RESUMEN
The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating the expression of numerous genes involved in several pathways. Monoallelic defects in the BCL11B gene leading to loss-of-function are associated with a wide spectrum of phenotypes, including neurological disorders with or without immunological features and susceptibility to hematological malignancies. From the genetic point of view, the landscape of BCL11B mutations reported so far does not fully explain the genotype-phenotype correlation. In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.
Asunto(s)
Proteínas Represoras , Proteínas Supresoras de Tumor , Humanos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Fenotipo , Mutación , Animales , Sistema Inmunológico/metabolismo , Sistema Hematopoyético/metabolismoRESUMEN
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.
Asunto(s)
Aterosclerosis , Diabetes Gestacional , Sistema Hematopoyético , Humanos , Femenino , Embarazo , Animales , Ratones , Diabetes Gestacional/genética , Placenta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Inflamasomas/metabolismo , Sistema Hematopoyético/metabolismoRESUMEN
Tristetraprolin (TTP), encoded by Zfp36 in mice, is one of the best-characterized tandem zinc-finger mRNA binding proteins involved in mRNA deadenylation and decay. TTPΔARE mice lack an AU-rich motif in the 3'-untranslated regions of TTP mRNA, leading to increased TTP mRNA stability and more TTP protein, resulting in elevated mRNA decay rates of TTP targets. We examined the effect of TTP overexpression on the hematopoietic system in both young and middle-aged mice using TTPΔARE mice and found alterations in blood cell frequencies, with loss of platelets and B220 cells and gains of eosinophils and T cells. TTPΔARE mice also have skewed primitive populations in the bone marrow, with increases in myeloid-biased hematopoietic stem cells (HSCs) but decreases in granulocyte/macrophage-biased multipotent progenitors (MPP3) in both young and middle-aged mice. Changes in the primitive cells' frequencies were associated with transcriptional alterations in the TTP overexpression cells specific to age as well as cell type. Regardless of age, there was a consistent elevation of transcripts regulated by TNFα and TGFß signaling pathways in both the stem and multipotent progenitor populations. HSCs with TTP overexpression had decreased reconstitution potential in murine transplants but generated hematopoietic environments that mitigated the inflammatory response to the collagen antibody-induced arthritis (CAIA) challenge, which models rheumatoid arthritis and other autoimmune disorders. This dampening of the inflammatory response was even present when there was only a small frequency of TTP overexpressing cells present in the middle-aged mice. We provide an analysis of the early hematopoietic compartments with elevated TTP expression in both young and middle-aged mice which inhibits the reconstitution potential of the HSCs but generates a hematopoietic system that provides dominant repression of induced inflammation.
Asunto(s)
Sistema Hematopoyético , Tristetraprolina , Animales , Ratones , Regiones no Traducidas 3' , Modelos Animales de Enfermedad , Sistema Hematopoyético/metabolismo , Inflamación/genética , Ratones Noqueados , Tristetraprolina/genética , Tristetraprolina/metabolismoRESUMEN
Bone is a vital tissue as it carries out various metabolic functions: support of the body, protection of the internal organs, mineral deposit and hematopoietic functions [...].
