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OBJECTIVES: To identify the effects of message-framing interventions on improving health outcomes of individuals in diabetes health education communication. METHODS: Four electronic databases including Web of Science, PubMed, EMBASE, and the Cochrane Library were the search engines used. The period of literature search was from their inception until December 2023. Randomized controlled trials (RCTs) and quasi-experimental trials reporting the effects of message-framing interventions for diabetes were included. RESULTS: The review included 10 studies. Many studies have investigated multiple health outcomes. Of the seven studies that evaluated behavioral health-related outcomes, all studies (7/7, 100%) found a positive effect, and four studies (4/7, 57.1%) found that there was no significant difference between gain and loss framing. Of the seven studies that assessed nonbehavioral health-related outcomes, six studies (6/7, 85.7%) reported a positive postintervention effect, whereas four studies (4/7, 57.1%) found that loss-framed messages were more effective. One study (1/7, 14.3%) reported that there was no effect of the message framing on mental health-related outcomes. CONCLUSIONS: In diabetes health education communication, message framing of gain and loss framing has a positive effect on health outcomes for individuals. The advantage of the loss framing is more significant in improving nonbehavioral health-related outcomes. PRACTICE IMPLICATIONS: When constructing a message to promote health outcomes for patients with diabetes, the message framing is worth applying, and the advantages of loss framing can be considered more. TRIAL REGISTRATION: PROSPERO registration ID: CRD42023445074. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=445074.
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BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of severe illness in infants, with no effective treatment. Results of a phase 2 trial suggested that ziresovir may have efficacy in the treatment of infants hospitalized with RSV infection. METHODS: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted in China, we enrolled participants 1 to 24 months of age who were hospitalized with RSV infection. Participants were randomly assigned, in a 2:1 ratio, to receive ziresovir (at a dose of 10 to 40 mg, according to body weight) or placebo, administered twice daily, for 5 days. The primary end point was the change from baseline to day 3 (defined as 48 hours after the first administration) in the Wang bronchiolitis clinical score (total scores range from 0 to 12, with higher scores indicating greater severity of signs and symptoms). The intention-to-treat population included all the participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo; the safety population included all the participants who received at least one dose of ziresovir or placebo. RESULTS: The intention-to-treat population included 244 participants, and the safety population included 302. The reduction from baseline in the Wang bronchiolitis clinical score at day 3 was significantly greater with ziresovir than with placebo (-3.4 points [95% confidence interval {CI}, -3.7 to -3.1] vs. -2.7 points [95% CI, -3.1 to -2.2]; difference, -0.8 points [95% CI, -1.3 to -0.3]; P = 0.002). The reduction in the RSV viral load at day 5 was greater in the ziresovir group than in the placebo group (-2.5 vs. -1.9 log10 copies per milliliter; difference, -0.6 log10 copies per milliliter [95% CI, -1.1 to -0.2]). Improvements were observed in prespecified subgroups, including in participants with a baseline bronchiolitis score of at least 8 and in those 6 months of age or younger. The incidence of adverse events related to the drug or placebo was 16% with ziresovir and 13% with placebo. The most common adverse events that were assessed by the investigator as being related to the drug or placebo were diarrhea (in 4% and 2% of the participants, respectively), an elevated liver-enzyme level (in 3% and 3%, respectively), and rash (in 2% and 1%). Resistance-associated mutations were identified in 15 participants (9%) in the ziresovir group. CONCLUSIONS: Ziresovir treatment reduced signs and symptoms of bronchiolitis in infants and young children hospitalized with RSV infection. No safety concerns were identified. (Funded by Shanghai Ark Biopharmaceutical; AIRFLO ClinicalTrials.gov number, NCT04231968.).
