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BACKGROUND: Akt signalling regulates glycolysis and drives the Warburg effect in cancer, thus decreased glucose utilisation is a pharmacodynamic marker of Akt inhibition. However, cancer cells can utilise alternative nutrients to glucose for energy such as lactate, which is often elevated in tumours together with increased acidity. We therefore hypothesised that lactic acidosis may confer resistance to Akt inhibition. METHODS: The effect of the pan-Akt inhibitor uprosertib (GSK2141795), on HCT116 and LS174T colon cancer cells was evaluated in the presence and absence of lactic acid in vitro. Expression of downstream Akt signalling proteins was determined using a phosphokinase array and immunoblotting. Metabolism was assessed using 1H nuclear magnetic resonance spectroscopy, stable isotope labelling and gas chromatography-mass spectrometry. RESULTS: Lactic acid-induced resistance to uprosertib was characterised by increased cell survival and reduced apoptosis. Uprosertib treatment reduced Akt signalling and glucose uptake irrespective of lactic acid supplementation. However, incorporation of lactate carbon and enhanced respiration was maintained in the presence of uprosertib and lactic acid. Inhibiting lactate transport or oxidative phosphorylation was sufficient to potentiate apoptosis in the presence of uprosertib. CONCLUSIONS: Lactic acidosis confers resistance to uprosertib, which can be reversed by inhibiting lactate transport or oxidative metabolism.
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Acidosis Láctica/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Proteína Oncogénica v-akt/genética , Acidosis Láctica/genética , Acidosis Láctica/metabolismo , Acidosis Láctica/patología , Inhibidores de la Angiogénesis/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Diaminas/farmacología , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Células HCT116 , Humanos , Ácido Láctico/farmacología , Proteína Oncogénica v-akt/antagonistas & inhibidores , Fosforilación Oxidativa/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Interleukin-6 (IL-6) is implicated in multiple biological functions including immunity, neural development, and haematopoiesis. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially lipid metabolic homeostasis. A working heart requires a high and constant energy input which is largely generated by fatty acid (FA) ß-oxidation. Under pathological conditions, the precise balance between cardiac FA uptake and metabolism is perturbed so that excessive FA is accumulated, thereby predisposing to myocardial dysfunction (cardiac lipotoxicity). In this review, we summarize the current evidence that suggests the involvement of IL-6 in lipid metabolism. Cardiac metabolic features and consequences of myocardial lipotoxicity are also briefly analyzed. Finally, the roles of IL-6 in cardiac FA uptake (i.e., serum lipid profile and myocardial FA transporters) and FA metabolism (namely, ß-oxidation, mitochondrial function, biogenesis, and FA de novo synthesis) are discussed. Overall, understanding how IL-6 transmits signals to affect lipid metabolism in the heart might allow for development of better clinical therapies for obesity-associated cardiac lipotoxicity.
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Cardiomiopatías/metabolismo , Ácidos Grasos/metabolismo , Homeostasis/genética , Interleucina-6/metabolismo , Miocardio/metabolismo , Obesidad/metabolismo , Animales , Transporte Biológico , Cardiomiopatías/genética , Cardiomiopatías/patología , Transporte de Electrón , Regulación de la Expresión Génica , Humanos , Interleucina-6/genética , Metabolismo de los Lípidos/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Miocardio/patología , Obesidad/genética , Obesidad/patología , Biogénesis de Organelos , Oxidación-ReducciónRESUMEN
Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 µg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro. Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.