Asunto(s)
Enfermedades Óseas Metabólicas , Sistema Hematopoyético , Humanos , Enfermedades Óseas Metabólicas/genética , Enfermedades Óseas Metabólicas/terapia , Huesos/metabolismo , Sistema Hematopoyético/metabolismo , Minerales , Biología MolecularRESUMEN
Acute Radiation Syndrome (ARS) is a syndrome involving damage to multiple organs caused by exposure to a high dose of ionizing radiation over a short period of time; even low doses of radiation damage the radiosensitive hematopoietic system and causes H-ARS. PLacenta eXpanded (PLX)-R18 is a 3D-expanded placenta-derived stromal cell product designated for the treatment of hematological disorders. These cells have been shown in vitro to secrete hematopoietic proteins, to stimulate colony formation, and to induce bone marrow migration. Previous studies in mice showed that PLX-R18 cells responded to radiation-induced hematopoietic failure by transiently secreting hematopoiesis related proteins to enhance reconstitution of the hematopoietic system. We assessed the potential effect of prophylactic PLX-R18 treatment on H-ARS. PLX-R18 cells were administered intramuscularly to C57BL/6 mice, −1 and 3 days after (LD70/30) total body irradiation. PLX R18 treatment significantly increased survival after irradiation (p < 0.0005). In addition, peripheral blood and bone marrow (BM) cellularity were monitored at several time points up to 30 days. PLX-R18 treatment significantly increased the number of colony-forming hematopoietic progenitors in the femoral BM and significantly raised peripheral blood cellularity. PLX-R18 administration attenuated biomarkers of bone marrow aplasia (EPO, FLT3L), sepsis (SAA), and systemic inflammation (sP-selectin and E-selectin) and attenuated radiation-induced inflammatory cytokines/chemokines and growth factors, including G-CSF, MIP-1a, MIP-1b, IL-2, IL-6 and MCP-1, In addition, PLX-R18 also ameliorated radiation-induced upregulation of pAKT. Taken together, prophylactic PLX-R18 administration may serve as a protection measure, mitigating bone marrow failure symptoms and systemic inflammation in the H-ARS model.
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Síndrome de Radiación Aguda , Sistema Hematopoyético , Ratones , Animales , Selectina E/uso terapéutico , Interleucina-2/uso terapéutico , Interleucina-6 , Ratones Endogámicos C57BL , Síndrome de Radiación Aguda/tratamiento farmacológico , Sistema Hematopoyético/metabolismo , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Citocinas , Biomarcadores , InflamaciónRESUMEN
PURPOSE OF REVIEW: Dysregulated apoptosis contributes to the pathogenesis of many hematologic malignancies. BH3-mimetics, antagonists of antiapoptotic BCL-2 proteins, represent novel, and promising cancer drugs. While the acute myelosuppressive effects of Venetoclax, the first Food and Drug Administration approved BCL-2 inhibitor, are fairly well described, little is known about side effects of novel BH3-mimetics and effects of chronic Venetoclax treatment. RECENT FINDINGS: Highly relevant publications focused on the effects of acute and chronic Venetoclax therapy, with focus on cell-type specific adaptive mechanisms, the emergence of clonal hematopoiesis, and the selection of BAX-mutated hematopoietic cells in patients treated with Venetoclax for a long period. Important advances were made in understanding primary and secondary Venetoclax resistance and prediction of Venetoclax response. Combination therapies of BH3-mimetics targeting different BCL-2 proteins are highly anticipated. However, human stem and progenitors require both MCL-1 and BCL-XL for survival, and serious myelosuppressive effects of combined MCL-1/BCL-XL inhibition can be expected. SUMMARY: Long-term studies are indispensable to profile the chronic side effects of Venetoclax and novel BH3-mimetics and better balance their risk vs. benefit in cancer therapy. Combination therapies will be powerful, but potentially limited by severe myelosuppression. For precision medicine, a better knowledge of BCL-2 proteins in the healthy and diseased hematopoietic system is required.
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Antineoplásicos , Sistema Hematopoyético , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Células Madre Hematopoyéticas , Sistema Hematopoyético/metabolismo , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , Células Madre/metabolismoRESUMEN
Homeobox genes encode transcription factors that control basic developmental decisions. Knowledge of their hematopoietic activities casts light on normal and malignant immune cell development. Recently, we constructed the so-called lymphoid TALE-code that codifies expression patterns of all active TALE class homeobox genes in early hematopoiesis and lymphopoiesis. Here, we present the corresponding myeloid TALE-code to extend this gene signature, covering the entire hematopoietic system. The collective data showed expression patterns for eleven TALE homeobox genes and highlighted the exclusive expression of IRX1 in megakaryocyte-erythroid progenitors (MEPs), implicating this TALE class member in a specific myeloid differentiation process. Analysis of public profiling data from acute myeloid leukemia (AML) patients revealed aberrant activity of IRX1 in addition to IRX3 and IRX5, indicating an oncogenic role for these TALE homeobox genes when deregulated. Screening of RNA-seq data from 100 leukemia/lymphoma cell lines showed overexpression of IRX1, IRX3, and IRX5 in megakaryoblastic and myelomonocytic AML cell lines, chosen as suitable models for studying the regulation and function of these homeo-oncogenes. Genomic copy number analysis of IRX-positive cell lines demonstrated chromosomal amplification of the neighboring IRX3 and IRX5 genes at position 16q12 in MEGAL, underlying their overexpression in this cell line model. Comparative gene expression analysis of these cell lines revealed candidate upstream factors and target genes, namely the co-expression of GATA1 and GATA2 together with IRX1, and of BMP2 and HOXA10 with IRX3/IRX5. Subsequent knockdown and stimulation experiments in AML cell lines confirmed their activating impact in the corresponding IRX gene expression. Furthermore, we demonstrated that IRX1 activated KLF1 and TAL1, while IRX3 inhibited GATA1, GATA2, and FST. Accordingly, we propose that these regulatory relationships may represent major physiological and oncogenic activities of IRX factors in normal and malignant myeloid differentiation, respectively. Finally, the established myeloid TALE-code is a useful tool for evaluating TALE homeobox gene activities in AML.