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Antivirais , Hospitalização , Quinazolinas , Infecções por Vírus Respiratório Sincicial , Sulfonas , Tiazepinas , Feminino , Humanos , Lactente , Masculino , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Método Duplo-Cego , Hospitalização/estatística & dados numéricos , Análise de Intenção de Tratamento , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Pré-Escolar , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Hematopoietic stem cell transplantation (HSCT) is extensively employed in the treatment of hematological malignancies but is markedly constrained by the paucity of hematopoietic stem/progenitor cells (HSPCs). Recent studies have found that marrow adipose tissue (MAT) acts on hematopoiesis through complicated mechanisms. Therefore, the osteo-organoids fabricated in vivo using biomaterials loaded with recombinant human bone morphogenetic protein 2 (rhBMP-2) have been used as models of MAT for our research. To obtain sufficient amounts of therapeutic HSPCs and healthy MAT, we have developed amphiphilic chitosan (AC)-gelatin as carriers of rhBMP-2 to the regulate type conversion of adipose tissue and trap hematopoietic growth factors. Unlike medicine interventions or cell therapies, the traps based on AC not only attenuate the occupancy of adipocytes within the hematopoietic microenvironment while preserving stem cell factor concentrations, but also improve marrow metabolism by promoting MAT browning. In conclusion, this approach increases the proportion of HSPCs in osteo-organoids, and optimizes the composition and metabolic status of MAT. These findings furnish an experimental basis for regulating hematopoiesis in vivo through materials that promote the development of autologous HSPCs. Additionally, this approach presents a theoretical model of rapid adipogenesis for the study of adipose-related pathologies and potential pharmacological targets.
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Background: Bladder cancer, a highly fatal disease, poses a significant threat to patients. Positioned at 19q13.2-13.3, LIG1, one of the four DNA ligases in mammalian cells, is frequently deleted in tumour cells of diverse origins. Despite this, the precise involvement of LIG1 in BLCA remains elusive. This pioneering investigation delves into the uncharted territory of LIG1's impact on BLCA. Our primary objective is to elucidate the intricate interplay between LIG1 and BLCA, alongside exploring its correlation with various clinicopathological factors. Methods: We retrieved gene expression data of para-carcinoma tissues and bladder cancer (BLCA) from the GEO repository. Single-cell sequencing data were processed using the "Seurat" package. Differential expression analysis was then performed with the "Limma" package. The construction of scale-free gene co-expression networks was achieved using the "WGCNA" package. Subsequently, a Venn diagram was utilized to extract genes from the positively correlated modules identified by WGCNA and intersect them with differentially expressed genes (DEGs), isolating the overlapping genes. The "STRINGdb" package was employed to establish the protein-protein interaction (PPI) network.Hub genes were identified through the PPI network using the Betweenness Centrality (BC) algorithm. We conducted KEGG and GO enrichment analyses to uncover the regulatory mechanisms and biological functions associated with the hub genes. A machine-learning diagnostic model was established using the R package "mlr3verse." Mutation profiles between the LIG1^high and LIG1^low groups were visualized using the BEST website. Survival analyses within the LIG1^high and LIG1^low groups were performed using the BEST website and the GENT2 website. Finally, a series of functional experiments were executed to validate the functional role of LIG1 in BLCA. Results: Our investigation revealed an upregulation of LIG1 in BLCA specimens, with heightened LIG1 levels correlating with unfavorable overall survival outcomes. Functional enrichment analysis of hub genes, as evidenced by GO and KEGG enrichment analyses, highlighted LIG1's involvement in critical function such as the DNA replication, cellular senescence, cell cycle and the p53 signalling pathway. Notably, the mutational landscape of BLCA varied significantly between LIG1high and LIG1low groups.Immune infiltrating analyses suggested a pivotal role for LIG1 in immune cell recruitment and immune regulation within the BLCA microenvironment, thereby impacting prognosis. Subsequent experimental validations further underscored the significance of LIG1 in BLCA pathogenesis, consolidating its functional relevance in BLCA samples. Conclusions: Our research demonstrates that LIG1 plays a crucial role in promoting bladder cancer malignant progression by heightening proliferation, invasion, EMT, and other key functions, thereby serving as a potential risk biomarker.
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Biomarcadores Tumorais , DNA Ligase Dependente de ATP , Aprendizado de Máquina , Análise de Célula Única , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Humanos , Análise de Célula Única/métodos , Biomarcadores Tumorais/genética , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/metabolismo , Prognóstico , Masculino , Regulação Neoplásica da Expressão Gênica , Feminino , Redes Reguladoras de Genes , Mapas de Interação de Proteínas , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Biologia Computacional/métodos , Linhagem Celular Tumoral , IdosoRESUMO
Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal (n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.
