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1.
Cell ; 183(1): 94-109.e23, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32937105

RESUMO

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.


Assuntos
Macrófagos/metabolismo , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Idoso , Animais , Apoptose , Autofagia , Feminino , Coração/fisiologia , Homeostase , Humanos , Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/fisiologia , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/fisiologia , Fagocitose/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , c-Mer Tirosina Quinase/metabolismo
2.
Immunity ; 50(2): 390-402.e10, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709741

RESUMO

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both. The gene Bmal1 regulated expression of the chemokine CXCL2 to induce chemokine receptor CXCR2-dependent diurnal changes in the transcriptional and migratory properties of circulating neutrophils. These diurnal alterations, referred to as neutrophil aging, were antagonized by CXCR4 (C-X-C chemokine receptor type 4) and regulated the outer topology of neutrophils to favor homeostatic egress from blood vessels at night, resulting in boosted anti-microbial activity in tissues. Mice engineered for constitutive neutrophil aging became resistant to infection, but the persistence of intravascular aged neutrophils predisposed them to thrombo-inflammation and death. Thus, diurnal compartmentalization of neutrophils, driven by an internal timer, coordinates immune defense and vascular protection.


Assuntos
Vasos Sanguíneos/imunologia , Ritmo Circadiano/imunologia , Neutrófilos/imunologia , Fagocitose/imunologia , Animais , Vasos Sanguíneos/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Células Cultivadas , Senescência Celular/imunologia , Quimiocina CXCL2/imunologia , Quimiocina CXCL2/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Receptores CXCR4/imunologia , Receptores CXCR4/metabolismo , Fatores de Tempo
4.
Nanomedicine ; 14(3): 643-650, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29317346

RESUMO

ApoB-100 and Phosphatidylcholine-specific phospholipase C (PC-PLC) are important contributors to atherosclerosis development. ApoB-100 is the main structural protein of LDL, being directly associated with atherosclerosis plaque generation. PC-PLC is highly expressed in atherosclerosis lesions and contributes to their progression. We show how phosphatidylcholine-coated nanomicelles can be used for specific characterisation of atherosclerosis plaque. Results show that ApoB-100 in the protein corona of the nanomicelle targets the particles to atherosclerotic areas in apolipoprotein E-/- mice. Furthermore, PC-PLC selectively removes the polar heads from the phospholipid coating of the nanomicelles leading to their accumulation. To fully characterise the behaviour of the nanomicelles, we developed multimodal probes using a nanoemulsion step. Hybrid imaging revealed plaque accumulation of the nanomicelles and colocalisation with PC-PLC expression and ApoB-100 in the plaque. This study shows how protein corona composition and enzyme-driven nanomaterial accumulation can be used for detection of atherosclerosis.


Assuntos
Apolipoproteínas E/fisiologia , Compostos Férricos/química , Micelas , Nanocompostos/química , Placa Aterosclerótica/metabolismo , Coroa de Proteína/metabolismo , Fosfolipases Tipo C/metabolismo , Animais , Apolipoproteína B-100/metabolismo , Camundongos , Camundongos Knockout para ApoE , Nanocompostos/administração & dosagem , Placa Aterosclerótica/patologia , Coroa de Proteína/química , Fosfolipases Tipo C/química
5.
Langmuir ; 33(39): 10239-10247, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28882034

RESUMO

Iron oxide nanomaterial is a typical example of a magnetic resonance imaging probe for negative contrast. It has also been shown how this nanomaterial can be synthesized for positive contrast by modification of the composition and size of the core. However, the role of the organic coating in the relaxometric properties is largely unexplored. Here, maghemite nanoparticles with either excellent positive or very good negative contrast performance are obtained by modifying coating thickness while the core is kept unchanged. Different nanoparticles with tailored features as contrast agent according to the coating layer thickness have been obtained in a single-step microwave-driven synthesis by heating at different temperatures. A comprehensive analysis is conducted of how the composition and structure of the coating affects the final magnetic, relaxometric, and imaging performance. These results show how the organic coating plays a fundamental role in the intrinsic relaxometric parameters of iron oxide-based contrast media.

6.
Bioconjug Chem ; 26(1): 153-60, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25494619

RESUMO

Multifunctional nanoparticles are usually produced by sequential synthesis, with long multistep protocols. Our study reports a generic modular strategy for the parallel one-step multifunctionalization of different hydrophobic nanoparticles. The method was designed and developed by taking advantage of the natural noncovalent interactions between the fatty acid binding sites of the bovine serum albumin (BSA) and the aliphatic surfactants on different inorganic nanomaterials. As a general example of the approach, three different nanoparticles-iron oxide, upconverting nanophosphors, and gold nanospheres-were nanoemulsified in water with BSA. To support specific applications, multifunctional capability was incorporated with a variety of previously modified BSA modules. These modules include different conjugated groups, such as chelating agents for (68)Ga or (89)Zr and ligand molecules for enhanced in vivo targeting. A large library of 13 multimodal contrast agents was developed with this convergent strategy. This platform allows a highly versatile and easy tailoring option for efficient incorporation of functional groups. Finally, as demonstration of this versatility, a bimodal (PET/MRI) probe including a maleimide-conjugated BSA was selectively synthesized with an RGD peptide for in vivo imaging detection of tumor angiogenesis.