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Sistema Hematopoyético , Leucemia Mieloide Aguda , Expresión Génica Ectópica , Genes Homeobox , Sistema Hematopoyético/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Células Progenitoras Mieloides/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BH3 mimetics constitute a novel concept of antitumor therapy, inducing apoptosis via inhibition of pro-survival BCL-2 proteins. Programmed cell death is fundamental for physiological hematopoiesis; hence hematological side effects of these compounds are conceivable. Navitoclax and venetoclax have been studied extensively in the clinical setting; our knowledge of the more recently developed BCL-2 protein inhibitors specifically targeting MCL-1 or BCL-XL, however, is restricted mainly to preclinical experiments. To delineate possible adverse effects of novel BH3 mimetics on the human hematopoietic system, this review summarizes current knowledge of the function of specific antiapoptotic BCL-2 proteins in physiological hematopoiesis.
Asunto(s)
Antineoplásicos , Sistema Hematopoyético , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Línea Celular Tumoral , Sistema Hematopoyético/metabolismo , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína bcl-X/metabolismo , Proteína bcl-X/farmacologíaRESUMEN
Calcific aortic valve disease (CAVD), and its clinical manifestation that is calcific aortic valve stenosis, is the leading cause for valve disease within the developed world, with no current pharmacological treatment available to delay or halt its progression. Characterized by progressive fibrotic remodelling and subsequent pathogenic mineralization of the valve leaflets, valve disease affects 2.5% of the western population, thus highlighting the need for urgent intervention. Whilst the pathobiology of valve disease is complex, involving genetic factors, lipid infiltration, and oxidative damage, the immune system is now being accepted to play a crucial role in pathogenesis and disease continuation. No longer considered a passive degenerative disease, CAVD is understood to be an active inflammatory process, involving a multitude of pro-inflammatory mechanisms, with both the adaptive and the innate immune system underpinning these complex mechanisms. Within the valve, 15% of cells evolve from haemopoietic origin, and this number greatly expands following inflammation, as macrophages, T lymphocytes, B lymphocytes, and innate immune cells infiltrate the valve, promoting further inflammation. Whether chronic immune infiltration or pathogenic clonal expansion of immune cells within the valve or a combination of the two is responsible for disease progression, it is clear that greater understanding of the immune systems role in valve disease is required to inform future treatment strategies for control of CAVD development.