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Dieta Hiperlipídica , Ácidos Graxos Ômega-3 , Ratos Wistar , Triglicerídeos , Animais , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/sangue , Dieta Hiperlipídica/efeitos adversos , Ratos , Masculino , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , LipidômicaRESUMO
Chemical exposures may impact human metabolism and contribute to the etiology of neurodegenerative disorders like Alzheimer's Disease (AD). Identifying these small metabolites involves matching experimental spectra to reference spectra in databases. However, environmental chemicals or physiologically active metabolites are usually present at low concentrations in human specimens. The presence of noise ions can significantly degrade spectral quality, leading to false negatives and reduced identification rates. In response to this challenge, the Spectral Denoising algorithm removes both chemical and electronic noise. Spectral Denoising outperformed alternative methods in benchmarking studies on 240 tested metabolites. It improved high confident compound identifications at an average 35-fold lower concentrations than previously achievable. Spectral Denoising proved highly robust against varying levels of both chemical and electronic noise even with >150-fold higher intensity of noise ions than true fragment ions. For human plasma samples of AD patients that were analyzed on the Orbitrap Astral mass spectrometer, Denoising Search detected 2.3-fold more annotated compounds compared to the Exploris 240 Orbitrap instrument, including drug metabolites, household and industrial chemicals, and pesticides. This combination of advanced instrumentation with a superior denoising algorithm opens the door for precision medicine in exposome research.
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Nonsmall cell lung cancer (NSCLC), due to its lack of early symptoms, has become one of the leading causes of cancer-related deaths globally. Exosomes, small membrane vesicles secreted by cells, are widely present in human bodily fluids. In the bodily fluids of NSCLC patients, the quantity of extracellular vesicles is double that of healthy individuals, suggesting their potential as biomarkers for screening NSCLC. This study designed a dual-modal aptasensor that integrated excellent sensitivity in electrochemical detection and portability in fluorescence detection into one device. AuNPs were functionalized with exosome-capturing probes containing thiol-modified CD63 aptamers, which were immobilized on screen-printed gold electrodes. On the other hand, the carboxylated CD63 aptamer was immobilized on the surface of PB-modified g-C3N4 loaded with Co-SANs particles (Co@g-C3N4@PB). By combining these components, a sandwich structure (AuNPs/Apt1/Exo/Apt2- Co@g-C3N4@PB) was constructed, forming a probe for specific exosome recognition. First, the samples were preliminarily assessed for their positive or negative status under a fluorescence inverted microscope. Subsequently, a more in-depth quantitative analysis was conducted on suspected positive samples using electrochemical or fluorescence analysis methods. The detection limits for electrochemical analysis and fluorescence analysis were 66.68 and 33.5particles/mL, respectively. In the analysis of clinical serum exosome samples, the developed dual-modal aptasensor effectively distinguished serum specimens from those of NSCLC patients and healthy volunteers. This highlighted the inspection capability of the dual-modal adapter sensor, especially in point-of-care testing, making it a highly suitable tool for clinical applications.
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Fusarium root rot caused by the Fusarium species complex significantly affects the yield and quality of Angelica sinensis, a valuable medicinal herb. Traditional management primarily relies on chemical fungicides, which have led to pathogen resistance, environmental hazards, and concerns regarding public health and the active components in A. sinensis. This study explores the efficacy of a novel plant-derived biopesticide Shi Chuang Zhi Feng Ning (T1; SCZFN), alongside Bacillus subtilis wettable powder (T2) and a chemical fungicide (T3), in controlling root rot and understanding their impacts on the rhizosphere microbial community and root metabolome. Results of the field experiment demonstrated that treatments T1 and T3 achieved control efficiencies of 73.17% and 75.45%, respectively, significantly outperforming T2 (39.99%) and the control. High-throughput sequencing revealed that all treatments altered the diversity and structure of microbial communities, with T1 and T2 reducing the abundance of taxa linked to root rot, such as Muribaculaceae spp., Humicola spp., Fusarium spp., and Mycochlamys spp. Treatment T1 notably enhanced beneficial bacterial taxa, including Acidobacteria spp., Nitrospira spp., and Pedosphaeraceae spp., involved in carbon cycling and plant growth promotion. Metabolomic analysis identified 39, 105, and 45 differentially expressed metabolites (DEMs) across the treatments, demonstrating T1's potential to modulate the root metabolome effectively. Further, a correlation analysis demonstrated a stronger correlation between distinct microorganisms with significant influence and DEMs of T1 treatment compared to other treatments. These findings underscore biopesticide SCZFN's role in enhancing plant health and disease suppression in A. sinensis, providing insights into its biocontrol mechanisms and supporting the development of sustainable disease management strategies in its cultivation.