Assuntos
Meios de Contraste/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Bovinos , Meios de Contraste/farmacocinética , Meios de Contraste/toxicidade , Ácidos Graxos/metabolismo , Fibroblastos/efeitos dos fármacos , Maleimidas/química , Camundongos , Modelos Moleculares , Conformação Molecular , Nanopartículas/toxicidade , Oligopeptídeos/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Distribuição Tecidual
7.
Chemistry ; 21(29): 10450-6, 2015 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-26096657

RESUMO

The use of click chemistry reactions for the functionalization of nanoparticles is particularly useful to modify the surface in a well-defined manner and to enhance the targeting properties, thus facilitating clinical translation. Here it is demonstrated that olefin metathesis can be used for the chemoselective functionalization of iron oxide nanoparticles with three different examples. This approach enables, in one step, the synthesis and functionalization of different water-stable magnetite-based particles from oleic acid-coated counterparts. The surface of the nanoparticles was completely characterized showing how the metathesis approach introduces a large number of hydrophilic molecules on their coating layer. As an example of the possible applications of these new nanocomposites, a focus was taken on atherosclerosis plaques. It is also demonstrated how the in vitro properties of one of the probes, particularly its Ca(2+) -binding properties, mediate their final in vivo use; that is, the selective accumulation in atherosclerotic plaques. This opens promising new applications to detect possible microcalcifications associated with plaque vulnerability. The accumulation of the new imaging tracers is demonstrated by in vivo magnetic resonance imaging of carotids and aorta in the ApoE(-/-) mouse model and the results were confirmed by histology.


Assuntos
Alcenos/química , Aorta/química , Aorta/patologia , Aterosclerose/patologia , Compostos Férricos/química , Nanopartículas/química , Placa Aterosclerótica/química , Placa Aterosclerótica/patologia , Animais , Aterosclerose/diagnóstico , Química Click , Meios de Contraste , Imageamento por Ressonância Magnética , Camundongos
8.
Aging Cell ; 19(1): e13050, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31625260

RESUMO

While NLRP3-inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3-inflammasome protected mice from age-related increased insulin sensitivity, reduced IGF-1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the age-dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt-mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age-associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.


Assuntos
Sistema Cardiovascular/fisiopatologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Longevidade , Masculino , Camundongos , Transdução de Sinais
9.
Sci Rep ; 7(1): 13242, 2017 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-29038592

RESUMO

In vivo detection and quantification of inflammation is a major goal in molecular imaging. Furthermore, cell-specific detection of inflammation would be a tremendous advantage in the characterization of many diseases. Here, we show how this goal can be achieved through the synergistic combination of nanotechnology and nuclear imaging. One of the most remarkable features of this hybrid approach is the possibility to tailor the pharmacokinetics of the nanomaterial-incorporated biomolecule and radionuclide. A good example of this approach is the covalent binding of a large amount of a neutrophil-specific, hydrophobic peptide on the surface of 68Ga core-doped nanoparticles. This new nano-radiotracer has been used for non-invasive in vivo detection of acute inflammation with very high in vivo labelling efficiency, i.e. a large percentage of labelled neutrophils. Furthermore, we demonstrate that the tracer is neutrophil-specific and yields images of neutrophil recruitment of unprecedented quality. Finally, the nano-radiotracer was successfully detected in chronic inflammation in atherosclerosis-prone ApoE-/- mice after several weeks on a high-fat diet.


Assuntos
Radioisótopos de Gálio/metabolismo , Neutrófilos/metabolismo , Pneumonia/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Radioisótopos de Gálio/toxicidade , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Tomografia por Emissão de Pósitrons , Traçadores Radioativos
10.
Nanomaterials (Basel) ; 5(4): 1880-1890, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-28347101

RESUMO

Iron oxide nanoparticles have long been studied as a T2 contrast agent in MRI due to their superparamagnetic behavior. T1-based positive contrast, being much more favorable for clinical application due to brighter and more accurate signaling is, however, still limited to gadolinium- or manganese-based imaging tools. Though being the only available commercial positive-contrast agents, they lack an efficient argument when it comes to biological toxicity and their circulatory half-life in blood. The need arises to design a biocompatible contrast agent with a scope for easy surface functionalization for long circulation in blood and/or targeted imaging. We hereby propose an extremely fast microwave synthesis for fluorescein-labeled extremely-small iron oxide nanoparticles (fdIONP), in a single step, as a viable tool for cell labeling and T1-MRI. We demonstrate the capabilities of such an approach through high-quality magnetic resonance angiographic images of mice.

11.
Nanomaterials (Basel) ; 4(2): 408-438, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28344230

RESUMO

The production of magnetic nanoparticles of utmost quality for biomedical imaging requires several steps, from the synthesis of highly crystalline magnetic cores to the attachment of the different molecules on the surface. This last step probably plays the key role in the production of clinically useful nanomaterials. The attachment of the different biomolecules should be performed in a defined and controlled fashion, avoiding the random adsorption of the components that could lead to undesirable byproducts and ill-characterized surface composition. In this work, we review the process of creating new magnetic nanomaterials for imaging, particularly for the detection of atherosclerotic plaque, in vivo. Our focus will be in the different biofunctionalization techniques that we and several other groups have recently developed. Magnetic nanomaterial functionalization should be performed by chemoselective techniques. This approach will facilitate the application of these nanomaterials in the clinic, not as an exception, but as any other pharmacological compound.

12.
Br J Pharmacol ; 167(6): 1311-28, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22747838

RESUMO

BACKGROUND AND PURPOSE: MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243A > G mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors. EXPERIMENTAL APPROACH: We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease. KEY RESULTS: According to our results, supplementation with riboflavin or coenzyme Q(10) effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models. CONCLUSIONS AND IMPLICATIONS: Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment.


Assuntos
Fibroblastos , Síndrome MELAS/tratamento farmacológico , Modelos Biológicos , Saccharomyces cerevisiae , Autofagia/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Genes Mitocondriais/genética , Humanos , Mutação , RNA de Transferência de Leucina/genética , Espécies Reativas de Oxigênio , Riboflavina/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia
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