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Angiotensina II/administración & dosificación , Cardiomiopatías/inmunología , Cardiomiopatías/patología , Interleucina-6/inmunología , Miocitos Cardíacos/inmunología , Miocitos Cardíacos/patología , Factor de Transcripción STAT3/inmunología , Animales , Cardiomiopatías/inducido químicamente , Células Cultivadas , Hipertrofia/inmunología , Hipertrofia/patología , Interleucina-6/genética , Masculino , Ratones , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacosRESUMEN
Protein kinase B2 (AKT2) is implicated in diverse process of cardiomyocyte signaling including survival and metabolism. However, the role of AKT2 in myocardium development and the signaling pathway is rarely understood. Therefore, we sought to determine the effect of AKT2 deletion on heart development and its downstream targets. By using experimental animal models and neonatal rat cardiomyocytes (NRCMs), we observed that AKT2 deficiency induces retardation of heart development and increased systemic blood pressure (BP) without affecting cardiac function. Further investigation suggested that deficiency of AKT2 in myocardium results in diminished MEF2A abundance, which induced decreased size of cardiomyocytes. We additionally confirmed that EndoG, which is also regulated by AKT2, is a suppressor of MEF2A in myocardium. Finally, our results proved that AKT2 deficiency impairs the response to ß-adrenergic stimuli that normally causes hypertrophy in cardiomyocytes by downregulating MEF2A expression. Our data are the first to show the important role of AKT2 in determining the size of myocardium, its deficiency causes retardation of cardiomyocyte development. We also proved a novel pathway of heart development involving EndoG and MEF2A regulated by AKT2.
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Endodesoxirribonucleasas/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/deficiencia , Animales , Diferenciación Celular , Tamaño de la Célula , Células Cultivadas , Endodesoxirribonucleasas/antagonistas & inhibidores , Endodesoxirribonucleasas/genética , Técnicas de Silenciamiento del Gen , Corazón/crecimiento & desarrollo , Factores de Transcripción MEF2/antagonistas & inhibidores , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Ratones , Ratones Noqueados , Miocardio/citología , Miocardio/metabolismo , Miocitos Cardíacos/citología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , ARN Interferente Pequeño/genética , Ratas , Transducción de SeñalRESUMEN
OBJECTIVE: Obesity is associated with metabolic disorder and chronic inflammation that plays a crucial role in cardiovascular diseases. IL-6 is involved in regulating obesity-related lipid metabolism and inflammation. In this study, we sought to determine the role of IL-6 in high-fat diet (HFD)-induced cardiomyopathy and explore the signaling pathway. METHODS: Female, 5-week-old IL-6 knockout (KO) and littermate mice were fed a normal diet (ND, 10% fat) or HFD (45% fat) for 14 weeks. At the end of treatment, cardiac function was assessed by echocardiography. Adipose tissues and plasma were collected for further measurement. Immunohistology of CD68 was performed to detect inflammation in the heart. Masson's trichrome staining and Oil Red O staining was applied to evaluated cardiac fibrosis and lipid accumulation. Real-time PCR and Western immunoblotting analyses on heart tissue were used to explore the underlying mechanism. RESULTS: IL-6 KO mice displayed increased insulin resistance compared to WT mice at baseline. When fed HFD, IL-6 KO mice showed decreased gains in body weight and fat mass, increased insulin resistance relative to IL-6 KO mice feed ND. Furthermore, IL-6 KO mice developed cardiac dysfunction during HFD-induced obesity. Histological analysis suggested increased lipid accumulation, fibrosis and inflammation without affecting cardiac morphology during HFD treatment in the heart of IL-6 KO mice. Finally, IL-6 deficiency increased the phosphorylation of AMPK and ACC in the heart during HFD-induced obesity. CONCLUSION: Our results suggest that IL-6 contributes to limit lipid metabolic disorder, cardiac hypertrophy, fibrosis, inflammation and myocardium lipotoxicity during HFD-induced obesity.
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Interleucina-6/deficiencia , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Cardiomegalia/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatías/fisiopatología , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Femenino , Fibrosis/metabolismo , Fibrosis/fisiopatología , Técnicas de Inactivación de Genes , Corazón/fisiopatología , Inflamación/metabolismo , Inflamación/patología , Resistencia a la Insulina , Interleucina-6/genética , Interleucina-6/metabolismo , Metabolismo de los Lípidos , Ratones , Ratones Noqueados , Miocardio/metabolismo , Miocardio/patología , Obesidad/fisiopatología , FosforilaciónRESUMEN
The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2-/-) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.