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Objectives: This research aims to analyze how exposure to fine particulate matter (PM2.5) and ambient heat during pregnancy increases the risk of congenital hydronephrosis (CH) in newborns. Methods: A case-control study was conducted to investigate the relationship between exposure to PM2.5 and ambient heat during pregnancy and the occurrence of CH in newborns. The study, which was conducted from 2015 to 2020, included 409 infants with CH as the case group and 409 infants without any abnormalities as the control group. Using spatial remote sensing technology, the exposure of each pregnant mother to PM2.5 concentration was meticulously mapped. Additionally, data on the ambient temperature of exposure for each participant were also collected. A logistics regression model was used to calculate the influence of exposure to PM2.5 and ambient heat on the occurrence of CH. Stratified analysis and interaction analysis were used to study the interaction between ambient heat exposure and PM2.5 on the occurrence of CH. Results: At the 6th week of gestation, exposure to PM2.5 may increase the risk of CH. For every 10 µg/m3 increase in PM2.5 exposure, the risk of CH increased by 2% (95%CI = 0.98, 1.05) at a p-value of >0.05, indicating that there was no significant relationship between the results. Exposure to intense heat at 6th and 7th weeks of gestation increased the risk of CH. Specifically, for every 1°C increase in heat exposure, the risk of CH in offspring increased by 21% (95%CI = 1.04, 1.41) during the 6th week and 13% during the 7th week (95%CI = 1.02, 1.24). At 5th and 6th weeks of gestation, the relative excess risk due to interaction (RERI) was greater than 0 at the 50th percentile (22.58°C), 75th percentile (27.25°C), and 90th percentile (29.13°C) of daily maximum temperature (Tmax) distribution, indicating that the risk of CH was higher when exposed to both ambient heat and PM2.5 at the same time compared to exposure to a single risk factor. Conclusion: Exposure to higher levels of PM2.5 and ambient heat during pregnancy increases the risk of CH in infants. There was a positive interaction between exposure to intense heat and high concentration of PM2.5 on the occurrence of CH.
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Temperatura Alta , Hidronefrose , Exposição Materna , Material Particulado , Humanos , Feminino , Material Particulado/efeitos adversos , Material Particulado/análise , China/epidemiologia , Gravidez , Temperatura Alta/efeitos adversos , Estudos de Casos e Controles , Recém-Nascido , Hidronefrose/etiologia , Exposição Materna/efeitos adversos , Exposição Materna/estatística & dados numéricos , Adulto , Masculino , Fatores de Risco , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análiseRESUMO
AIMS: Ischemic stroke remains a challenge in medical research because of the limited treatment options. Recombinant human tissue plasminogen activator (rtPA) is the primary treatment for recanalization. However, nearly 50% of the patients experience complications that result in ineffective reperfusion. The precise factors contributing to ineffective reperfusion remain unclear; however, recent studies have suggested that immune cells, notably neutrophils, may influence the outcome of rtPA thrombolysis via mechanisms such as the formation of neutrophil extracellular traps. This study aimed to explore the nonthrombolytic effects of rtPA on neutrophils and highlight their contribution to ineffective reperfusion. METHODS: We evaluated the effects of rtPA treatment on middle cerebral artery occlusion in rats. We also assessed neutrophil infiltration and activation after rtPA treatment in vitro and in vivo in a small cohort of patients with massive cerebral ischemia (MCI). RESULTS: rtPA increased neutrophil infiltration into the brain microvessels and worsened blood-brain barrier damage during ischemia. It also increased the neutrophil counts of the patients with MCI. CONCLUSION: Neutrophils play a crucial role in promoting ischemic injury and blood-brain barrier disruption, making them potential therapeutic targets.
