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Many studies have explored the relationship between metacognition and academic achievement in mathematics, but the results vary. In this study, meta-analysis was used to explore this relationship between metacognition and academic achievement in mathematics and influencing factors. According to the literature search, a total of 147 studies (1986-2024) and 338 independent samples met the inclusion criteria (n = 698,096). The results revealed metacognition was significantly positively correlated with academic achievement in mathematics, r = 0.32, 95 % CI [0.30, 0.34], Z = 28.49. Moreover, the moderating effects of age, domain, and culture were significant (p < 0.01). In conclusion, Metacognition is closely associated with academic achievement in mathematics but also that age, domain, and culture have a considerable impact on their relationship. More specifically, the degree of correlation between metacognition and academic achievement in mathematics was on the rise from preschool to high school, while it was lower in college. Compared with general field metacognition, mathematical metacognition is more closely linked to mathematics academic achievement. Lastly, compared with British and American countries, Chinese metacognition was more closely related to academic achievement in mathematics.
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BACKGROUND: Perianal fistulas pose dual challenges to Crohn's disease (CD) patients. Low patient compliance due to the complexity of existing examination methods plagues the treatment and follow-up management of perianal CD. AIM: To determine the accuracy of endoanal ultrasound (EUS) and shear wave elastography (SWE) for evaluating perianal fistulizing CD (PFCD) activity. METHODS: This was a retrospective cohort study. A total of 67 patients from August 2022 to December 2023 diagnosed with CD were divided into three groups: Non-anal fistula group (n = 23), low-activity perianal fistulas [n = 19, perianal disease activity index (PDAI) ≤ 4], high-activity perianal fistulas (n = 25, PDAI > 4) based on the PDAI. All patients underwent assessments including EUS + SWE, pelvic magnetic resonance [pelvic magnetic resonance imaging (MRI)], C-reactive protein, fecal calprotectin, CD activity index, PDAI. RESULTS: The percentage of fistulas indicated by pelvic MRI and EUS was consistent at 82%, and there was good consistency in the classification of perianal fistulas (Kappa = 0.752, P < 0.001). Significant differences were observed in the blood flow Limberg score (χ 2 = 8.903, P < 0.05) and shear wave velocity (t = 2.467, P < 0.05) between group 2 and 3. Shear wave velocity showed a strong negative correlation with magnetic resonance novel index for fistula imaging in CD (Magnifi-CD) score (r = -0.676, P < 0.001), a weak negative correlation with the PDAI score (r = -0.386, P < 0.05), and a weak correlation between the Limberg score and the PDAI score (r = 0.368, P < 0.05). CONCLUSION: EUS combined with SWE offers a superior method for detecting and quantitating the activity of perianal fistulas in CD patients. It may be the ideal tool to assess PFCD activity objectively for management strategies.
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Purpose: While previous research has highlighted the influence of family, school, and peer factors on smartphone addiction and sleep quality, the cumulative effects of these risk factors and their underlying causal relationships remain poorly understood. Therefore, based on the cumulative risk model and the bioecological model of human development, this study examined the longitudinal associations between cumulative ecological risk and smartphone addiction and sleep quality. Methods: A survey was conducted among 653 Chinese university freshmen (mean age 18.56) at two distinct time points, with a 6-month interval. The initial assessment focused on family, school, and peer risk factors, while the subsequent assessment focused on smartphone addiction and sleep quality. Results: Approximately 63.71% of university freshmen were found to be at risk of exposure. Compared to other risk-exposure groups, the group with no-risk exposure exhibited the lowest scores for smartphone addiction and sleep quality. The relationships between cumulative ecological risk and smartphone addiction and sleep quality displayed a linear pattern and a discernible "gradient effect". Smartphone addiction was identified as a fully mediating factor in the link between cumulative ecological risk and sleep quality, with a mediating effect value of 0.08 (representing 44.44% of the total effect). Conclusion: University freshmen face various risks associated with their families, schools, and peers. The cumulative ecological risk can, directly and indirectly, impact sleep quality by influencing smartphone addiction. Given the observed "gradient effect" of cumulative ecological risk on smartphone addiction and sleep quality, it is imperative to adopt comprehensive risk prevention strategies to mitigate the impact of each risk factor.
