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1.
Science ; 368(6490)2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355002

RESUMO

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.


Assuntos
Adaptação Fisiológica/imunologia , Glicogênio/metabolismo , Interleucina-13/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Resistência Física/imunologia , Animais , Glicemia/metabolismo , Linhagem Celular , Ácidos Graxos/metabolismo , Feminino , Humanos , Interleucina-13/sangue , Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mioblastos/metabolismo , Oxirredução , Condicionamento Físico Animal , Corrida , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-32400164

RESUMO

Tuning the optical and electrical properties by stacking different layers of two-dimensional (2D) materials enables us to create unusual physical phenomena. Here, we demonstrate an alternative approach to enhance charge separation and alter physical properties in van der Waals heterojunctions with type-II band alignment by using thin dielectric spacers. To illustrate our working principle, we implement a hexagonal boron nitride (h-BN) sieve layer in between an InSe/GeS heterojunction. The optical transitions at the junctions studied by photoluminescence and the ultrafast pump-probe technique show quenching of emission without h-BN layers exhibiting an indirect recombination process. This quenching effect due to strong interlayer coupling was confirmed with Raman spectroscopic studies. In contrast, h-BN layers in between InSe and GeS show strong enhancement in emission, giving another degree of freedom to tune the heterojunction property. The two-terminal photoresponse study supports the argument by showing a large photocurrent density for an InSe/h-BN/GeS device by avoiding interlayer charge recombination. The enhanced charge separation with h-BN mediation manifests a photoresponsivity and detectivity of 9 × 102 A W-1 and 3.4 × 1014 Jones, respectively. Moreover, a photogain of 1.7 × 103 shows a high detection of electrons for the incident photons. Interestingly, the photovoltaic short-circuit current is switched from positive to negative, whereas the open-circuit voltage changes from negative to positive. Our proposed enhancement of charge separation with 2D-insulator mediation, therefore, provides a useful route to manipulate the physical properties of heterostructures and for the future development of high-performance optoelectronic devices.

3.
Elife ; 92020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32396064

RESUMO

Metabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-g/lipopolysaccharide (M1) and tumor-conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specific Bmal1 knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1a-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1a activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1a regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

4.
iScience ; 23(3): 100928, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32151973

RESUMO

Obesity commonly co-exists with fatty liver disease with increasing health burden worldwide. Family with Sequence Similarity 13, Member A (FAM13A) has been associated with lipid levels and fat mass by genome-wide association studies (GWAS). However, the function of FAM13A in maintaining metabolic homeostasis in vivo remains unclear. Here, we demonstrated that rs2276936 in this locus has allelic-enhancer activity in massively parallel reporter assays (MPRA) and reporter assay. The DNA region containing rs2276936 regulates expression of endogenous FAM13A in HepG2 cells. In vivo, Fam13a-/- mice are protected from high-fat diet (HFD)-induced fatty liver accompanied by increased insulin sensitivity and reduced glucose production in liver. Mechanistically, loss of Fam13a led to the activation of AMP-activated protein kinase (AMPK) and increased mitochondrial respiration in primary hepatocytes. These findings demonstrate that FAM13A mediates obesity-related dysregulation of lipid and glucose homeostasis. Targeting FAM13A might be a promising treatment of obesity and fatty liver disease.

5.
J Neurochem ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31693761

RESUMO

Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta (Aß) senile plaques in patients' brain tissues. Elevated levels of interleukin-1beta (IL-1ß) have been identified in cerebrospinal fluid of living AD patients and in animal models of AD. Increased expression of IL-1ß and iron accumulation have been identified in microglial cells that cluster around amyloid plaques in AD mouse models and post-mortem brain tissues of AD patients. The goals of this study were to determine the effects of Aß on the secretion of IL-1ß by microglial cells and whether iron status influences this pro-inflammatory signaling cue. Immortalized microglial (IMG) cells were incubated with Aß with or without iron. qRT-PCR and western blot analyses showed that Aß induces biosynthesis of IL-1ß by IMG cells. IMG cells secrete the mature form of IL-1ß in a caspase 1-dependent manner. Incubation with iron provoked a greater pro-inflammatory response. Inhibition of the iron transporter divalent metal transporter 1 protected IMG cells against Aß-induced inflammation. Potentiation of Aß-elicited IL-1ß induction by iron was also antagonized by ROS inhibitors, supporting the model that divalent metal transporter 1-mediated iron loading and subsequent increase in ROS contribute to the inflammatory effects of Aß in microglia. Immunoblotting and immunofluorescence microscopy indicate that iron enhances Aß activation of NF-κB signaling to promote IL-1ß synthesis. These results support the hypothesis that Aß stimulates IL-1ß expression by activating NF-κB signaling in microglia cells. Most importantly, iron appears to exacerbate the pro-inflammatory effects of Aß to increase IL-1ß levels.