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Inmunidad Adaptativa , Estenosis de la Válvula Aórtica/inmunología , Válvula Aórtica/inmunología , Válvula Aórtica/patología , Calcinosis/inmunología , Sistema Hematopoyético/inmunología , Sistema Inmunológico/inmunología , Inmunidad Innata , Animales , Válvula Aórtica/metabolismo , Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/fisiopatología , Calcinosis/metabolismo , Calcinosis/fisiopatología , Citocinas/metabolismo , Hematopoyesis , Sistema Hematopoyético/metabolismo , Sistema Hematopoyético/patología , Humanos , Sistema Inmunológico/metabolismo , Sistema Inmunológico/fisiopatología , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos , Cardiopatía Reumática/inmunología , Cardiopatía Reumática/metabolismo , Cardiopatía Reumática/fisiopatología , Transducción de SeñalRESUMEN
Humans benefit from nuclear technologies but consequently experience nuclear disasters or side effects of iatrogenic radiation. Hematopoietic system injury first arises upon radiation exposure. As an intricate new layer of genetic control, the posttranscriptional m6A modification of RNA has recently come under investigation and has been demonstrated to play pivotal roles in multiple physiological and pathological processes. However, how the m6A methylome functions in the hematopoietic system after irradiation remains ambiguous. Here, we uncovered the time-varying epitranscriptome-wide m6A methylome and transcriptome alterations in γ-ray-exposed mouse bone marrow. 4 Gy γ-irradiation rapidly (5 min and 2 h) and severely impaired the mouse hematopoietic system, including spleen and thymus weight, blood components, tissue inflammation and malondialdehyde (MDA) levels. The m6A content and expression of m6A related enzymes were altered. Gamma-irradiation triggered dynamic and reversible m6A modification profiles and altered mRNA expression, where both m6A fold-enrichment and mRNA expression most followed the (5 min_up/2 h_down) pattern. The CDS enrichment region preferentially upregulated m6A peaks at 5 min. Moreover, the main GO and KEGG pathways were closely related to metabolism and the classical radiation response. Finally, m6A modifications correlated with transcriptional regulation of genes in multiple aspects. Blocking the expression of m6A demethylases FTO and ALKBH5 mitigated radiation hematopoietic toxicity. Together, our findings present the comprehensive landscape of mRNA m6A methylation in the mouse hematopoietic system in response to γ-irradiation, shedding light on the significance of m6A modifications in mammalian radiobiology. Regulation of the epitranscriptome may be exploited as a strategy against radiation damage.
Asunto(s)
Médula Ósea , Sistema Hematopoyético , Adenosina/análogos & derivados , Animales , Sistema Hematopoyético/metabolismo , Metilación , Ratones , ARN Mensajero/metabolismoRESUMEN
The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.
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Linaje de la Célula/genética , Desarrollo Embrionario/genética , Sistema Hematopoyético/embriología , Sistema Hematopoyético/metabolismo , Mutación , Células Sanguíneas/citología , Células Sanguíneas/metabolismo , Células Clonales/citología , Células Clonales/metabolismo , Análisis Mutacional de ADN , Feto/citología , Feto/embriología , Feto/metabolismo , Estratos Germinativos/citología , Estratos Germinativos/metabolismo , Salud , Sistema Hematopoyético/citología , Humanos , Cariotipificación , Masculino , Mesodermo/citología , Mesodermo/embriología , Mesodermo/metabolismo , Tasa de Mutación , Especificidad de Órganos/genética , Factores de Tiempo , Secuenciación Completa del Genoma , Flujo de TrabajoRESUMEN
Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase, a highly conserved enzyme widely expressed in eukaryotic cells, which accounts for a majority of the serine/threonine phosphatase activity in cells implicated in regulation of immune signaling pathways and antiviral response. However, most of studies about PP2A have been conducted in mammals but few in crustaceans. In this study, two subunits of PP2A (named as CqPP2Ab and CqPP2Ac) were characterized to be involved in white spot syndrome virus (WSSV) infection in the haematopoietic tissue (Hpt) cells from red claw crayfish Cherax quadricarinatus. The open reading frame (ORF) of CqPP2Ab was 1341 bp encoding 446 amino acids with seven WD40 domains, and the ORF of CqPP2Ac was 930 bp encoding 309 amino acids with a PP2Ac domain. Tissue distribution analysis showed that the mRNA transcript of CqPP2Ab and CqPP2Ac were both widely expressed in all the tested tissues with the highest expression in hemocyte, followed by high expression in Hpt. The gene expressions of CqPP2Ab and CqPP2Ac were both significantly down-regulated at 6 h post WSSV infection (6 hpi) in Hpt cells. Importantly, the expression of viral immediate early gene IE1 and late viral gene envelope protein VP28 were both significantly increased post WSSV infection after gene silencing of CqPP2Ab or CqPP2Ac in Hpt cells, suggesting that CqPP2Ab and CqPP2Ac could inhibit WSSV infection in Hpt cells, probably by increasing the antimicrobial substances expression in consideration to the significantly reduced expression of anti-lipopolysaccharide factor, crustin, and lysozyme after gene silencing of CqPP2Ab or CqPP2Ac, respectively. These findings provide a new light on the mechanism of WSSV infection and the antiviral response in crustaceans.
