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1.
Pediatr Blood Cancer ; 71(5): e30915, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38369689

RESUMO

OBJECTIVE: The occurrence of unpredictable pain crises are the principal determinant of the quality of life for patients with venous malformations (VM). A definite coagulation phenomenon, characterized by an increase in D-dimer levels and the presence of phleboliths within the malformation, has been previously reported. By applying Virchow's triad and evaluating intralesional samples, our objective is to delineate the coagulation profile and the extent of endothelial dysfunction within the malformation. METHODS: With the authorization of the Ethics Committee, a research project was undertaken on intralesional and extralesional blood samples from 30 pediatric patients afflicted with spongiform VM. Thromboelastometry analyses were performed using ROTEM Sigma, and the concentration of syndecan-1 was determined by ELISA. RESULTS: In the ROTEM analyses, the A5, A10, and maximum clot firmness (MCF) values were below the established reference ranges in the intralesional samples in both the EXTEM and INTEM assays, indicating that intralesional clots had significant instability. Furthermore, during the investigation of the delayed fibrinolysis phase using recombinant tissue plasminogen activator (rtPA) in EXTEM analysis, widespread hyperfibrinolysis was observed intralesional. Additionally, analysis of syndecan-1 showed significant differences between extralesional and intralesional levels (p < .026) and controls (p < .03), suggesting differences in the state of endothelium. CONCLUSIONS: For the first time, we developed a comprehensive understanding of the coagulopathic profile of VM and the role of endothelial dysfunction in its pathogenesis. These findings will enable the implementation of targeted therapies based on the individual coagulation profiles.


Assuntos
Transtornos da Coagulação Sanguínea , Doenças Vasculares , Humanos , Criança , Tromboelastografia , Ativador de Plasminogênio Tecidual , Sindecana-1 , Qualidade de Vida , Transtornos da Coagulação Sanguínea/etiologia , Testes de Coagulação Sanguínea
2.
Clin Genet ; 101(3): 296-306, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34850385

RESUMO

Segmental overgrowth has been widely described in patients with congenital vascular anomalies. However, segmental undergrowth has been poorly characterized, and no large series of patients have been published. We present the clinical and molecular characteristics a cohort of 37 patients with vascular malformations and segmental undergrowth. True undergrowth was only considered when the musculoskeletal system was involved to avoid confusion with other causes of segmental reduction, as in lipodystrophy or the long-term osteopenia seen in patients with Servelle-Martorell syndrome. Deep high-throughput sequencing was performed in tissue samples from 20 patients using a custom panel. We identified three groups: undergrowth associated with (1) venous, (2) capillary-venous, and (3) lymphatic-capillary-venous malformations. Congenital or early childhood onset undergrowth can occur with or without associated overgrowth. Different likely pathogenic or pathogenic variants were detected in 13 of 20 (65%) tissue samples in the PIK3CA, TEK, GNAQ, or GNA11 genes. In conclusion, the eponymous Servelle-Martorell syndrome should not be used as a synonym for undergrowth. Segmental undergrowth should be considered a characteristic associated with vascular malformations. Patients with PIK3CA variants show all different combinations of overgrowth and undergrowth. Thus, the term PROS (PIK3CA-related overgrowth spectrum) does not cover the entire spectrum.


Assuntos
Anormalidades Musculoesqueléticas , Malformações Vasculares , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/genética , Humanos , Anormalidades Musculoesqueléticas/genética , Mutação/genética , Estudos Retrospectivos , Malformações Vasculares/genética
3.
J Allergy Clin Immunol ; 131(5): 1393-9.e5, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23265858