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Factor Inductor de la Apoptosis/metabolismo , Apoptosis , Núcleo Celular/metabolismo , Endodesoxirribonucleasas/metabolismo , Isquemia Miocárdica/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transporte Activo de Núcleo Celular , Animales , Caspasas/metabolismo , Hipoxia de la Célula , Células Cultivadas , Citocromos c/metabolismo , Fragmentación del ADN , Células HEK293 , Humanos , Ratones , Mitocondrias Cardíacas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Ratas , Ratas Sprague-DawleyRESUMEN
The aetiology of every human disease lies in a combination of genetic and environmental factors, each contributing in varying proportions. While genomics investigates the former, a comparable holistic paradigm was proposed for environmental exposures in 2005, marking the onset of exposome research. Since then, the exposome definition has broadened to include a wide array of physical, chemical, and psychosocial factors that interact with the human body and potentially alter the epigenome, the transcriptome, the proteome, and the metabolome. The chemical exposome, deeply intertwined with the metabolome, includes all small molecules originating from diet as well as pharmaceuticals, personal care and consumer products, or pollutants in air and water. The set of techniques to interrogate these exposures, primarily mass spectrometry and nuclear magnetic resonance spectroscopy, are also extensively used in metabolomics. Recent advances in untargeted metabolomics using high resolution mass spectrometry have paved the way for the development of methods able to provide in depth characterisation of both the internal chemical exposome and the endogenous metabolome simultaneously. Herein we review the available tools, databases, and workflows currently available for such work, and discuss how these can bridge the gap between the study of the metabolome and the exposome.
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Contaminantes Ambientales , Exposoma , Humanos , Exposición a Riesgos Ambientales/efectos adversos , Metaboloma , Metabolómica/métodosRESUMEN
Modifying the environment around particles (e.g., introducing a secondary phase or external field) can affect the way they interact and assemble, thereby giving control over the physical properties of a dynamic system. Here, graphene oxide (GO) photonic liquids that respond to a magnetic field are demonstrated for the first time. Magnetic nanoparticles are used to provide a continuous magnetizable liquid environment around the GO liquid crystalline domains. In response to a magnetic field, the alignment of magnetic nanoparticles, coupled with the diamagnetic property of GO nanosheets, drives the reorientation and alignment of the nanosheets, enabling switchable photonic properties using a permanent magnet. This phenomenon is anticipated to be extendable to other relevant photonic systems of shape-anisotropic nanoparticles and may open up opportunities for developing GO-based optical materials and devices.
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Stimulus-responsive materials that display circularly polarized luminescence (CPL) have attracted great attention for application in chiral sensors and smart displays. However, due to difficulties in the regulation of chiral structures, fine control of CPL remains a challenge. Here, it is demonstrated that cellulose nanocrystal shape-memory polymers (CNC-SMPs) with luminescent components enable mechanically responsive CPL. The chiral nematic organization of CNCs in the material gives rise to a photonic bandgap. By manipulating the photonic bandgap or luminescence wavelengths of the luminescent CNC-SMPs, precise control of CPL emission with varied wavelengths and high dissymmetry factors (glum ) is achieved. Specifically, CPL emission can be switched reversibly by treating the luminescent CNC-SMPs with hot-pressing and recovery by heating. Pressure-responsive CPL with tunable glum values is ascribed to the pressure-responsive photonic bandgaps. Moreover, colorimetric and CPL-active patterns are created by imprinting desired forms into SMP samples. This study demonstrates a novel way to fabricate smart CPL systems using biomaterials.