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Péptidos Antimicrobianos/inmunología , Proteínas de Artrópodos/inmunología , Astacoidea/inmunología , Regulación de la Expresión Génica/inmunología , Proteína Fosfatasa 2/inmunología , Virus del Síndrome de la Mancha Blanca 1/inmunología , Secuencia de Aminoácidos , Animales , Péptidos Antimicrobianos/genética , Péptidos Antimicrobianos/metabolismo , Proteínas de Artrópodos/genética , Proteínas de Artrópodos/metabolismo , Astacoidea/genética , Astacoidea/virología , Secuencia de Bases , Perfilación de la Expresión Génica/métodos , Sistema Hematopoyético/citología , Sistema Hematopoyético/inmunología , Sistema Hematopoyético/metabolismo , Hemocitos/citología , Hemocitos/inmunología , Hemocitos/metabolismo , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Subunidades de Proteína/genética , Subunidades de Proteína/inmunología , Subunidades de Proteína/metabolismo , Análisis de Secuencia de ADN/métodos , Homología de Secuencia de Aminoácido , Virus del Síndrome de la Mancha Blanca 1/fisiologíaRESUMEN
Recent advances in molecular profiling provide descriptive datasets of complex differentiation landscapes including the haematopoietic system, but the molecular mechanisms defining progenitor states and lineage choice remain ill-defined. Here, we employed a cellular model of murine multipotent haematopoietic progenitors (Hoxb8-FL) to knock out 39 transcription factors (TFs) followed by RNA-Seq analysis, to functionally define a regulatory network of 16,992 regulator/target gene links. Focussed analysis of the subnetworks regulated by the B-lymphoid TF Ebf1 and T-lymphoid TF Gata3 revealed a surprising role in common activation of an early myeloid programme. Moreover, Gata3-mediated repression of Pax5 emerges as a mechanism to prevent precocious B-lymphoid differentiation, while Hox-mediated activation of Meis1 suppresses myeloid differentiation. To aid interpretation of large transcriptomics datasets, we also report a new method that visualises likely transitions that a progenitor will undergo following regulatory network perturbations. Taken together, this study reveals how molecular network wiring helps to establish a multipotent progenitor state, with experimental approaches and analysis tools applicable to dissecting a broad range of both normal and perturbed cellular differentiation landscapes.
Asunto(s)
Linaje de la Célula/fisiología , Sistema Hematopoyético/metabolismo , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula/genética , Epigenómica , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Ratones , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide/metabolismo , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Células Precursoras de Linfocitos B , Factores de Transcripción/genéticaRESUMEN
Blood development in multicellular organisms relies on specific tissue microenvironments that nurture hematopoietic precursors and promote their self-renewal, proliferation, and differentiation. The mechanisms driving blood cell homing and their interactions with hematopoietic microenvironments remain poorly understood. Here, we use the Drosophila melanogaster model to reveal a pivotal role for basement membrane composition in the formation of hematopoietic compartments. We demonstrate that by modulating extracellular matrix components, the fly blood cells known as hemocytes can be relocated to tissue surfaces where they function similarly to their natural hematopoietic environment. We establish that the Collagen XV/XVIII ortholog Multiplexin in the tissue-basement membranes and the phagocytosis receptor Eater on the hemocytes physically interact and are necessary and sufficient to induce immune cell-tissue association. These results highlight the cooperation of Multiplexin and Eater as an integral part of a homing mechanism that specifies and maintains hematopoietic sites in Drosophila.