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Globally increased nitrogen (N) to phosphorus (P) ratios (N/P) affect the structure and functioning of terrestrial ecosystems, but few studies have addressed the variation of foliar N/P over time in subtropical forests. Foliar N/P indicates N versus P limitation in terrestrial ecosystems. Quantifying long-term dynamics of foliar N/P and their potential drivers is crucial for predicting nutrient status and functioning in forest ecosystems under global change. We detected temporal trends of foliar N/P, quantitatively estimated their potential drivers and their interaction between plant types (evergreen vs. deciduous and trees vs. shrubs), using 1811 herbarium specimens of 12 widely distributed species collected during 1920-2010 across China's subtropical forests. We found significant decreases in foliar P concentrations (23.1%) and increases in foliar N/P (21.2%). Foliar N/P increased more in evergreen species (22.9%) than in deciduous species (16.9%). Changes in atmospheric CO2 concentrations ( P CO 2 $$ {\mathrm{P}}_{{\mathrm{CO}}_2} $$ ), atmospheric N deposition and mean annual temperature (MAT) dominantly contributed to the increased foliar N/P of evergreen species, while P CO 2 $$ {\mathrm{P}}_{{\mathrm{CO}}_2} $$ , MAT, and vapor pressure deficit, to that of deciduous species. Under future Shared Socioeconomic Pathway (SSP) scenarios, increasing MAT and P CO 2 $$ {\mathrm{P}}_{{\mathrm{CO}}_2} $$ would continuously increase more foliar N/P in deciduous species than in evergreen species, with more 12.9%, 17.7%, and 19.4% versus 6.1%, 7.9%, and 8.9% of magnitudes under the scenarios of SSP1-2.6, SSP3-7.0, and SSP5-8.5, respectively. The results suggest that global change has intensified and will progressively aggravate N-P imbalance, further altering community composition and ecosystem functioning of subtropical forests.
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Ecosistema , Bosques , Nitrógeno , Fósforo , ChinaRESUMEN
BACKGROUND: Cine magnetic resonance (MR) images have been used for real-time MR guided radiation therapy (MRgRT). However, the onboard MR systems with low-field strength face the problem of limited image quality. PURPOSE: To improve the quality of cine MR images in MRgRT using prior image information provided by the patient planning and positioning MR images. METHODS: This study employed MR images from 18 pancreatic cancer patients who received MR-guided stereotactic body radiation therapy. Planning 3D MR images were acquired during the patient simulation, and positioning 3D MR images and 2D sagittal cine MR images were acquired before and during the beam delivery, respectively. A deep learning-based framework consisting of two cycle generative adversarial networks (CycleGAN), Denoising CycleGAN and Enhancement CycleGAN, was developed to establish the mapping between the 3D and 2D MR images. The Denoising CycleGAN was trained to first denoise the cine images using the time domain cine image series, and the Enhancement CycleGAN was trained to enhance the spatial resolution and contrast by taking advantage of the prior image information from the planning and positioning images. The denoising performance was assessed by signal-to-noise ratio (SNR), structural similarity index measure, peak SNR, blind/reference-less image spatial quality evaluator (BRISQUE), natural image quality evaluator, and perception-based image quality evaluator scores. The quality enhancement performance was assessed by the BRISQUE and physician visual scores. In addition, the target contouring was evaluated on the original and processed images. RESULTS: Significant differences were found for all evaluation metrics after Denoising CycleGAN processing. The BRISQUE and visual scores were also significantly improved after sequential Denoising and Enhancement CycleGAN processing. In target contouring evaluation, Dice similarity coefficient, centroid distance, Hausdorff distance, and average surface distance values were significantly improved on the enhanced images. The whole processing time was within 20 ms for a typical input image size of 512 × 512. CONCLUSION: Taking advantage of the prior high-quality positioning and planning MR images, the deep learning-based framework enhanced the cine MR image quality significantly, leading to improved accuracy in automatic target contouring. With the merits of both high computational efficiency and considerable image quality enhancement, the proposed method may hold important clinical implication for real-time MRgRT.
