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1.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
2.
Health Phys ; 115(1): 65-76, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29787432

RESUMO

Interleukin-11 was developed to reduce chemotherapy-induced thrombocytopenia; however, its clinical use was limited by severe adverse effects in humans. PEGylated interleukin-11 (BBT-059), developed by Bolder Biotechnology, Inc., exhibited a longer half-life in rodents and induced longer-lasting increases in hematopoietic cells than interleukin-11. A single dose of 1.2 mg kg of BBT-059, administered subcutaneously to CD2F1 mice (12-14 wk, male) was found to be safe in a 14 d toxicity study. The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to Co gamma total-body irradiation. A single dose of 0.3 mg kg, administered either 24 h pre-, 4 h post-, or 24 h postirradiation increased the survival of mice to 70-100% from lethal doses of radiation. Preadministration (-24 h) of the drug conferred a significantly (p < 0.05) higher survival compared to 24 h post-total-body irradiation. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pretreated with BBT-059. The drug also increased bone marrow cellularity and megakaryocytes and accelerated multilineage hematopoietic recovery. In addition, BBT-059 inhibited the induction of radiation-induced hematopoietic biomarkers, thrombopoietin, erythropoietin, and Flt-3 ligand. These results indicate that BBT-059 is a promising radiation countermeasure, demonstrating its potential to be used both pre- and postirradiation for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Sistema Hematopoético/efeitos dos fármacos , Interleucina-11/administração & dosagem , Polietilenoglicóis/química , Lesões Experimentais por Radiação/tratamento farmacológico , Irradiação Corporal Total/efeitos adversos , Síndrome Aguda da Radiação/etiologia , Animais , Relação Dose-Resposta à Radiação , Sistema Hematopoético/patologia , Sistema Hematopoético/efeitos da radiação , Interleucina-11/química , Masculino , Camundongos , Lesões Experimentais por Radiação/etiologia
3.
Ecotoxicol Environ Saf ; 152: 121-131, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29407778

RESUMO

Silver nanoparticles (Ag NPs) are known for their antibacterial properties and are used in a growing number of nano-enabled products, with inevitable concerns for releases to the environment. Nanoparticles may also be antigenic and toxic to the haematopoietic system, but the immunotoxic effect of Ag NPs on non-target species such as fishes is poorly understood. This study aimed to assess the effect of Ag NP exposure via the water on the haematopoietic system of rainbow trout, Oncorhynchus mykiss, and to determine whether or not the hazard from Ag NPs was different from that of AgNO3. Fish were exposed for 7 days to a control (dechlorinated Plymouth freshwater), dispersant control, 1µgl-1 Ag as AgNO3 or 100µgl-1 Ag NPs. Animals were sampled on days 0, 4 and 7 for haematology, tissue trace metal concentration, biochemistry for evidence of oxidative stress/inflammation in the spleen and histopathology of the blood cells and spleen. The Ag NP treatment significantly increased the haematocrit, but the haematological changes were within the normal physiological range of the animal. Thrombocytes in spleen prints at day 4, and melanomacrophage deposits at day 7 in the spleen, of Ag NP exposed-fish displayed significant increases compared to all the other treatments within the time point. A dialysis experiment confirmed that dissolution rates were very low and any pathology observed is likely from the NP form rather than dissolved metal released from it. Overall, the data showed subtle differences in the effects of Ag NPs compared to AgNO3 on the haematopoietic system. The lack of pathology in the circulating blood cells and melanomacrophage deposits in the spleen suggests a compensatory physiological effort by the spleen to maintain normal circulating haematology during Ag NP exposure.