Asunto(s)
Proteoglicanos Tipo Condroitín Sulfato/genética , Colágeno/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiología , Hematopoyesis/genética , Sistema Hematopoyético/metabolismo , Receptores de Superficie Celular/genética , Animales , Membrana Basal/metabolismo , Diferenciación Celular , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Colágeno/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Receptores de Superficie Celular/metabolismoRESUMEN
The present study was conceptualized to delineate radioprotective efficacy of a formulation G-003M (a combination of podophyllotoxin and rutin) against radiation-induced damage to the lymphohematopoietic system of mice. C57BL/6J mice, treated with G-003M 1 h prior to 9 Gy lethal dose, were assessed for reactive oxygen species (ROS)/nitric oxide (NO) generation, antioxidant alterations, Annexin V/PI and TUNEL staining for apoptosis, modulation of apoptotic proteins, cell proliferation, histological alterations in thymus and cell cycle arrest in bone marrow cells. Induction of granulocyte colony-stimulating factor (G-CSF), granulocytes macrophage colony-stimulating factor (GM-CSF), interleukin-IL-6, IL-10, IL-1α, and IL-1ß in response to G-003M was also evaluated in different groups of mice. Haematopoietic reconstitution with G-003M was explored by examining endogenous spleen colony-forming units (CFU-S) in irradiated animals. G-003M significantly inhibited ROS/NO, malondialdehyde (MDA) and restored cellular antioxidant glutathione in the thymus of irradiated animals. G-003M pre-treatment significantly (p < 0.001) restrained apoptosis in thymocytes via upregulation of Bcl2 and down-regulation of Bax, p53 and caspase-3. Stimulation of cell proliferation and inhibition of apoptosis by G-003M, restored architecture of thymus in irradiated animals within 30 days as evaluated by histological analysis. G-003M arrested cells at the G2/M phase by inducing reversible cell cycle arrest. Peak expression of G-CSF (45-fold) and IL-6 (60-fold) as well as moderate induction of GM-CSF, IL-10, IL-1α by G-003M helped in haematopoietic recovery of irradiated mice. A higher number of endogenous CFU-S in G-003M pre-treated irradiated mice suggested haematopoietic recovery. Data obtained from the current study affirms that G-003M can be proved as a potential radioprotective agent against radiation damage.
Asunto(s)
Citocinas/metabolismo , Sistema Hematopoyético/efectos de los fármacos , Sistema Hematopoyético/efectos de la radiación , Podofilotoxina/farmacología , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Rutina/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Ciclo Celular/efectos de los fármacos , Ciclo Celular/efectos de la radiación , Combinación de Medicamentos , Sistema Hematopoyético/metabolismo , Sistema Hematopoyético/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Distribución Aleatoria , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Acute exposure to ionizing radiation leads to Hematopoietic Acute Radiation Syndrome (H-ARS). To understand the inter-strain cellular and molecular mechanisms of radiation sensitivity, adult males of two strains of minipig, one with higher radiosensitivity, the Gottingen minipig (GMP), and another strain with comparatively lower radiosensitivity, the Sinclair minipig (SMP), were exposed to total body irradiation (TBI). Since Insulin-like Growth Factor-1 (IGF-1) signaling is associated with radiation sensitivity and regulation of cardiovascular homeostasis, we investigated the link between dysregulation of cardiac IGF-1 signaling and radiosensitivity. The adult male GMP; n = 48, and SMP; n = 24, were irradiated using gamma photons at 1.7-2.3 Gy doses. The animals that survived to day 45 after irradiation were euthanized and termed the survivors. Those animals that were euthanized prior to day 45 post-irradiation due to severe illness or health deterioration were termed the decedents. Cardiac tissue analysis of unirradiated and irradiated animals showed that inter-strain radiosensitivity and survival outcomes in H-ARS are associated with activation status of the cardiac IGF-1 signaling and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant gene expression. Our data link H-ARS with dysregulation of cardiac IGF-1 signaling, and highlight the role of oxidative stress and cardiac antioxidant response in radiation sensitivity.