7.
Nanomaterials (Basel) ; 9(7)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336802

RESUMO

Herein, ternary metallic nanocatalysts (NCs) consisting of Au clusters decorated with a Pt shell and a Ni oxide core underneath (called NPA) on carbon nanotube (CNT) support were synthesized by combining adsorption, precipitation, and chemical reduction methods. By a retrospective investigation of the physical structure and electrochemical results, we elucidated the effects of Pt/Ni ratios (0.4 and 1.0) and Au contents (2 and 9 wt.%) on the nanostructure and corresponding oxygen reduction reaction (ORR) activity of the NPA NCs. We found that the ORR activity of NPA NCs was mainly dominated by the Pt-shell thickness which regulated the depth and size of the surface decorated with Au clusters. In the optimal case, NPA-1004006 (with a Pt/Ni of 0.4 and Au of ~2 wt.%) showed a kinetic current (JK) of 75.02 mA cm-2 which was nearly 17-times better than that (4.37 mA cm-2) of the commercial Johnson Matthey-Pt/C (20 wt.% Pt) catalyst at 0.85 V vs. the reference hydrogen electrode. Such a high JK value resulted in substantial improvements in both the specific activity (by ~53-fold) and mass activity (by nearly 10-fold) in the same benchmark target. Those scenarios rationalize that ORR activity can be substantially improved by a syngeneic effect at heterogeneous interfaces among nanometer-sized NiOx, Pt, and Au clusters on the NC surface.

8.
ACS Appl Mater Interfaces ; 11(27): 24269-24278, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31250634

RESUMO

Two-dimensional ternary materials are attracting widespread interest because of the additional degree of freedom available to tailor the material property for a specific application. An In1-xSnxSe phototransistor possessing tunable ultrahigh mobility by Sn-doping engineering is demonstrated in this study. A striking feature of In1-xSnxSe flakes is the reduction in the oxide phase compared to undoped InSe, which is validated by spectroscopic analyses. Moreover, first-principles density functional calculations performed for the In1-xSnxSe crystal system reveal the same effective mass when doped with Sn atoms. Hence, because of an increased lifetime owing to the enhanced crystal quality, the carriers in In1-xSnxSe have higher mobility than in InSe. The internally boosted electrical properties of In1-xSnxSe exhibit ultrahigh mobility of 2560 ± 240 cm2 V-1 s-1 by suppressing the interfacial traps with substrate modification and channel encapsulation. As a phototransistor, the ultrathin In1-xSnxSe flakes are highly sensitive with a detectivity of 1014 Jones. It possesses a large photoresponsivity and photogain (Vg = 40 V) as high as 3 × 105 A W-1 and 0.5 × 106, respectively. The obtained results outperform all previously reported performances of InSe-based devices. Thus, the doping-engineered In1-xSnxSe-layered semiconductor finds a potential application in optoelectronics and meets the demand for faster electronic technology.