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Fibrinolíticos , Neutrófilos , Proteínas Recombinantes , Ativador de Plasminogênio Tecidual , Ativador de Plasminogênio Tecidual/farmacologia , Ativador de Plasminogênio Tecidual/uso terapêutico , Animais , Humanos , Masculino , Neutrófilos/efeitos dos fármacos , Ratos , Proteínas Recombinantes/farmacologia , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Ratos Sprague-Dawley , Idoso , Barreira Hematoencefálica/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Infiltração de Neutrófilos/efeitos dos fármacos , Pessoa de Meia-Idade , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Modelos Animais de DoençasRESUMO
Regional responses to inhaled toxicants are essential to understand the pathogenesis of lung disease under exposure to air pollution. We evaluated the effect of combined allergen sensitization and ozone exposure on eliciting spatial differences in lipid distribution in the mouse lung that may contribute to ozone-induced exacerbations in asthma. Lung lobes from male and female BALB/c mice were cryosectioned and acquired by high resolution mass spectrometry imaging (MSI). Processed MSI peak annotations were validated by LC-MS/MS data from scraped tissue slides and microdissected lung tissue. Images were normalized and segmented into clusters. Interestingly, segmented clusters overlapped with stained serial tissue sections, enabling statistical analysis across biological replicates for morphologically relevant lung regions. Spatially distinct lipids had higher overall degree of unsaturated fatty acids in distal lung regions compared to proximal regions. Furthermore, the airway and alveolar epithelium exhibited significantly decreased sphingolipid and glycerophospholipid abundance in females, but not in males. We demonstrate the potential role of lipid saturation in healthy lung function and highlight sex differences in regional lung lipid distribution following ozone exposure. Our study provides a framework for future MSI experiments capable of relative quantification across biological replicates and expansion to multiple sample types, including human tissue.
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Graphene-like molecules with multiple zigzag edges are emerging as promising gain materials for organic lasers. Their emission wavelengths can vary widely, ranging from visible to near-infrared (NIR), as the molecular size increases. Specifically, rhombus-shaped molecular graphenes with two pairs of parallel zigzag edges, known as [n]rhombenes, are excellent candidates for NIR lasers due to their small energy gaps. However, synthesizing large-size rhombenes with emission beyond 800â nm in solution remains a significant challenge. In this study, we present a straightforward synthesis of an aryl-substituted [4]rhombene derivative, [4]RB-Ar, using a method that combines intramolecular radical-radical coupling with Bi(OTf)3-mediated cyclization of vinyl ethers. The structure of [4]RB-Ar was confirmed through X-ray crystallographic analysis. Bond length analysis and theoretical calculations indicate that aromatic sextets are predominantly localized along the molecule's long axis. Significantly, [4]RB-Ar demonstrates narrow amplified spontaneous emission at around 834â nm when dispersed in polystyrene thin films. Moreover, solution-processed distributed feedback lasers employing [4]RB-Ar as the active gain material display tunable narrow emissions in the range of 830 to 844â nm.
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Two previously uncharacterized compounds, an aconitine-type C19-diterpenoid alkaloid (1) and a napelline-type diterpenoid alkaloid C20-diterpenoid alkaloid (2), as well as ten known compounds (3-12), were isolated from Aconitum pendulum. Their structures were elucidated based on spectroscopic data, including 1D and 2Dâ NMR, IR, HR-ESI-MS, and single-crystal X-ray diffraction analysis. The anti-insecticidal activities of these compounds were evaluated by contact toxicity tests against two-spotted spider mites, and compounds 1, 2, and 9 showed moderate contact toxicity, with LC50 values of 0.86±0.09, 0.95±0.23, and 0.89±0.19â mg/mL, respectively. This study highlights the potential use of diterpenoid alkaloids as natural plant-derived pesticides for the management of plant pests.