RESUMO

BACKGROUND: Invariant natural killer T (iNKT) cells recognize lipids presented by CD1d and have been implicated in the pathogenesis of allergic asthma. Recognition of plant pollen lipids by iNKT cells and their role in allergic responses are poorly defined. OBJECTIVE: Our goal was to investigate whether iNKT cells can be activated by monocyte-derived dendritic cells (DCs) exposed to lipid antigens from Olea europaea. METHODS: DCs generated in vitro were exposed to O europaea pollen grains or lipids isolated from them. Expression of lipid-presenting molecules (CD1), as well as maturation markers (HLA-DR, HLA-I, CD86, and CD80 molecules), on DCs was analyzed. iNKT cell activation after coculture with DCs was evaluated based on expansion, cytokine production, and cytotoxicity tests. RESULTS: DCs upregulated CD1d and CD86 expression and downregulated CD1a expression after exposure to a whole extract of olive pollen lipids. CD1d and CD1a were regulated at the transcriptional level in a peroxisome proliferator-activated receptor γ activation-dependent manner. Polar lipids, diacylglycerols, free fatty acids, and triacylglycerols isolated from pollen grains upregulate CD1d. The increase in CD1d expression on the DC cell surface induced by polar lipids was not regulated at the RNA level. iNKT cells efficiently recognize DCs treated with the different lipids isolated from olive pollen grains. CONCLUSIONS: Lipids from O europaea pollen upregulate CD1d and CD86 molecules on DCs, which are then able to activate iNKT cells through a CD1d-dependent pathway.


Assuntos
Antígenos CD1d/biossíntese , Células Dendríticas/imunologia , Metabolismo dos Lipídeos/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Olea/imunologia , Pólen/imunologia , Regulação para Cima/imunologia , Alérgenos/efeitos adversos , Alérgenos/imunologia , Antígenos CD1d/genética , Antígenos CD1d/fisiologia , Células Dendríticas/metabolismo , Diglicerídeos/imunologia , Humanos , Imunofenotipagem , Metabolismo dos Lipídeos/genética , Ativação Linfocitária/genética , Células T Matadoras Naturais/metabolismo , Olea/efeitos adversos , Pólen/efeitos adversos
4.
Nat Cardiovasc Res ; 2: 144-158, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36949957

RESUMO

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

5.
Mol Metab ; 31: 1-13, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31918912

RESUMO

OBJECTIVE: An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85α in BAT (BATp85αKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications. METHODS: We generated BATp85αKO mice using Cre-LoxP technology, specifically deleting p85α in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85αKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality. RESULTS: Our results suggest that the loss of p85α in BAT improves its thermogenic functionality, high-fat diet-induced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis. CONCLUSIONS: Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85α has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications.


Assuntos
Tecido Adiposo Marrom/metabolismo , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Obesidade/metabolismo , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/deficiência , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/induzido quimicamente
6.
Cell Rep ; 33(4): 108326, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33113366

RESUMO

Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1ß in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1ß production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.


Assuntos
Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/metabolismo , Resistência à Insulina/genética , Obesidade/genética , Envelhecimento , Animais , Humanos , Camundongos
7.
Rev Esp Cardiol (Engl Ed) ; 72(9): 760-766, 2019 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31078457

RESUMO

Clinical trials have unequivocally shown that cholesterol-lowering drugs decrease the risk of atherosclerotic cardiovascular disease in an exceptionally wide range of individuals. Yet, even when treated optimally according to current standards, many individuals still experience life-threatening ischemic events. Emerging experimental and clinical evidence strongly suggests that persistent inflammation is a major driver of this residual risk, which has opened the door to the application of anti-inflammatory drugs for cardiovascular disease prevention. Here, we review our current knowledge of the biology of interleukin-1ß, a key regulator of inflammation in atherosclerotic plaque and the target of the first clinical trial to demonstrate that an anti-inflammatory drug can effectively reduce cardiovascular risk. We discuss the challenges faced by interleukin-1ß inhibitors and other anti-inflammatory compounds in their translation to the clinical scenario, and identify other potential targets within this signaling pathway that hold promise in the cardiovascular setting.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , Interleucina-1beta/metabolismo , Guias de Prática Clínica como Assunto , Humanos , Interleucina-1beta/efeitos dos fármacos
8.
Endocrinology ; 159(1): 323-340, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040448