Assuntos
Sistema Hematopoético/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Oncorhynchus mykiss/sangue , Nitrato de Prata/toxicidade , Prata/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Sistema Hematopoético/patologia , Modelos Teóricos , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia
4.
J Pediatr Hematol Oncol ; 40(1): e9-e12, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29200145

RESUMO

We reported the outcome of 150 children newly diagnosed with multisystem langerhans cell histiocytosis following a langerhans cell histiocytosis-II-based protocol (arm B). However, the continuation treatment was extended to 56 weeks and etoposide was omitted from the continuation treatment. Risk organ (RO) involvement was defined as: liver (≥3 cm with or without functional impairment); spleen (≥2 cm below the costal margin in the midclavicular line); hematopoietic system (hemoglobin <100 g/L, and/or white blood cell count <4.0×10/L, and/or platelets <100×10/L). The lungs are not considered a RO in the current study. For the 59 patients with RO involvement (RO+), the rapid response rate (week 6) was 61.0% and the 3-year overall survival 73.4%±5.9%. Rapid responders had a better 3-year survival rate than poor responders (90.9%±5.0% vs. 45.7%±11.0%, P<0.001). Ninety-one patients without RO involvement (RO-) had a relatively low 3-year cumulative reactivation rate (10.7%). No deaths occurred in this subgroup and the 3-year overall survival of RO- patients was 100%. Poor responders of RO+ patients had an extremely poor prognosis. An effective salvage therapy is essential for this high-risk group. The initial treatment intensity and duration of continuation therapy both impact disease reactivation in RO- patients.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Medição de Risco , Adolescente , Criança , Pré-Escolar , China , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/patologia , Hospitais Pediátricos , Humanos , Lactente , Hepatopatias , Masculino , Terapia de Salvação , Esplenopatias , Taxa de Sobrevida , Resultado do Tratamento
5.
Leukemia ; 32(1): 194-202, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28642594

RESUMO

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.


Assuntos
Diferenciação Celular/genética , Fator de Transcrição GATA2/genética , Sistema Hematopoético/patologia , Mutação/genética , Transcrição Genética/genética , Animais , Células COS , Feminino , Predisposição Genética para Doença/genética , Genótipo , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
6.
Cell Physiol Biochem ; 43(2): 457-464, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28922655

RESUMO

BACKGROUND/AIMS: The hematopoietic system is vulnerable to ionizing radiation and is often severely damaged by radiation. Molecules affecting radioresistance include Toll-like receptor 2. We investigated whether Zymosan-A, a novel TLR2 agonist, can protect the hematopoietic system from radiation-induced damage after total body irradiation. METHODS: Mice were exposed to total body radiation after treatment with Zymosan-A or normal saline, and their survival was recorded. Tissue damage was evaluated by hematoxylin-eosin staining. The number of nucleated cells in bone marrow was determined by flow cytometry. Cell viability and apoptosis assay were determined by CCK-8 assay and flow cytometry assay. Enzyme-linked immunosorbent assay was used to detect the level of cytokines. RESULTS: Zymosan-A protected mice from radiation-induced death and prevented radiation-induced hematopoietic system damage. Zymosan-A also promoted cell viability and inhibited cell apoptosis caused by radiation, induced radioprotective effects via TLR2, upregulated IL-6, IL-11, IL-12, and TNF-α in vivo. CONCLUSION: Zymosan-A can provide protection against radiation-induced hematopoietic system damage by targeting the TLR2 signaling pathway. Thus, Zymosan-A can be potentially effective radioprotectant.


Assuntos
Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/efeitos da radiação , Protetores contra Radiação/farmacologia , Receptor 2 Toll-Like/metabolismo , Zimosan/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular , Sistema Hematopoético/patologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação
7.
Hum Gene Ther ; 28(11): 1105-1115, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28806883

RESUMO

The possibility of editing complex genomes in a targeted fashion has revolutionized basic research as well as biomedical and biotechnological applications in the last 5 years. The targeted introduction of genetic changes has allowed researchers to create smart model systems for basic research, bio-engineers to modify crops and farm animals, and translational scientists to develop novel treatment approaches for inherited and acquired disorders for which curative treatment options are not yet available. With the rapid development of genome editing tools, in particular zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR-Cas system, a wide range of therapeutic options have been-and will be-developed at an unprecedented speed, which will change the clinical routine of various disciplines in a revolutionary way. This review summarizes the fundamentals of genome editing and the current state of research. It particularly focuses on the advances made in employing engineered nucleases in hematopoietic stem cells for the treatment of primary immunodeficiencies and hemoglobinopathies, provides a perspective of combining gene editing with the chimeric antigen receptor T cell technology, and concludes by presenting targeted epigenome editing as a novel potential treatment option.