9.
Environ Sci Process Impacts ; 21(6): 930-937, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31089603

RESUMO

Bentonite is considered for use as a buffer material in the final disposal repositories of radioactive waste. Long-lived 135Cs with a half-life of 2.3 × 106 years is a key radionuclide in high-level waste, and lots of 137Cs with a half-life of 30.2 years exists in low-level waste. Therefore, the adsorption of Cs on bentonite is a critical issue in evaluating the long-term safety of radioactive waste disposal. In this study, EXAFS techniques were used to characterize the time-dependent process from the beginning of adsorption to equilibrium. From the results of this study, we found changes including to the Cs adsorption sites, the Cs-O distance between Cs and the oxygen atom, and that the adsorption of Cs ions occurred before the reaction reached equilibrium. The fraction of OS complexes when Cs was adsorbed on bentonite can refer to the CN (Cs-O1st)/CN (Cs-O2nd) ratio of coordination numbers, and this study found that the OS complex was the major adsorption species when Cs adsorbed onto bentonite. In addition to the ratio CN (Cs-O1st)/CN (Cs-O2nd) providing information on the adsorption site, we also discussed the change of Cs-O1st and Cs-O2nd bond distances to identify the adsorption sites at different times. Comparing the XRD patterns of montmorillonite and bentonite, we found that the interlayer collapsed after Cs was adsorbed onto montmorillonite, but it expanded after Cs was adsorbed onto bentonite. From the results of EXAFS fitting, we found that the movement of Cs ions was from regular interlayer sites to expanded interlayer sites, which caused the interatomic distance of Cs-O2nd to decrease with an increase in time. It was revealed that the adsorption of Cs on bentonite occurred in two steps. The first step includes the rapid uptake of Cs by attachment to the oxygen atoms of the H2O molecules at the regular interlayer sites, especially for the OS complexes. The second step includes a slower process where dehydrated Cs ions move from the regular interlayer sites to the expanded interlayer sites. In this study, Cs L3-edge EXAFS spectroscopy was conducted for the Cs adsorbed on bentonite to identify the Cs adsorption sites over time, as this is important in evaluating the mobility of Cs in the environment. These results are beneficial in finding the process of Cs adsorption on bentonite, which could be used for the design of the final disposal of spent nuclear fuel.


Assuntos
Bentonita/química , Radioisótopos de Césio/química , Poluentes Radioativos/química , Adsorção , Césio/química , Resíduos Radioativos , Eliminação de Resíduos/métodos
10.
J Synchrotron Radiat ; 26(Pt 1): 59-73, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30655469

RESUMO

A method based on wave optics together with electron tracking is used to analyze synchrotron radiation from a segmented undulator in a double or multi mini-ß function lattice storage ring. Radiation brilliance and transverse coherence features are investigated, where the former is calculated with the Wigner distribution function and the latter is evaluated by integrating the photon flux and cross-spectral density to exhibit the coherent flux and overall degree of coherence. To be specific, radiation properties for a single undulator in a typically single mini-ß function and a tandem undulator in a double mini-ßy lattice are compared in this work. As a result, both, brilliance and coherent flux can be enhanced by a second tandem undulator at the Taiwan Photon Source.

11.
Sensors (Basel) ; 18(9)2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30223459

RESUMO

Scanning electron microscopy has been developed for topographic analysis at the nanometer scale. Herein, we present a silicon p-n diode with multi-annular configuration to detect backscattering electrons (BSE) in a homemade desktop scanning electron microscope (SEM). The multi-annular configuration enables the enhancement of the topography contrast of 82.11 nA/µm as compared with the commercial multi-fan-shaped BSE detector of 40.08 nA/µm. Additionally, we integrated it with lateral p-n junction processing and aluminum grid structure to increase the sensitivity and efficiency of the multi-annular BSE detector that gives higher sensitivity of atomic number contrast and better surface topography contrast of BSE images for low-energy detection. The responsivity data also shows that MA-AL and MA p-n detectors have higher gain value than the MA detector does. The standard deviation of measurements is no higher than 1%. These results verify that MA p-n and MA-AL detectors are stable and can function well in SEM for low-energy applications. It is demonstrated that the multi-annular (MA) detectors are well suited for imaging in SEM systems.