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Background: Transcranial direct current stimulation (tDCS) applied to particular brain areas may reduce a smoker's smoking cravings. Most studies on tDCS mechanisms are performed on brains in the resting state. Therefore, brain activity changes induced by tDCS during tasks need to be further studied. Methods: Forty-six male smokers were randomised to receive anodal tDCS of the left/right dorsolateral prefrontal cortex (DLPFC) or sham tDCS. A go/no-go task was performed before and after stimulation, respectively. Brain activity and functional connectivity (FC) changes during the task state before and after tDCS were used for comparison. Results: This study revealed that the anodal stimulation over one DLPFC area caused decreased activity in the ipsilateral precuneus during the go task state. Right DLPFC stimulation increased the FC between the bilateral DLPFCs and the right anterior cingulate cortex (ACC), which is closely associated with cognition and inhibition of executive functions. Additionally, the study showed variations in brain activity depending on whether the anode was positioned over the right or left DLPFC (R-DLPFC or L-DLPFC). Conclusion: During the go task, tDCS might exert a suppressive effect on some brain areas, such as the precuneus. Stimulation on the R-DLPFC might strengthen the FC between the right ACC and the bilateral DLPFCs, which could enhance the ability of behavioural decision-making and inhibition to solve conflicts effectively. Stimulating the L-DLPFC alone could increase the FC of bilateral DLPFCs with some brain regions associated with response inhibition.
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Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bisN4-methylthiosemicarbazone (CuATSM), an agent used for clinical molecular imaging and that potently inhibits ferroptosis, prevented SMC phenotypic switch, neointimal formation and arterial inflammation in mice. These results indicate that pro-ferroptosis stress is likely to promote SMC phenotypic switch during neointimal formation and imply that inhibition of ferroptotic stress may be a promising translational approach to treat CVDs with SMC phenotype switch.
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Desdiferenciación Celular , Miocitos del Músculo Liso , Ratones , Animales , Células Cultivadas , Homeostasis , Miocitos del Músculo Liso/metabolismo , Músculo Liso , Proliferación CelularRESUMEN
Sorting nexin 16(SNX16),a member of the SNX family,contains a phoxhomology domain that is prone to bind with phosphatidylinositol-3-phosphate domain and a C-terminal coiled-coil domain. SNX16 participates in diverse cellular processes such as endocytosis,protein sorting,and signal transduction. The dysfunctions of SNX16 are demonstrated to be involved in the occurrence of several diseases.Here,we review the structural characteristics and biological functions of SNX16 and discuss the regulatory role of SNX16 in diseases,surveying how SNX16 can be applied to the prevention and treatment of related disorders.
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Endosomas , Nexinas de Clasificación , Nexinas de Clasificación/química , Nexinas de Clasificación/metabolismo , Endosomas/metabolismo , Transporte de Proteínas , Transducción de SeñalRESUMEN
Metabolic-associated fatty liver disease (MAFLD), which is previously known as non-alcoholic fatty liver disease (NAFLD), represents a major health concern worldwide with limited therapy. Here, we provide evidence that ferroptosis, a novel form of regulated cell death characterized by iron-driven lipid peroxidation, was comprehensively activated in liver tissues from MAFLD patients. The canonical-GPX4 (cGPX4), which is the most important negative controller of ferroptosis, is downregulated at protein but not mRNA level. Interestingly, a non-canonical GPX4 transcript-variant is induced (inducible-GPX4, iGPX4) in MAFLD condition. The high fat-fructose/sucrose diet (HFFD) and methionine/choline-deficient diet (MCD)-induced MAFLD pathologies, including hepatocellular ballooning, steatohepatitis and ï¬brosis, were attenuated and aggravated, respectively, in cGPX4-and iGPX4-knockin mice. cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes. Knockdown of iGPX4 by siRNA alleviated lipid stress, ferroptosis and cell injury. Mechanistically, the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress, and thus promotes ferroptosis. Co-immunoprecipitation and nano LC-MS/MS analyses confirmed the interaction between iGPX4 and cGPX4. Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis, and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.
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AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.