Assuntos
Edição de Genes/tendências , Engenharia Genética/tendências , Sistema Hematopoético/patologia , Hemoglobinopatias/terapia , Sistemas CRISPR-Cas/genética , Epigenômica/tendências , Hemoglobinopatias/genética , Hemoglobinopatias/patologia , Humanos
9.
J Radiat Res ; 57(4): 356-62, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27006381

RESUMO

Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4-dihydroxyphenyl lactic acid. It is a potent antioxidant that functions by scavenging free radicals. Here, we used a 30-day survival assay to investigate the radioprotective effects of RA. Mice were treated with RA once per day for 10 consecutive days starting at 3 days before gamma irradiation at 7.5 Gy until 7 days post irradiation. Mice treated with 100 and 200 mg/kg body weight (bw) of RA had 30-day survival rates of 89% and 72%, respectively, compared with 32% in the control group, and the differences were statistically significant (P = 0.0008 and 0.0421, respectively). Spleen colony-forming units (CFU-S), the number of nucleated cells in the bone marrow (BMNC), bone marrow DNA content, and hematological parameters of the peripheral blood were measured to investigate the radioprotective effect of RA on the hematopoietic system. The treatment groups that received RA at 50, 100 and 150 mg/kg bw and whole-body exposure to 5.5 Gy of (137)Cs γ- radiation had significantly higher CFU-S, BMNC and DNA content than the irradiation-only group. Assessment of hematological parameters in the peripheral blood showed that the treatment groups receiving RA at doses of 50, 100 and 150 mg/kg bw had higher white blood cell counts, hemoglobin and platelets than the radiation-only group. These results suggested that the administration of RA promoted the recovery of peripheral blood cells in irradiated mice.


Assuntos
Cinamatos/farmacologia , Cinamatos/uso terapêutico , Depsídeos/farmacologia , Depsídeos/uso terapêutico , Sistema Hematopoético/patologia , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Animais , Plaquetas/efeitos dos fármacos , Células da Medula Óssea/efeitos da radiação , Contagem de Células , Cinamatos/administração & dosagem , Cinamatos/química , Ensaio de Unidades Formadoras de Colônias , DNA/metabolismo , Depsídeos/administração & dosagem , Depsídeos/química , Sistema Hematopoético/efeitos dos fármacos , Camundongos , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/patologia , Protetores contra Radiação/química , Baço/efeitos dos fármacos , Análise de Sobrevida
10.
PLoS One ; 9(12): e114530, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25485970

RESUMO

The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature ("Core" OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/secundário , Células Epiteliais/patologia , Sistema Hematopoético/patologia , Osteoblastos/patologia , Neoplasias da Próstata/patologia , Nicho de Células-Tronco/genética , Células Estromais/patologia , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Diferenciação Celular , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica , Sistema Hematopoético/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Neovascularização Patológica/genética , Análise de Sequência com Séries de Oligonucleotídeos , Osteoblastos/metabolismo , Osteogênese/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/metabolismo , Células Tumorais Cultivadas
11.
J Exp Med ; 211(8): 1689-702, 2014 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-24980047

RESUMO

Development of autoimmune diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), involves the inflammatory action of Th1 and Th17 cells, but the underlying signaling mechanism is incompletely understood. We show that the kinase TPL2 is a crucial mediator of EAE and is required for the pathological action of Th17 cells. TPL2 serves as a master kinase mediating the activation of multiple downstream pathways stimulated by the Th17 signature cytokine IL-17. TPL2 acts by linking the IL-17 receptor signal to the activation of TAK1, which involves a dynamic mechanism of TPL2-TAK1 interaction and TPL2-mediated phosphorylation and catalytic activation of TAK1. These results suggest that TPL2 mediates TAK1 axis of IL-17 signaling, thereby promoting autoimmune neuroinflammation.