Asunto(s)
Síndrome de Radiación Aguda/metabolismo , Corazón/efectos de la radiación , Sistema Hematopoyético/efectos de la radiación , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal/efectos de la radiación , Síndrome de Radiación Aguda/etiología , Síndrome de Radiación Aguda/patología , Animales , Rayos gamma/efectos adversos , Sistema Hematopoyético/metabolismo , Sistema Hematopoyético/patología , Masculino , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo/efectos de la radiación , Tolerancia a Radiación/efectos de la radiación , Porcinos , Porcinos EnanosRESUMEN
BACKGROUND: The effect of phase-change material blood containers on the quality of stored red blood cells (RBCs) transported in the Qinghai-Tibet Plateau remains to be studied. STUDY DESIGN AND METHODS: RBCs stored in a phase-change material blood container were transported from Chengdu to Tibet and then back to Chengdu. The detection time points were the 1st day of fresh-collected RBCs (group 1), the 14th day of resting refrigerated storage (group 2), and the 14th day of plateau transportation under refrigerated storage in the container (group 3). RBC counts, hemoglobin (HGB) content, free hemoglobin (FHb) content, blood biochemical indexes, hemorheologic indexes and 2,3-DPG content were detected. RESULTS: Compared with group 2, RBC counts and HGB were decreased, and the mean corpuscular volume (MCV), FHb and K+ content were increased in group 3. The glucose consumption and lactic acid production were significantly increased in groups 2 and 3. Compared with group 2, the 2,3-DPG content and whole blood viscosity were decreased in group 3. After resting refrigerated storage and plateau transportation, the RBC quality still met the national standard (GB18469-2012 whole blood and component blood quality requirements). CONCLUSION: The phase-change material blood container can be maintained at a constant temperature under plateau environmental conditions, ensuring that the quality of the stored RBCs is compliant with GB18469-2012 whole blood and component blood quality requirements.
Asunto(s)
Conservación de la Sangre/instrumentación , Eritrocitos/química , Manejo de Especímenes/instrumentación , Transportes , 2,3-Difosfoglicerato/sangre , Recuento de Eritrocitos , Glucosa/metabolismo , Sistema Hematopoyético/metabolismo , Hemoglobinas/metabolismo , Humanos , Ácido Láctico/sangre , TibetRESUMEN
Recent genome-wide studies have revealed a plethora of germline variants that significantly influence the susceptibility to acute lymphoblastic leukemia (ALL), thus providing compelling evidence for genetic inheritance of this blood cancer. In particular, hematopoietic transcription factors (eg, ETV6, PAX5, IKZF1) are most frequently implicated in familial ALL, and germline variants in these genes confer strong predisposition (albeit with incomplete penetrance). Studies of germline risk factors for ALL provide unique insights into the molecular etiology of this leukemia.
Asunto(s)
Hematopoyesis/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Sistema Hematopoyético/metabolismo , Sistema Hematopoyético/fisiología , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Factores de Riesgo , Factores de Transcripción/metabolismoRESUMEN
One of the major regulatory challenges of animal development is to precisely coordinate in space and time the formation, specification, and patterning of cells that underlie elaboration of the basic body plan. How does the vertebrate plan for the nervous and hematopoietic systems, heart, limbs, digestive, and reproductive organs derive from seemingly similar population of cells? These systems are initially established and patterned along the anteroposterior axis (AP) by opposing signaling gradients that lead to the activation of gene regulatory networks involved in axial specification, including the Hox genes. The retinoid signaling pathway is one of the key signaling gradients coupled to the establishment of axial patterning. The nested domains of Hox gene expression, which provide a combinatorial code for axial patterning, arise in part through a differential response to retinoic acid (RA) diffusing from anabolic centers established within the embryo during development. Hence, Hox genes are important direct effectors of retinoid signaling in embryogenesis. This review focuses on describing current knowledge on the complex mechanisms and regulatory processes, which govern the response of Hox genes to RA in several tissue contexts including the nervous system during vertebrate development.
Asunto(s)
Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Tretinoina/metabolismo , Animales , Encéfalo/embriología , Encéfalo/metabolismo , Sistema Cardiovascular/embriología , Sistema Cardiovascular/metabolismo , Sistema Hematopoyético/embriología , Sistema Hematopoyético/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Transducción de SeñalRESUMEN
Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.