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Biological systems exploit restricted degrees of freedom to drive self-assembly of nano- and microarchitectures. Simplified systems, such as colloidal nanoparticles that behave as lyotropic liquid crystalline mesophases in confined geometric spaces, may be used to mimic biological structures. Cellulose nanocrystals (CNCs) are colloidally stable nanoparticles that self-assemble into chiral nematic (ChN) liquid crystalline mesophases. To date, the self-assembly of ChN mesophases of CNCs has been studied under confinement conditions within curved surfaces or under drying conditions that impose curvatures that can be exploited to control ChN ordering; however, their self-assembly has not been investigated in geometries with square cross-sections under static conditions. Here, we show that because of surface anchoring on perpendicular surfaces, the ChN CNC phase is unable to bend with the 90° angle of the square capillary under increasing confinement. Instead, the ChN phase forms radial layers in the shape of concentric squircle shells. With increasing layer distance from the capillary wall, the squircles transition into concentric cylinder shells. In larger capillaries, the radial shell layers appear as a continuous spiral pattern that engulfs fragmented ChN pseudolayers, a defect to accommodate the cylindrical confinement of the mesophase. These results are useful for understanding the fundamentals of self-assembling systems and development of new technologies.
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Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and a poor prognosis. In recent years, poly-ADP ribose polymerase (PARP) inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation, and subsequent RNA splicing defects. In this work, we demonstrate that the loss of RBM39 induces splicing defects in key DNA damage repair genes in ovarian cancer, leading to increased sensitivity to cisplatin and various PARP inhibitors. The addition of indisulam also improved olaparib response in mice bearing PARP inhibitor-resistant tumors. These findings demonstrate that combining RBM39 degraders and PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.
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Antineoplásicos , Neoplasias Ováricas , Femenino , Humanos , Animales , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteína BRCA1/genética , Mutación , Factores de Empalme de ARN/genética , ARN , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Empalme del ARN , Ftalazinas/farmacología , Ftalazinas/uso terapéuticoRESUMEN
Graphene oxide (GO) is an important nanomaterial for producing photonic liquids due to its ability to display full-color reflections in water. However, the poor stability of GO photonic liquids and unsatisfactory dispersibility of GO nanosheets in hydrophobic liquid media have been significant drawbacks to developing photonic materials based on GO. Here, stable GO hydrophobic photonic liquids are demonstrated for the first time. GO nanosheets are directed into different hydrophobic liquid media, including reactive liquid precursors like tetraethoxysilane and ethyl acrylate, in the presence of phase transfer additives. These liquids exhibit tunable reflection wavelength up to â¼1300 nm with improved stability relative to aqueous GO photonic suspensions at elevated temperatures or under ambient conditions. Supported by an entropy-driven depletion mechanism, hydrophobic additives can effectively mediate the self-assembly of GO to produce tunable photonic liquids without the need to adjust GO concentrations. Furthermore, simultaneous infrared and visible light reflection can be achieved, enabling infrared photonic GO liquids to display visible colors. The improved stability and tunable photonic properties of hydrophobic GO liquids will open a way for developing GO-based optical materials and devices.
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Photonic materials that can selectively reflect light across the visible spectrum are valuable for applications in optical devices, sensors, and decoration. Although two-dimensional (2D) colloids that stack into layers with spacing of hundreds of nanometers are able to selectively diffract light, controlling their separation in solution has proven challenging. In this work, we investigate the role of additives to control the photonic properties of hybrid colloidal suspensions of graphene oxide (GO). We discovered that low concentrations of colloidal additives like cellulose nanocrystals (CNCs) and clay nanoparticles (hectorite) added to GO suspensions lead to dramatic color changes. These hybrid colloidal suspensions demonstrate tunable structural colors and temperature-sensitive properties that likely originate from the entropically driven ejection of guests between the sheets, and from the interactions between colloidal electrical double layers and additional counterions. On the other hand, blending polymeric or molecular additives with GO suspensions either deteriorates or does not impact the photonic properties. These results are helpful to understand the interaction between GO suspensions and additives over different length scales, and open a path to advancing photonic materials based on hybrid colloidal suspensions.