Assuntos
Autoimunidade/imunologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-17/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Sistema Hematopoético/patologia , Humanos , Ativação Linfocitária/imunologia , MAP Quinase Quinase Quinases/deficiência , Camundongos Knockout , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas/deficiência , Tolerância a Radiação , Células Th17/imunologia
12.
Sci Transl Med ; 6(244): 244re5, 2014 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25009232

RESUMO

Transmission of Plasmodium falciparum malaria parasites requires formation and development of gametocytes, yet all but the most mature of these sexual parasite forms are absent from the blood circulation. We performed a systematic organ survey in pediatric cases of fatal malaria to characterize the spatial dynamics of gametocyte development in the human host. Histological studies revealed a niche in the extravascular space of the human bone marrow where gametocytes formed in erythroid precursor cells and underwent development before reentering the circulation. Accumulation of gametocytes in the hematopoietic system of human bone marrow did not rely on cytoadherence to the vasculature as does sequestration of asexual-stage parasites. This suggests a different mechanism for the sequestration of gametocytes that could potentially be exploited to block malaria transmission.


Assuntos
Medula Óssea/parasitologia , Estágios do Ciclo de Vida , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Plasmodium falciparum/crescimento & desenvolvimento , Medula Óssea/patologia , Criança , Sistema Hematopoético/parasitologia , Sistema Hematopoético/patologia , Humanos
13.
Free Radic Biol Med ; 68: 52-64, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24287141

RESUMO

Here we describe a novel strategy for mitigation of ionizing radiation-induced hematopoietic syndrome by suppressing the activity of MKP3, resulting in ERK activation and enhanced abundance of hematopoietic stem cells, using the antioxidant flavonoid baicalein (5,6,7-trihydroxyflavone). It offered complete protection to mouse splenic lymphocytes against radiation-induced cell death. Inhibitors of ERK and Nrf-2 could significantly abrogate baicalein-mediated radioprotection in lymphocytes. Baicalein inhibited phosphatase MKP3 and thereby enhanced phosphorylation of ERK and its downstream proteins such as Elk and Nrf-2. It also increased the nuclear levels of Nrf-2 and the mRNA levels of its dependent genes. Importantly, baicalein administration to mice before radiation exposure led to significant recovery of loss of bone marrow cellularity and also inhibited cell death. Administration of baicalein increased the hematopoietic stem cell frequency as measured by side-population assay and also by antibody staining. Further, baicalein offered significant protection against whole-body irradiation (WBI; 7.5Gy)-induced mortality in mice. Interestingly, we found that baicalein works by activating the same target molecules ERK and Nrf-2 both in vitro and in vivo. Finally, administration of all-trans-retinoic acid (inhibitor of Nrf-2) significantly abrogated baicalein-mediated protection against WBI-induced mortality in mice. Thus, in contrast to the generalized conception of antioxidants acting as radioprotectors, we provide a rationale that antioxidants exhibit pleiotropic effects through the activation of multiple cellular signaling pathways.


Assuntos
Antioxidantes/metabolismo , Fosfatase 6 de Especificidade Dupla/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Sistema Hematopoético/efeitos da radiação , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Fosfatase 6 de Especificidade Dupla/antagonistas & inibidores , Flavanonas/administração & dosagem , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação/efeitos da radiação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Irradiação Corporal Total
14.
Autophagy ; 9(11): 1737-49, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24135495

RESUMO

Hematopoietic stem cells (HSCs) are inherently quiescent and self-renewing, yet can differentiate and commit to multiple blood cell types. Intracellular mitochondrial content is dynamic, and there is an increase in mitochondrial content during differentiation and lineage commitment in HSCs. HSCs reside in a hypoxic niche within the bone marrow and rely heavily on glycolysis, while differentiated and committed progenitors rely on oxidative phosphorylation. Increased oxidative phosphorylation during differentiation and commitment is not only due to increased mitochondrial content but also due to changes in mitochondrial cytosolic distribution and efficiency. These changes in the intracellular mitochondrial landscape contribute signals toward regulating differentiation and commitment. Thus, a functional relationship exists between the mitochondria in HSCs and the state of the HSCs (i.e., stemness vs. differentiated). This review focuses on how autophagy-mediated mitochondrial clearance (i.e., mitophagy) may affect HSC mitochondrial content, thereby influencing the fate of HSCs and maintenance of hematopoietic homeostasis.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Animais , Autofagia , Células-Tronco Hematopoéticas/patologia , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Humanos , Mitocôndrias/metabolismo , Modelos Biológicos
15.
PLoS One ; 8(7): e69106, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23922686