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Aconitum , Alcaloides , Diterpenos , Aconitum/química , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Animais , Tetranychidae/efeitos dos fármacos , Estrutura Molecular , Conformação Molecular , Cristalografia por Raios X , Inseticidas/química , Inseticidas/isolamento & purificação , Inseticidas/farmacologia , Modelos MolecularesRESUMO
The application of a liquid crystal (LC) in displays has driven the development of novel LC elements. In this Letter, polarization variable line-space (PVLS) gratings based on photoalignment are fabricated, and their variable-spacing properties are derived using the vector diffraction theory. Both transmissive and reflective PVLS gratings are fabricated to validate the correctness of the derivation. Experimental results indicate that PVLS gratings have a wider wavelength response bandwidth than that of polarization volume grating (PVG). PVLS gratings have angle selectivity, and a large incident angle causes wavelength blueshift. Additionally, the relationship between wavelength and focal length indicates its anomalous dispersion as a diffractive optical element. These results of photoalignment-based PVLS gratings provide valuable insights for the advancement of displays and have the potential to improve visual experiences.
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The main reason for the high mortality rate of non-small cell lung cancer is that patients are usually diagnosed at an advanced stage of the disease. Exosomes, small membrane vesicles secreted by normal cells or tumor cells, play a significant role in the progression of NSCLC. This study successfully optimized the preparation of artificial nanoenzymes self-coupling with horseradish peroxidase (IrO2NPs@HRP-AptCD63), without adding any ligand, demonstrating remarkable catalytic activity suitable for detecting the EGFR protein on the surface of NSCLC exosomes. When fused with the CD63 aptamer for identifying NSCLC exosomes, IrO2NPs@HRP showed enhanced catalytic activity in the 3,3',5,5'-tetramethylbenzidine-H2O2 oxidation-reduction system, thereby enhancing the colorimetric signal. This phenomenon can be distinguished by the naked eye and quantified using a UV-Vis spectrophotometer. Meanwhile, as the redox reaction occurs, the current signal of 3,3',5,5'-tetramethylbenzidine-H2O2, acting as an electrolyte, changes. The developed aptasensor generates dual-mode signal outputs, firstly, to visually assess the samples for their positive or negative status, and subsequently employ more in-depth electrochemical or colorimetric analysis methods for a detailed quantitative analysis of suspected positive samples. The detection limits of electrochemical analysis and colorimetric analysis were 0.9 × 103 particles/mL and 0.14 × 103 particles/mL, respectively. Compared with traditional biomarkers such as CA125, this method exhibits exceptional specificity, capable of simultaneously distinguishing serum exosomes of healthy volunteers, COPD patients, and NSCLC patients, promoting exosome detection in mouse models for tumor monitoring. Additionally, it elucidates the changes in EGFR protein expression on the surface of serum exosomes throughout the developmental trajectory.
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Aptâmeros de Nucleotídeos , Carcinoma Pulmonar de Células não Pequenas , Exossomos , Peroxidase do Rábano Silvestre , Irídio , Neoplasias Pulmonares , Oxirredução , Exossomos/química , Exossomos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Aptâmeros de Nucleotídeos/química , Irídio/química , Peroxidase do Rábano Silvestre/química , Peroxidase do Rábano Silvestre/metabolismo , Animais , Camundongos , Nanopartículas Metálicas/química , Técnicas BiossensoriaisRESUMO
Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.
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Relógios Circadianos , Microbioma Gastrointestinal , Células Supressoras Mieloides , Animais , Camundongos , Células Supressoras Mieloides/metabolismo , Humanos , Metástase Neoplásica , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Camundongos Endogâmicos C57BL , Masculino , Microambiente Tumoral , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Feminino , Camundongos Endogâmicos BALB C , Linhagem Celular TumoralRESUMO
Trichloroethylene (TCE) is a commonly used organic solvent in industry. Our previous studies have found that TCE can cause liver injury accompanied by macrophage polarization, but the specific mechanism is unclear. The epigenetic regulation of macrophage polarization is mainly focused on histone modification. Histone lysine demethylase 4A (KDM4A) is involved in the activation of macrophages. In this study, we used a mouse model we investigated the role of KDM4A in the livers of TCE-drinking mice and found that the expression of KDM4A, M1-type polarization indicators, and related inflammatory factors in the livers of TCE-drinking mice. In the study, BALB/c mice were randomly divided into four groups: 2.5 mg/mL TCE dose group and 5.0 mg/mL TCE dose group, the vehicle control group, and the blank control group. We found that TCE triggered M1 polarization of mouse macrophages, characterized by the expression of CD11c and robust production of inflammatory cytokines. Notably, exposure to TCE resulted in markedly increased expression of KDM4A in macrophages. Functionally, the increased expression of KDM4A significantly impaired the expression of H3K9me3 and H3K9me2 and increased the expression of H3K9me1. In addition, KDM4A potentially represents a novel epigenetic modulator, with its upregulation connected to ß-catenin activation, a signal critical for the pro-inflammatory activation of macrophages. Furthermore, KDM4A inhibitor JIB-04 treatment resulted in a decrease in ß-catenin expression and prevented TCE-induced M1 polarization and the expression of the pro-inflammatory cytokines TNF-α and IL-1ß. These results suggest that the association of KDM4A and Wnt/ß-catenin cooperatively establishes the activation and polarization of macrophages and global changes in H3K9me3/me2/me1. Our findings identify KDM4A as an essential regulator of the polarization of macrophages and the expression of inflammatory cytokines, which might serve as a potential target for preventing and treating liver injury caused by TCE.