12.
Nanoscale ; 10(39): 18642-18650, 2018 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-30260359

RESUMO

Flexible optoelectronic devices facilitated by the piezotronic effect have important applications in the near future in many different fields ranging from solid-state lighting to biomedicine. Two-dimensional materials possessing extraordinary mechanical strength and semiconducting properties are essential for realizing nanopiezotronics and piezo-phototronics. Here, we report the first demonstration of piezo-phototronic properties in In1-xSnxSe flexible devices by applying systematic mechanical strain under photoexcitation. Interestingly, we discover that the dark current and photocurrent are increased by five times under a bending strain of 2.7% with a maximum photoresponsivity of 1037 AW-1. In addition, the device can act as a strain sensor with a strain sensitivity up to 206. Based on these values, the device outperforms the same class of devices in two-dimensional materials. The underlying mechanism responsible for the discovered behavior can be interpreted in terms of piezoelectric potential gating, allowing the device to perform like a phototransistor. The strain-induced gate voltage assists in the efficient separation of photogenerated charge carriers and enhances the mobility of In1-xSnxSe, resulting in good performance on a freeform surface. Thus, our multifunctional device is useful for the development of a variety of advanced applications and will help meet the demand of emerging technologies.

13.
J Biol Chem ; 293(20): 7853-7863, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29610275

RESUMO

Microglia are immune cells of the central nervous system and are implicated in brain inflammation. However, how brain microglia modulate transport and metabolism of the essential metal iron in response to pro- and anti-inflammatory environmental cues is unclear. Here, we characterized uptake of transferrin (Tf)-bound iron (TBI) and non-Tf-bound iron (NTBI) by immortalized microglial (IMG) cells. We found that these cells preferentially take up NTBI in response to the proinflammatory stimulus lipopolysaccharide (LPS) or ß-amyloid (Aß). In contrast, the anti-inflammatory cytokine interleukin 4 (IL-4) promoted TBI uptake. Concordant with these functional data, levels of the Tf receptor (TfR) in IMG cells were up-regulated in response to IL-4, whereas divalent metal transporter-1 (DMT1) and ferritin levels increased in response to LPS or Aß. Similar changes in expression were confirmed in isolated primary adult mouse microglia treated with pro- or anti-inflammatory inducers. LPS-induced changes in IMG cell iron metabolism were accompanied by notable metabolic changes, including increased glycolysis and decreased oxidative respiration. Under these conditions, the extracellular acidification rate was increased, compatible with changes in the cellular microenvironment that would support the pH-dependent function of DMT1. Moreover, LPS increased heme oxygenase-1 (HO1) expression in IMG cells, and iron released because of HO1 activity increased the intracellular labile free-iron pool. Together, this evidence indicates that brain microglia preferentially acquire iron from Tf or from non-Tf sources, depending on their polarization state; that NTBI uptake is enhanced by the proinflammatory response; and that under these conditions microglia sequester both extra- and intracellular iron.


Assuntos
Proteínas de Transporte de Cátions/genética , Ferro/metabolismo , Microglia/metabolismo , Receptores da Transferrina/genética , Transferrina/genética , Peptídeos beta-Amiloides/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Transporte de Cátions/metabolismo , Linhagem Celular Transformada , Microambiente Celular , Ferritinas/genética , Ferritinas/metabolismo , Regulação da Expressão Gênica , Glicólise/efeitos dos fármacos , Glicólise/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Concentração de Íons de Hidrogênio , Inflamação , Transporte de Íons , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Microglia/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Cultura Primária de Células , Receptores da Transferrina/metabolismo , Transdução de Sinais , Transferrina/metabolismo
14.
Cell ; 173(1): 117-129.e14, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29570992

RESUMO

Angiogenesis, the formation of new blood vessels by endothelial cells (ECs), is an adaptive response to oxygen/nutrient deprivation orchestrated by vascular endothelial growth factor (VEGF) upon ischemia or exercise. Hypoxia is the best-understood trigger of VEGF expression via the transcription factor HIF1α. Nutrient deprivation is inseparable from hypoxia during ischemia, yet its role in angiogenesis is poorly characterized. Here, we identified sulfur amino acid restriction as a proangiogenic trigger, promoting increased VEGF expression, migration and sprouting in ECs in vitro, and increased capillary density in mouse skeletal muscle in vivo via the GCN2/ATF4 amino acid starvation response pathway independent of hypoxia or HIF1α. We also identified a requirement for cystathionine-γ-lyase in VEGF-dependent angiogenesis via increased hydrogen sulfide (H2S) production. H2S mediated its proangiogenic effects in part by inhibiting mitochondrial electron transport and oxidative phosphorylation, resulting in increased glucose uptake and glycolytic ATP production.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Aminoácidos Sulfúricos/deficiência , Sulfeto de Hidrogênio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator 4 Ativador da Transcrição/antagonistas & inibidores , Fator 4 Ativador da Transcrição/genética , Aminoácidos Sulfúricos/metabolismo , Animais , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Isquemia/metabolismo , Isquemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Condicionamento Físico Animal , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética
15.
Small ; 14(2)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29134759