RESUMO

Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation-induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg) starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG) function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240±8 vs. 165±10, P<0.01). This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27±8 vs. 149±22, in 1,000 erythrocytes, P<0.01). JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy.


Assuntos
Sistema Hematopoético/efeitos dos fármacos , Indóis/farmacologia , Intestino Delgado/efeitos dos fármacos , Piperazinas/farmacologia , Protetores contra Radiação/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Histamínicos/metabolismo , Glândulas Salivares/efeitos dos fármacos , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Medula Óssea/efeitos da radiação , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Sistema Hematopoético/patologia , Sistema Hematopoético/efeitos da radiação , Humanos , Intestino Delgado/patologia , Intestino Delgado/efeitos da radiação , Ligantes , Masculino , Mutagênicos/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H4 , Glândulas Salivares/patologia , Glândulas Salivares/efeitos da radiação , Compostos de Sulfidrila/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Irradiação Corporal Total
16.
Tissue Antigens ; 82(1): 1-15, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23745569

RESUMO

It is well established that interactions between CD4(+) T cells and major histocompatibility complex class II (MHCII) positive antigen-presenting cells (APCs) of hematopoietic origin play key roles in both the maintenance of tolerance and the initiation and development of autoimmune and inflammatory disorders. In sharp contrast, despite nearly three decades of intensive research, the functional relevance of MHCII expression by non-hematopoietic tissue-resident cells has remained obscure. The widespread assumption that MHCII expression by non-hematopoietic APCs has an impact on autoimmune and inflammatory diseases has in most instances neither been confirmed nor excluded by indisputable in vivo data. Here we review and put into perspective conflicting in vitro and in vivo results on the putative impact of MHCII expression by non-hematopoietic APCs--in both target organs and secondary lymphoid tissues--on the initiation and development of representative autoimmune and inflammatory disorders. Emphasis will be placed on the lacunar status of our knowledge in this field. We also discuss new mouse models--developed on the basis of our understanding of the molecular mechanisms that regulate MHCII expression--that constitute valuable tools for filling the severe gaps in our knowledge on the functions of non-hematopoietic APCs in inflammatory conditions.


Assuntos
Doenças Autoimunes/imunologia , Sistema Hematopoético/imunologia , Sistema Hematopoético/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Inflamação/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Especificidade de Órgãos/imunologia
17.
PLoS One ; 8(4): e57833, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23593116

RESUMO

Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Linfócitos/patologia , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/patologia , Animais , Proliferação de Células , Sobrevivência Celular , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Humanos , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Camundongos , Camundongos Transgênicos , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Análise de Sobrevida , Transgenes/genética
18.
J Exp Med ; 210(5): 969-85, 2013 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-23569325

RESUMO

Bone homeostasis is maintained by the coupled actions of hematopoietic bone-resorbing osteoclasts (OCs) and mesenchymal bone-forming osteoblasts (OBs). Here we identify early B cell factor 1 (Ebf1) and the transcriptional coregulator Zfp521 as components of the machinery that regulates bone homeostasis through coordinated effects in both lineages. Deletion of Zfp521 in OBs led to impaired bone formation and increased OB-dependent osteoclastogenesis (OC-genesis), and deletion in hematopoietic cells revealed a strong cell-autonomous role for Zfp521 in OC progenitors. In adult mice, the effects of Zfp521 were largely caused by repression of Ebf1, and the bone phenotype of Zfp521(+/-) mice was rescued in Zfp521(+/-):Ebf1(+/-) mice. Zfp521 interacted with Ebf1 and repressed its transcriptional activity. Accordingly, deletion of Zfp521 led to increased Ebf1 activity in OBs and OCs. In vivo, Ebf1 overexpression in OBs resulted in suppressed bone formation, similar to the phenotype seen after OB-targeted deletion of Zfp521. Conversely, Ebf1 deletion led to cell-autonomous defects in both OB-dependent and cell-intrinsic OC-genesis, a phenotype opposite to that of the Zfp521 knockout. Thus, we have identified the interplay between Zfp521 and Ebf1 as a novel rheostat for bone homeostasis.


