem cell population of the vertebrate embryo. We uncovered that trunk NCCs display glucose oxidation as a prominent metabolic phenotype, in contrast to what is seen for cranial NCCs, which instead rely on aerobic glycolysis. In addition, only one pathway downstream of glucose uptake is not sufficient for trunk NCC development. Indeed, glycolysis, mitochondrial respiration and the pentose phosphate pathway are all mobilized and integrated for the coordinated execution of diverse cellular programs, epithelial-to-mesenchymal transition, adhesion, locomotion, proliferation and differentiation, through regulation of specific gene expression. In the absence of glucose, the OXPHOS pathway fueled by pyruvate failed to promote trunk NCC adaptation to environmental stiffness, stemness maintenance and fate-decision making. These findings highlight the need for trunk NCCs to make the most of the glucose pathway potential to meet the high metabolic demands appropriate for their development.


Asunto(s)
Glucosa , Cresta Neural , Codorniz , Codorniz/crecimiento & desarrollo , Codorniz/metabolismo , Animales , Cresta Neural/crecimiento & desarrollo , Cresta Neural/metabolismo , Glucosa/metabolismo , Tubo Neural/citología , Células Cultivadas , Técnicas In Vitro , Fosforilación Oxidativa , Redes y Vías Metabólicas , Adhesión Celular
2.
J Exp Med ; 219(10)2022 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-36094518

RESUMEN

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.


Asunto(s)
Síndrome de Job , TYK2 Quinasa , Humanos , Interferón gamma/metabolismo , Interleucina-23 , Síndrome de Job/genética , TYK2 Quinasa/deficiencia , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismo
3.
Med Mycol ; 59(2): 180-188, 2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-32526033

RESUMEN

Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients' peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients' PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.


Asunto(s)
Candidiasis Mucocutánea Crónica/genética , Candidiasis Mucocutánea Crónica/microbiología , Familia , Mutación con Ganancia de Función , Factor de Transcripción STAT1/genética , Células Th17/inmunología , Adolescente , Proliferación Celular , Preescolar , Femenino , Citometría de Flujo , Expresión Génica , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Irán , Masculino , Fosforilación , Células Th17/patología , Adulto Joven
4.
Curr Protoc Cell Biol ; 88(1): e109, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32609435

RESUMEN

Neural crest cells constitute a unique population of progenitor cells with extensive stem cell capacities able to navigate throughout various environments in the embryo and are a source of multiple cell types, including neurons, glia, melanocytes, smooth muscles, endocrine cells, cardiac cells, and also skeletal and supportive tissues in the head. Neural crest cells are not restricted to the embryo but persist as well in adult tissues where they provide a reservoir of stem cells with great therapeutic promise. Many fundamental questions in cell, developmental, and stem cell biology can be addressed using this system. During the last decades there has been an increased availability of elaborated techniques, animal models, and molecular tools to tackle neural crest cell development. However, these approaches are often very challenging and difficult to establish and they are not adapted for rapid functional investigations of mechanisms driving cell migration and differentiation. In addition, they are not adequate for collecting pure populations of neural crest cells usable in large scale analyses and for stem cell studies. Transferring and adapting the neural crest system in tissue culture may then represent an attractive alternative, opening up numerous prospects. Here we describe a simple method for establishing primary cultures of neural crest cells derived from trunk neural tubes using the avian embryo as a source of cells. This protocol is suited for producing pure populations of neural crest cells that can be processed for cytological, cellular, and functional approaches aimed at characterizing their phenotype, behavior, and potential. © 2020 Wiley Periodicals LLC. Basic Protocol: Primary cultures of avian trunk neural crest cells Support Protocol: Adaptations for immunofluorescence labeling and videomicroscopy.


Asunto(s)
Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Cresta Neural/metabolismo , Células Madre/citología , Animales , Embrión de Mamíferos/citología , Melanocitos/citología , Cresta Neural/citología , Fenotipo
5.
J Clin Immunol ; 38(7): 787-793, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30255293

RESUMEN

PURPOSE: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). METHODS: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rß1 expression on T cell blasts, and sequenced candidate genes. RESULTS: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rß1 was completely abolished in the four patients with IL12RB1 mutations. CONCLUSIONS: IL-12Rß1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rß1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rß1-deficient patient, notified for the first time in this study.


Asunto(s)
Susceptibilidad a Enfermedades , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Infecciones por Mycobacterium/etiología , Infecciones por Mycobacterium/metabolismo , Receptores de Interleucina-12/deficiencia , Adolescente , Adulto , Alelos , Vacuna BCG/inmunología , Biomarcadores , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunofenotipificación , Lactante , Irán/epidemiología , Masculino , Mutación , Infecciones por Mycobacterium/epidemiología , Infecciones por Mycobacterium/prevención & control , Pronóstico , Adulto Joven
6.
Mol Biol Rep ; 40(8): 4857-60, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23649768

RESUMEN

Acute renal allograft rejection remains an important problem following kidney transplantation. Several immunological and non-immunological factors intervene in renal graft rejection. Glutathione S-transferase super family is one of the important enzymes for biotransformation of both exogenous and endogenous xenobiotic compounds such as immunosuppressive drugs. The new class of this family is omega that includes two subunits GSTO1 and GSTO2. In this study 282 samples were collected from renal recipients of Namazi hospital in Shiraz-Iran during 2007-2010 years. Also 300 healthy samples as control group were collected from Shiraz population, included in our study. The primary outcome of this study was defined as biopsy-proven acute rejection during 1 year of renal transplantation. We applied polymerase chain reaction-restriction fragment length polymorphism method for determination of GSTO2 N142D polymorphism. Our result showed no significant association between GSTO2 polymorphism and acute rejection. Also this genetic variant has no significant effect with the risk of end stage renal disease. Cadaveric donor type for acute rejection significantly differed between acute rejection and non acute rejection patients (P=0.004). The combination effect of donor type and GSTO2 polymorphism indicates DD genotype with cadaver donor type increase risk of acute rejection (OR=3.82, 95% CI 1.80-12.37, P=0.02).


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Glutatión Transferasa/genética , Rechazo de Injerto/genética , Trasplante de Riñón/efectos adversos , Polimorfismo Genético/genética , Sustitución de Aminoácidos/genética , Genotipo , Humanos , Modelos Logísticos , Oportunidad Relativa , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción
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