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Vesículas Extracelulares , Sirtuinas , Humanos , Ratones , Animales , Anciano , Preescolar , Fibronectinas/metabolismo , Factores de Transcripción/metabolismo , Ratones Noqueados , Envejecimiento , Angiotensina II/farmacología , Inflamación/metabolismo , Músculo Esquelético/metabolismo , Proteínas del Choque Térmico HSP40/metabolismoRESUMEN
Foliar stable nitrogen (N) isotopes (δ15 N) generally reflect N availability to plants and have been used to infer about changes thereof. However, previous studies of temporal trends in foliar δ15 N have ignored the influence of confounding factors, leading to uncertainties on its indication to N availability. In this study, we measured foliar δ15 N of 1811 herbarium specimens from 12 plant species collected in southern China forests from 1920 to 2010. We explored how changes in atmospheric CO2 , N deposition and global warming have affected foliar δ15 N and N concentrations ([N]) and identified whether N availability decreased in southern China. Across all species, foliar δ15 N significantly decreased by 0.82 over the study period. However, foliar [N] did not decrease significantly, implying N homeostasis in forest trees in the region. The spatiotemporal patterns of foliar δ15 N were explained by mean annual temperature (MAT), atmospheric CO2 ( P CO 2 ), atmospheric N deposition, and foliar [N]. The spatiotemporal trends of foliar [N] were explained by MAT, temperature seasonality, P CO 2 , and N deposition. N deposition within the rates from 5.3 to 12.6 kg N ha-1 year-1 substantially contributed to the temporal decline in foliar δ15 N. The decline in foliar δ15 N was not accompanied by changes in foliar [N] and therefore does not necessarily reflect a decline in N availability. This is important to understand changes in N availability, which is essential to validate and parameterize biogeochemical cycles of N.
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Dióxido de Carbono , Hojas de la Planta , China , Nitrógeno/análisis , Isótopos de Nitrógeno/análisis , Hojas de la Planta/química , Plantas , ÁrbolesRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes a wide range of cognitive impairments. Although COPD-Smoking comorbidity is common, the relationship between smoking and cognitive function in COPD-Smoking comorbidity remains unclear. This study aimed to investigate the effect of smoking on cognitive function like attention in COPD-Smoking patients. METHODS: In this study, we used the Montreal Cognitive Assessment (MoCA) scale and resting-state functional magnetic resonance imaging (fMRI) to explore the effect of smoking on attention in patients with COPD. RESULTS: Behavioral analysis revealed that among patients with COPD the smokers had a shorter course of COPD and showed a worse attention performance than the non-smokers. Resting-state fMRI analysis revealed that among patients with COPD smokers showed lower regional homogeneity (ReHo) value of the fusiform gyrus than non-smokers. Importantly, the ReHo of the fusiform gyrus is positively associated with attention and mediates the effect of smoking on attention in COPD. CONCLUSIONS: In summary, our study provides behavioral and neurobiological evidence supporting the positive effect of smoking on attention in COPD. This may be helpful for understanding and treating COPD and even other diseases comorbid with smoking.
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Enfermedad Pulmonar Obstructiva Crónica , Fumar , Atención , Comorbilidad , Humanos , Imagen por Resonancia Magnética/métodos , Fumar/epidemiologíaRESUMEN
PURPOSE: Previously developed Voxel Spread Function (VSF) method (Yablonskiy, et al, MRM, 2013;70:1283) provides solution to correct artifacts induced by macroscopic magnetic field inhomogeneity in the images obtained by multi-Gradient-Recalled-Echo (mGRE) techniques. The goal of this study was to develop a library-driven approach for fast VSF implementation. METHODS: The VSF approach describes the contribution of the magnetic field inhomogeneity effects on the mGRE signal decay in terms of the F-function calculated from mGRE phase and magnitude images. A pre-calculated library accounting for a variety of background field gradients caused by magnetic field inhomogeneity was used herein to speed up the calculation of F-function. Quantitative R2* maps from the mGRE data collected from two healthy volunteers were generated using the library as validation. RESULTS: As compared with direct calculation of the F-function based on a voxel-wise approach, the new library-driven method substantially reduces computational time from several hours to few minutes, while, at the same time, providing similar accuracy of R2* mapping. CONCLUSION: The new procedure proposed in this study provides a fast post-processing algorithm that can be incorporated in the quantitative analysis of mGRE data to account for background field inhomogeneity artifacts, thus can facilitate the applications of mGRE-based quantitative techniques in clinical practices.