Assuntos
Histona Desmetilases com o Domínio Jumonji , Macrófagos , Camundongos Endogâmicos BALB C , Tricloroetileno , Animais , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Tricloroetileno/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Citocinas/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Histona DesmetilasesRESUMO
The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well-described with a single compartment disposition with first-order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure-response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry-over effect from prior insulin administration was incorporated into the model through a time-dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies.
Assuntos
Administração Intranasal , Glicemia , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Glucagon , Modelos Biológicos , Humanos , Glucagon/farmacocinética , Glucagon/administração & dosagem , Adulto , Masculino , Glicemia/efeitos dos fármacos , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Relação Dose-Resposta a Droga , Idoso , Adulto Jovem , Disponibilidade BiológicaRESUMO
This was an observational study of patients with benign breast tumors intended to investigate and compare the predictive value of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) for hypertension in the recovery room. Logistic regression analysis was used to determine the association between these body fat anthropometric indices and hypertension. Receiver operating characteristic curve (ROC) analysis was performed to assess the comparative predictive ability. A total of 689 women were evaluated. Patients with BMI ≥28 (kg/m2), WC > 85 cm, WHR ≥0.82, and WHtR ≥0.5 had a significantly higher probability of increased systolic blood pressure (SBP) and diastolic blood pressure (DBP) than patients with less than threshold values (all P < 0.05). The areas under the ROC curve (AUC) of BMI, WC, and WHtR where all modestly significant (all AUC ≥0.65) and nearly identical at 0.6592, 0.65, and 0.6724, respectively. Conclusion: body fat anthropometric indices are useful predicting hypertension during recovery from general anesthesia in patients with benign breast tumors undergoing day surgery; WHtR outperformed the other indices and nearly identical.
RESUMO
Enhancement of vascular remodeling in affected brain tissue is a novel therapy for acute ischemic stroke (AIS). However, conclusions regarding angiogenesis after AIS remain ambiguous. Vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2) are potent regulators of angiogenesis and vascular permeability. We aimed to investigate the association between VEGFA/VEGFR2 expression in the acute stage of stroke and prognosis of patients with AIS. We enrolled 120 patients with AIS within 24 h of stroke onset and 26 healthy controls. Plasma levels of VEGFA and VEGFR2 were measured by enzyme-linked immunosorbent assay (ELISA). The primary endpoint was an unfavorable outcome defined as a modified Rankin Scale (mRS) score > 2 at 3 months after AIS. Univariate and multivariate logistic regression analyses were used to identify risk factors affecting prognosis. Plasma VEGFA and VEGFR2 were significantly higher in patients with AIS than in health controls, and also significantly higher in patients with unfavorable than those with favorable outcomes. Moreover, both VEGFA and VEGFR2 showed a significantly positive correlation with mRS at 3 months. Univariate and multivariate analyses showed VEGFA and VEGFR2 remained associated with unfavorable outcomes, and adding VEGFA and VEGFR2 to the clinical model significantly improved risk reclassification (continuous net reclassification improvement, 105.71%; integrated discrimination improvement, 23.45%). The new risk model curve exhibited a good fit with an area under the receiver operating characteristic curve (ROC) curve of 0.9166 (0.8658-0.9674). Plasma VEGFA and VEGFR2 are potential markers for predicting prognosis; thus these two plasma biomarkers may improve risk stratification in patients with AIS.