Assuntos
Osso e Ossos/patologia , Linhagem da Célula/genética , Regulação da Expressão Gênica , Sistema Hematopoético/patologia , Homeostase/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Reabsorção Óssea/fisiopatologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiopatologia , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Deleção de Genes , Células Germinativas/metabolismo , Haploinsuficiência , Mesoderma/patologia , Camundongos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese , Fenótipo , Transcrição Genética , Regulação para Cima/genética
19.
Exp Hematol ; 41(6): 518-529.e5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23435313

RESUMO

Hoxa9 is expressed in hematopoietic stem and progenitor cells, although this expression is usually diminished as these cells undergo differentiation. In addition, aberrant expression of Hoxa9 is strongly associated with both T cell and myeloid leukemia in mice and humans. Despite this strong association, enforced expression of Hoxa9 in murine bone marrow or thymus has only shown a modest ability to transform cells. To investigate this question, we used Vav regulatory elements to generate a transgenic mouse that targets Hoxa9 overexpression to all hematopoietic tissues. High-level expression of the Hoxa9 transgene in the hematopoietic compartment was associated with embryonic lethality, as no pups from founders that expressed high levels of the transgene were born live. However, offspring of an additional founder line, which expressed lower levels of Hoxa9, developed a precursor T cell lymphoblastic leukemia/lymphoma, accompanied by spontaneous Notch1 mutations. In contrast to most murine models of leukemia associated with Hoxa9 overexpression, the Vav-Hoxa9 mice did not overexpress other Hoxa cluster genes, mir196b (a microRNA that is embedded in the Hoxa locus), Meis1, or Pbx3. The Hoxa9 transgenic mouse reported in this study provides a suitable system for the study of Hoxa9 collaborators that drive myeloid and lymphoid malignant transformation.


Assuntos
Transformação Celular Neoplásica/genética , Genes Homeobox , Proteínas de Homeodomínio/fisiologia , Leucemia Prolinfocítica de Células T/genética , Animais , Células da Medula Óssea/patologia , Células Cultivadas/patologia , Feminino , Regulação Leucêmica da Expressão Gênica , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Genes Letais , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Proteína Meis1 , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Proteínas Proto-Oncogênicas c-vav/genética , Receptor Notch1/genética , Proteínas Recombinantes de Fusão/fisiologia
20.
Curr Opin Cell Biol ; 25(2): 254-64, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23347562

RESUMO

The functional versatility of Wnt/ß-catenin signaling can be seen by its ability to act in stem cells of the embryo and of the adult as well as in cancer stem cells. During embryogenesis, stem cells demonstrate a requirement for ß-catenin in mediating the response to Wnt signaling for their maintenance and transition from a pluripotent state. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to specification of different tissues. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signaling in stem and progenitor cells is subverted in cancer cells to allow malignant progression. Intensive work is currently being performed to resolve how intrinsic and extrinsic factors that regulate Wnt/ß-catenin signaling coordinate the stem and cancer stem cell states.


Assuntos
Células-Tronco Neoplásicas/metabolismo , Células-Tronco/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Animais , Transformação Celular Neoplásica , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Sistema Hematopoético/citologia , Sistema Hematopoético/metabolismo , Sistema Hematopoético/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Mucosa Intestinal/metabolismo , Intestinos/citologia , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Células-Tronco Neoplásicas/patologia , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Pele/citologia , Pele/metabolismo , Células-Tronco/citologia , Sumoilação , Transcrição Genética , Ubiquitinação , beta Catenina/metabolismo
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