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Hierarchical biological materials, such as osteons and plant cell walls, are complex structures that are difficult to mimic. Here, we combine liquid crystal systems and polymerization techniques within confined systems to develop complex structures. A single-domain concentric chiral nematic polymeric fiber was obtained by confining cellulose nanocrystals (CNCs) and hydroxyethyl acrylate inside a capillary tube followed by UV-initiated polymerization. The concentric chiral nematic structure continues uniformly throughout the length of the fiber. The pitch of the chiral nematic structure could be controlled by changing the CNC concentration. We tracked the formation of the concentric structure over time and under different conditions with variation of the tube orientation, CNC concentration, CNC type, and capillary tube size. We show that the inner radius of the capillary tube is important and a single-domain structure was only obtained inside small-diameter tubes. At low CNC concentration, the concentric chiral nematic structure did not completely cover the cross-section of the fiber. The highly ordered structure was studied using imaging techniques and X-ray diffraction, and the mechanical properties and structure of the chiral nematic fiber were compared to a pseudo-nematic fiber. CNC polymeric fibers could become a platform for many applications from photonics to complex hierarchical materials.
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Deep neural networks (DNNs) are vulnerable to adversarial examples where inputs with imperceptible perturbations mislead DNNs to incorrect results. Despite the potential risk they bring, adversarial examples are also valuable for providing insights into the weakness and blind-spots of DNNs. Thus, the interpretability of a DNN in the adversarial setting aims to explain the rationale behind its decision-making process and makes deeper understanding which results in better practical applications. To address this issue, we try to explain adversarial robustness for deep models from a new perspective of neuron sensitivity which is measured by neuron behavior variation intensity against benign and adversarial examples. In this paper, we first draw the close connection between adversarial robustness and neuron sensitivities, as sensitive neurons make the most non-trivial contributions to model predictions in the adversarial setting. Based on that, we further propose to improve adversarial robustness by stabilizing the behaviors of sensitive neurons. Moreover, we demonstrate that state-of-the-art adversarial training methods improve model robustness by reducing neuron sensitivities, which in turn confirms the strong connections between adversarial robustness and neuron sensitivity. Extensive experiments on various datasets demonstrate that our algorithm effectively achieves excellent results. To the best of our knowledge, we are the first to study adversarial robustness using neuron sensitivities.
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Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Modelos Neurológicos , Algoritmos , Inteligencia ArtificialRESUMEN
Interfaces of metal-oxide heterostructured electrocatalyst are critical to their catalytic activities due to the significant interfacial effects. However, there are still obscurities in the essence of interfacial effects caused by crystalline defects and mismatch of electronic structure at metal-oxide nanojunctions. To deeply understand the interfacial effects, we engineered crystalline-defect Pd-Cu2O interfaces through non-epitaxial growth by a facile redox route. The Pd-Cu2O nanoheterostructures exhibit much higher electrocatalytic activity toward glucose oxidation than their single counterparts and their physical mixture, which makes it have a promising potential for practical application of glucose biosensors. Experimental study and density functional theory (DFT) calculations demonstrated that the interfacial electron accumulation and the shifting up of d bands center of Cu-Pd toward the Fermi level were responsible for excellent electrocatalytic activity. Further study found that Pd(3â¯1â¯0) facets exert a strong metal-oxide interface interaction with Cu2O(1â¯1â¯1) facets due to their lattice mismatch. This leads to the sinking of O atoms and protruding of Cu atoms of Cu2O, and the Pd crystalline defects, further resulting in electron accumulation at the interface and the shifting up of d bands center of Cu-Pd, which is different from previously reported charge transfer between the interfaces. Our findings could contribute to design and development of advanced metal-oxide heterostructured electrocatalysts.