RESUMO

One of the key challenges in artificial photosynthesis is to design a photocatalyst that can bind and activate the CO2 molecule with the smallest possible activation energy and produce selective hydrocarbon products. In this contribution, a combined experimental and computational study on Ni-nanocluster loaded black TiO2 (Ni/TiO2[Vo] ) with built-in dual active sites for selective photocatalytic CO2 conversion is reported. The findings reveal that the synergistic effects of deliberately induced Ni nanoclusters and oxygen vacancies provide (1) energetically stable CO2 binding sites with the lowest activation energy (0.08 eV), (2) highly reactive sites, (3) a fast electron transfer pathway, and (4) enhanced light harvesting by lowering the bandgap. The Ni/TiO2[Vo] photocatalyst has demonstrated highly selective and enhanced photocatalytic activity of more than 18 times higher solar fuel production than the commercial TiO2 (P-25). An insight into the mechanisms of interfacial charge transfer and product formation is explored.

16.
Mol Metab ; 6(10): 1186-1197, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29031719

RESUMO

OBJECTIVE: Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. METHODS: We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and ß-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. RESULTS: Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6-/- macrophages and to a lesser extent, in Pparδ/γ-/- macrophages. In concert, ß-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ-/- or Stat6-/- mice. CONCLUSIONS: Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.


Assuntos
Tecido Adiposo Branco/metabolismo , Ativação de Macrófagos/fisiologia , Macrófagos/fisiologia , Tecido Adiposo Branco/patologia , Animais , Apoptose/fisiologia , Morte Celular/fisiologia , Homeostase , Inflamação/metabolismo , Inflamação/patologia , Interleucina-4/metabolismo , Metabolismo dos Lipídeos , Lipólise/fisiologia , Lipopolissacarídeos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Obesidade/patologia , PPAR delta/agonistas , PPAR delta/genética , PPAR gama/agonistas , PPAR gama/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Transcriptoma
17.
Circulation ; 135(21): 2028-2040, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28280233

RESUMO

BACKGROUND: Although in vitro studies and investigations in animal models and small clinical populations have suggested that ceramides may represent an intermediate link between overnutrition and certain pathological mechanisms underlying cardiovascular disease (CVD), no prospective studies have investigated the association between plasma ceramides and risk of CVD. METHODS: The study population consisted of 980 participants from the PREDIMED trial (Prevención con Dieta Mediterránea), including 230 incident cases of CVD and 787 randomly selected participants at baseline (including 37 overlapping cases) followed for ≤7.4 years. Participants were randomized to a Mediterranean diet supplemented with extra virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Plasma ceramide concentrations were measured on a liquid chromatography tandem mass spectrometry metabolomics platform. The primary outcome was a composite of nonfatal acute myocardial infarction, nonfatal stroke, or cardiovascular death. Hazard ratios were estimated with weighted Cox regression models using Barlow weights to account for the case-cohort design. RESULTS: The multivariable hazard ratios (HR) and 95% confidence intervals (CIs) comparing the extreme quartiles of plasma concentrations of C16:0, C22:0, C24:0, and C24:1 ceramides were 2.39 (1.49-3.83, Ptrend<0.001), 1.91 (1.21-3.01, Ptrend=0.003), 1.97 (1.21-3.20, Ptrend=0.004), and 1.73 (1.09-2.74, Ptrend=0.011), respectively. The ceramide score, calculated as a weighted sum of concentrations of four ceramides, was associated with a 2.18-fold higher risk of CVD across extreme quartiles (HR, 2.18; 95% CI, 1.36-3.49; Ptrend<0.001). The association between baseline ceramide score and incident CVD varied significantly by treatment groups (Pinteraction=0.010). Participants with a higher ceramide score and assigned to either of the 2 active intervention arms of the trial showed similar CVD risk to those with a lower ceramide score, whereas participants with a higher ceramide score and assigned to the control arm presented significantly higher CVD risk. Changes in ceramide concentration were not significantly different between Mediterranean diet and control groups during the first year of follow-up. CONCLUSIONS: Our study documented a novel positive association between baseline plasma ceramide concentrations and incident CVD. In addition, a Mediterranean dietary intervention may mitigate potential deleterious effects of elevated plasma ceramide concentrations on CVD. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN35739639.