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Artefactos , Imagen por Resonancia Magnética , Algoritmos , Encéfalo , Humanos , Procesamiento de Imagen Asistido por Computador , Campos MagnéticosRESUMEN
BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is a worldwide public health problem with no established pharmacological therapy. Here, we explored the potential benefit of P7C3-A20, a novel aminopropyl carbazole compound with neuroprotective activity, in a NAFLD model, induced in mice by a high-fat diet (HFD). EXPERIMENTAL APPROACH: C57BL/6J mice were given a HFD (42% fat content) for 16 weeks to induce NAFLD. P7C3-A20 (20 mg·kg-1 ·day-1 ) was given by gavage for 2 weeks. Indirect calorimetry, histological analysis, immunoblotting, immunohistochemistry, and biomedical examinations were performed. Gut microbiota were determined using a 16S ribosomal RNA sequencing analysis. KEY RESULTS: P7C3-A20 treatment reduced body weight gain/adiposity, improved insulin resistance, promoted energy expenditure (O2 consumption/CO2 production), inhibited lipid oxidation, suppressed hepatic inflammation (Kupffer cell number and pro-inflammatory factors), decreased necroptosis/apoptosis (receptor-interacting protein kinase 3, cleaved caspase-3, and TUNEL), and alleviated liver fibrosis and injury. Mechanistically, P7C3-A20 stimulated FGF21 and FGF1 via activating liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), which further resulted in a reduced nuclear translocation of CREB-regulated transcription coactivator 2 (CRTC2). In AMPKα2 knockout mice, the protection of P7C3-A20 against HFD-induced metabolism abnormalities and fat accumulation, as well as the elevation of blood FGF21 and FGF1, was abolished. P7C3-A20 increased the gut microbiota species richness. Moreover, it enhanced the proportions of Akkermansia, Lactobacillus, and Prevotellaceae, while reducing the proportions of Enterobacteriaceae, Escherichia, and Parasutterella. CONCLUSIONS AND IMPLICATIONS: P7C3-A20 increased levels of NAD+ and alleviated NAFLD through stimulating FGF21 and FGF1 in an LKB1/AMPK/CRTC2-dependent manner and shaping gut microbiota. LINKED ARTICLES: This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
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Carbazoles/farmacología , Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Proteínas Quinasas Activadas por AMP , Animales , Dieta Alta en Grasa , Factor 1 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos , Hígado , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológicoRESUMEN
Glucose homeostasis is tightly controlled by balance between glucose production and uptake in liver tissue upon energy shortage condition. Altered glucose homeostasis contributes to the pathophysiology of metabolic disorders including diabetes and obesity. Here, we aimed to analyse the change of proteomic profile upon prolonged fasting in mice with isobaric tag for relative and absolute quantification (iTRAQ) labelling followed by liquid chromatography-mass spectrometry (LC/MS) technology. Adult male mice were fed or fasted for 16 hours and liver tissues were collected for iTRAQ labelling followed by LC/MS analysis. A total of 322 differentially expressed proteins were identified, including 189 upregulated and 133 downregulated proteins. Bioinformatics analyses, including Gene Ontology analysis (GO), Kyoto encyclopaedia of genes and genomes analysis (KEGG) and protein-protein interaction analysis (PPI) were conducted to understand biological process, cell component, and molecular function of the 322 differentially expressed proteins. Among 322 hepatic proteins differentially expressed between fasting and fed mice, we validated three upregulated proteins (Pqlc2, Ehhadh and Apoa4) and two downregulated proteins (Uba52 and Rpl37) by western-blotting analysis. In cultured HepG2 hepatocellular cells, we found that depletion of Pqlc2 by siRNA-mediated knockdown impaired the insulin-induced glucose uptake, inhibited GLUT2 mRNA level and suppressed the insulin-induced Akt phosphorylation. By contrast, knockdown of Pqlc2 did not affect the cAMP/dexamethasone-induced gluconeogenesis. In conclusion, our study provides important information on protein profile change during prolonged fasting with iTRAQ- and LC-MS/MS-based quantitative proteomics, and identifies Pqlc2 as a potential regulator of hepatic glucose metabolism and insulin signalling pathway in this process.