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BACKGROUND: NF-E2-related factor 2 (Nrf2) is a transcription factor playing cytoprotective effects in various pathological processes including oxidative stress and cardiac hypertrophy. Despite being a potential therapeutic target to treat several cardiomyopathies, the signaling underlying Nrf2-dependent cardioprotective action remains largely uncharacterized. AIM: This study aimed to explore the signaling mediating the role of Nrf2 in the development of hypertensive cardiac pathogenesis by analyzing the response to Angiotensin II (Ang II) in the presence or absence of Nrf2 expression, both in vivo and in vitro. RESULTS: Our results indicated that Nrf2 deficiency exacerbated cardiac damage triggered by Ang II infusion. Mechanistically, our study shows that Ang II-triggered hypertrophy and inflammation is exacerbated in the absence of Nrf2 expression and points to the involvement of the IL-6/STAT3 signaling pathway in this event. Indeed, our results show that IL-6 abundance triggered by Ang II is increased in the absence of Nrf2 and demonstrate the requirement of IL-6 in STAT3 activation and cardiac inflammation induced by Ang II. CONCLUSION: Our results show that Nrf2 is important for the protection of the heart against Ang II-induced cardiac hypertrophy and inflammation by mechanisms involving the regulation of IL-6/STAT3-dependent signaling.
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Cardiomegalia/metabolismo , Inflamación/metabolismo , Interleucina-6/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Transcripción STAT3/metabolismo , Angiotensina II , Animales , Animales Recién Nacidos , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Células Cultivadas , Inflamación/inducido químicamente , Inflamación/genética , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Ratas Sprague-Dawley , Transducción de Señal/genéticaRESUMEN
Novel aerogel materials with periodic structures derived from chiral nematic liquid crystalline cellulose nanocrystals (CNCs) are reported. The liquid crystalline structure of phase-separated CNCs is locked by a simple solvent exchange method or silica condensation. Both cellulose and silica/cellulose aerogel materials were obtained after critical point drying, and subsequent calcination of the silica/cellulose composite afforded a silica aerogel with periodic order. Gas adsorption and electron microscopy studies revealed that these materials have high surface areas and a unique chiral nematic structure imparted from the helicoidal CNC template. This is a new, scalable approach to aerogel materials with highly anisotropic structures. The high porosity and periodic, chiral features of these new materials may make them suitable for applications that require anisotropic properties or as hard templates for the construction of other ordered aerogels.
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OBJECTIVE: Protein kinase B2 (AKT2) is implicated in cardiomyocyte survival during various stress conditions. However, the role of AKT2 in heart function, cardiac hypertrophy and blood pressure (BP) control during hypertension is not fully understood. Therefore, we sought to determine whether the deletion of AKT2 protects cardiac function during angiotensin II/high-salt-diet (AngII/HSD) treatment and find out the signaling pathway. METHODS: Male C57BL/6J (wild type), AKT2 knockout and interleukin (IL)-6 knockout mice were fed a 4% NaCl diet for 5 weeks. In the last week, mice were split in two groups and infused subcutaneously with either vehicle or AngII (1.5âµg/h per mouse) for 1 week. Then, BP and cardiac function were assessed. Immunohistology of IL-6 and monocyte chemoattractant protein 1 was performed to detect inflammation in the heart. Masson's trichrome staining was performed to evaluate cardiac fibrosis. Heart tissue homogenates and neonatal mice cardiomyocytes were collected to analyze oxidative stress. RESULTS: Compared with wild-type mice, AKT2 knockout mice maintained BP and showed better left ventricle ejection fraction, lower level of fibrosis, reduced oxidative stress, reduced IL-6 expression and less macrophage infiltration, when treated with AngII/HSD. IL-6 knockout mice treated with AngII/HSD also showed alleviated left ventricular function, fibrosis, oxidative stress and macrophage infiltration compared with wild type. CONCLUSION: AKT2 deficiency prevents the development of AngII/HSD-induced hypertension, cardiac dysfunction and myocardial injury including oxidative stress, fibrosis and inflammation by suppressing IL-6 expression. These data reveal an important role of the AKT2-IL-6 pathway in mediating AngII/HSD-induced hypertension and cardiomyopathy.