RESUMO

It is unknown how the lack of insulin receptor (IR)/insulinlike growth factor I receptor (IGFIR) in a tissue-specific manner affects brown fat development and mitochondrial integrity and function, as well as its effect on the redistribution of the adipose organ and the metabolic status. To address this important issue, we developed IR/IGFIR double-knockout (DKO) in a brown adipose tissue-specific manner. Lack of those receptors caused severe brown fat atrophy, enhanced beige cell clusters in inguinal fat; loss of mitochondrial mass; mitochondrial damage related to cristae disruption; and the loss of proteins involved in autophagosome formation, mitophagy, mitochondrial quality control, and dynamics and thermogenesis. More important, DKO mice showed an impaired thermogenesis upon cold exposure, based on a failure in the mitochondrial fission mechanisms and a much lower uncoupling protein 1 transcription rate and content. As a result, DKO mice under normal conditions showed an obesity susceptibility, revealed by increased body fat mass and insulin resistance. Upon consumption of a high-fat diet, DKO mice displayed frank obesity, as shown by increased body weight, increased adiposity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia, all consistent with a metabolic syndrome. Collectively, our data suggest a cause-and-effect relationship between failure in brown fat thermogenesis and increased adiposity and obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Síndrome Metabólica/metabolismo , Dinâmica Mitocondrial , Obesidade/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Termogênese , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Bege/ultraestrutura , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/ultraestrutura , Adiposidade , Animais , Atrofia , Dieta Hiperlipídica/efeitos adversos , Hiperinsulinismo/etiologia , Hipertrigliceridemia/etiologia , Resistência à Insulina , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Obesidade/etiologia , Obesidade/patologia , Obesidade/fisiopatologia , Especificidade de Órgãos , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Aumento de Peso
9.
Endocrinology ; 157(4): 1495-511, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26910308

RESUMO

Brown fat is a thermogenic tissue that generates heat to maintain body temperature in cold environments and dissipate excess energy in response to overfeeding. We have addressed the role of the IGFIR in the brown fat development and function. Mice lacking IGFIR exhibited normal brown adipose tissue/body weight in knockout (KO) vs control mice. However, lack of IGFIR decreased uncoupling protein 1 expression in interscapular brown fat and beige cells in inguinal fat. More importantly, the lack of IGFIR resulted in an impaired cold acclimation. No differences in the total fat volume were found in the KO vs control mice. Epididymal fat showed larger adipocytes but with a lower number of adipocytes in KO vs control mice at age 12 months. In addition, KO mice showed a sustained moderate hyperinsulinemia and hypertriglyceridemia upon time and hepatic insulin insensitivity associated with lipid accumulation, with the outcome of a global insulin resistance. In addition, we found that the expression of uncoupling protein 3 in the skeletal muscle was decreased and its expression was increased in the heart in parallel with the expression of beta-2 adrenergic receptors. Upon nonobesogenic high-fat diet, we found a severe insulin resistance in the liver and in the skeletal muscle, but unchanged insulin sensitivity in the heart. In conclusion, our data suggest that IGFIR it is not an essential growth factor in the brown fat development in the presence of the IR and very high plasma levels of IGF-I, but it is indispensable for full brown fat functionality.


Assuntos
Tecido Adiposo Marrom/metabolismo , Glucose/metabolismo , Resistência à Insulina , Receptor IGF Tipo 1/metabolismo , Termogênese , Aclimatação , Adipócitos/metabolismo , Animais , Western Blotting , Temperatura Baixa , Epididimo/metabolismo , Expressão Gênica , Homeostase , Hiperinsulinismo/genética , Hipertrigliceridemia/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Especificidade de Órgãos , Receptor IGF Tipo 1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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