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Proteómica , Animales , Glucosa , Masculino , Ratones , Transducción de SeñalRESUMEN
Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.
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MAP Quinasa Quinasa Quinasa 5/metabolismo , Melatonina/farmacología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Ubiquitinación/efectos de los fármacos , beta-Arrestina 1/metabolismo , Animales , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/farmacología , Estabilidad de Enzimas/efectos de los fármacos , Estabilidad de Enzimas/genética , MAP Quinasa Quinasa Quinasa 5/genética , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Ubiquitinación/genética , beta-Arrestina 1/genéticaRESUMEN
BACKGROUND AND PURPOSE: PDGF-BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor α7 subtype (α7nAChR) on PDGF-BB-induced proliferation and migration in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH: PNU-282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR activation on PDGF-BB-induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro-migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. KEY RESULTS: PDGF-BB induced pronounced migration and proliferation of VSMCs. Activation of α7nAChRs by PNU-282987 blocked PDGF-BB-induced migration but not proliferation in wild-type (WT) VSMCs, whereas this effect was absent in α7nAChR-knockout VSMCs. Accordingly, PNU-282987 attenuated PDGF-BB-induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU-282987 suppressed PDGF-BB-induced oxidative stress, as demonstrated by the alterations in ROS, H2 O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine or shRNA-mediated SIRT3 knockdown abolished the inhibitory effect of PNU-282987. PNU-282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU-282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU-282987 corrected the PDGF-BB-induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. CONCLUSIONS: Pharmacological activation of α7nAChRs inhibits PDGF-BB-induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs in mitochondria biology and PDGF-related diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
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Becaplermina/metabolismo , Sirtuina 3/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/genética , Familia-src Quinasas/metabolismoRESUMEN
Object recognition occurs even when environmental information is incomplete. Illusory contours (ICs), in which a contour is perceived though the contour edges are incomplete, have been extensively studied as an example of such a visual completion phenomenon. Despite the neural activity in response to ICs in visual cortical areas from low (V1 and V2) to high (LOC: the lateral occipital cortex) levels, the details of the neural processing underlying IC perception are largely not clarified. For example, how do the visual areas function in IC perception and how do they interact to archive the coherent contour perception? IC perception involves the process of completing the local discrete contour edges (contour completion) and the process of representing the global completed contour information (contour representation). Here, functional magnetic resonance imaging was used to dissociate contour completion and contour representation by varying each in opposite directions. The results show that the neural activity was stronger to stimuli with more contour completion than to stimuli with more contour representation in V1 and V2, which was the reverse of that in the LOC. When inspecting the neural activity change across the visual pathway, the activation remained high for the stimuli with more contour completion and increased for the stimuli with more contour representation. These results suggest distinct neural correlates of contour completion and contour representation, and the possible collaboration between the two processes during IC perception, indicating a neural connection between the discrete retinal input and the coherent visual percept.
Asunto(s)
Mapeo Encefálico , Percepción de Forma/fisiología , Corteza Visual/fisiología , Adulto , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Estimulación Luminosa , Adulto JovenRESUMEN
OBJECTIVE: To detect the value of qualitative and orientating diagnosis in the degeneration stage of cerebral cysticercosis with Gd-DTPA enhanced MR. METHODS: Sixty-nine cases of cerebral cysticercosis were diagnosed by enhanced MR as degeneration stage, and confirmed by immunological examination and/or by surgery. MR plain scanning was conducted for the same cases. RESULTS: The plain scanning showed single or multiple lesions with long T1 and long T2 signals, and the enhanced scanning showed nodular or annular lesions. The diameter of the lesion after enhanced scan was not more than 22 mm with an average value of 8.1 mm. Some cases showed single lesion on plain scanning but showed multiple lesions after enhanced scan. CONCLUSION: The enhanced MR shows more typical features of the degeneration stage cerebral cysticercosis. It can define the number, position and range of the lesions, and can improve the accuracy of differential diagnosis, and therefore be of importance in formulating treatment scheme and prognosis.