Assuntos
Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Ceramidas/sangue , Dieta Mediterrânea , Comportamento de Redução do Risco , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Cromatografia Líquida , Feminino , Humanos , Incidência , Modelos Lineares , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Análise Multivariada , Nozes , Azeite de Oliva , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de Risco , Espanha/epidemiologia , Espectrometria de Massas em Tandem , Fatores de Tempo
18.
Am J Respir Cell Mol Biol ; 56(6): 738-748, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28199134

RESUMO

Bioenergetics homeostasis is important for cells to sustain normal functions and defend against injury. The genetic controls of bioenergetics homeostasis, especially lipid metabolism, remain poorly understood in chronic obstructive pulmonary disease (COPD), the third leading cause of death in the world. Additionally, the biological function of most of the susceptibility genes identified from genome-wide association studies (GWASs) in COPD remains unclear. Here, we aimed to address (1) how fatty acid oxidation (FAO), specifically ß-oxidation, a key lipid metabolism pathway that provides energy to cells, contributes to cigarette smoke (CS)-induced COPD; and (2) whether-and if so, how-FAM13A (family with sequence similarity 13 member A), a well-replicated COPD GWAS gene, modulates the FAO pathway. We demonstrated that CS induced expression of carnitine palmitoyltransferase 1A (CPT1A), a key mitochondrial enzyme for the FAO pathway, thereby enhancing FAO. Pharmacological inhibition of FAO by etomoxir blunted CS-induced reactive oxygen species accumulation and cell death in lung epithelial cells. FAM13A promoted FAO, possibly by interacting with and activating sirutin 1, and increasing expression of CPT1A. Furthermore, CS-induced cell death was reduced in lungs from Fam13a-/- mice. Our results suggest that FAM13A, the COPD GWAS gene, shapes the cellular metabolic response to CS exposure by promoting the FAO pathway, which may contribute to COPD development.


Assuntos
Ácidos Graxos/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Acetilação , Animais , Brônquios/patologia , Carnitina O-Palmitoiltransferase/metabolismo , Morte Celular , Respiração Celular , Células Epiteliais/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Inativação Gênica , Humanos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Oxirredução , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo , Fumar/efeitos adversos
19.
Sci Rep ; 6: 36144, 2016 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-27824073

RESUMO

Several observations of the Nb long-lived Mossbauer phenomena are presented, in consequence of an irradiation increased by an order of magnitude compared with previous work. These are 1) two ß decays of 182Ta and 92mNb are enhanced, i.e., 182Ta is now 200 times faster than in previous results while 92mNb is twice as fast as normal; 2) γs emitted from two ß decays compete to eject electrons in a winner-takes-all rule, rather than by superposition; 3) abrupt spectral changes reveal three decay phases of 182Ta; 4) the biphoton γγ of 93mNb is released from the sample for the first time; 5) the γγ distribution is narrow, in contrast to the broad γγ spectrum obtained from independent nuclei; 6) Nb K-lines super-radiate along the long sample axis; 7) collective scattering of multipolar MeV γs. The manipulation of nuclear decay speeds demonstrated here highlights a potential application of this work in cleaning up the nuclear wastes.

20.
Immunity ; 45(3): 461-463, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27653596

RESUMO

Obesity shifts the immune phenotype from M2 macrophage polarization to M1, which causes metabolic dysfunction. In this issue of Immunity, Kumamoto et al. (2016) identify a tissue-resident mononuclear phagocyte population that promotes weight gain and glucose intolerance but are defined by the M2 marker CD301b.


Assuntos
Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Fagócitos/imunologia , Fagócitos/metabolismo , Animais , Biomarcadores/metabolismo , Intolerância à Glucose/imunologia , Humanos , Lectinas Tipo C/imunologia , Ganho de Peso/imunologia
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