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Microplastics are a growing concern as pollutants that impact both public health and the environment. However, the toxic effects of polypropylene microplastics (PP-MPs) are not well understood. This study aimed to investigate the effects of PP-MPs on cardiotoxicity and its underlying mechanisms. The cardiotoxicity of exposure to different amounts of PP-MPs were investigated in both ICR mice and H9C2 cells. Our results demonstrated that sub-chronic exposure to 5 and 50 mg/L PP-MPs led to myocardial structural damage, apoptosis, and fibrosis in mice cardiomyocytes. Flow cytometry analysis revealed that PP-MPs could decrease mitochondrial membrane potential and induce apoptosis in H9C2 cells. Western blotting revealed decreased expression of Bcl-2, poly(ADP-ribose) polymerase (PARP) and caspase 3 and increased expression of Bax, cleaved-PARP, and cleaved-caspase 3 in PP-MPs-treated cardiac tissue and H9C2 cells. These results confirmed the apoptotic effects induced by PP-MPs. Moreover, PP-MPs treatment triggered oxidative stress, as evidenced by the increased levels of malondialdehyde; reduction in glutathione peroxidase, superoxide dismutase, and catalase activities in mice cardiac tissues; and increased reactive oxygen species levels in H9C2 cells. Finally, western blotting demonstrated that exposure to PP-MPs significantly reduced the expression levels of Nrf2 and p-ERK proteins associated with MAPK-Nrf2 pathway in both cardiac tissue and H9C2 cells. Overall, our findings indicate that PP-MPs can induce cardiomyocyte apoptosis through MAPK-Nrf2 signaling pathway, which is triggered by oxidative stress. This study provides a foundation for determining the effects of PP-MPs on cardiotoxicity and their underlying mechanisms.

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The adzuki bean is a mature seed of the red bean leguminous plant, and people like to eat it because of its nutritious properties and moderate proportion of amino acids. Adzuki bean germination and the enrichment of GABA greatly improve the health effects of the adzuki bean. The effects of the GABA-rich adzuki bean on the expression of insulin-pathway-related genes and proteins in the liver of T2DM mice were studied via Western blotting and qPCR. The results showed that a GABA-rich adzuki bean diet could promote glycogen synthesis in the liver of T2DM mice, inhibit the activities of PEPCK and G-6-Pase, and significantly down-regulate the gene expression levels of PEPCK, G6PC and FOXO1 (p < 0.05) and the phosphorylation levels of FOXO1 and GSK3ß. In addition, it can also up-regulate the expression of the AMPKα gene and down-regulate the expression of the SREBP1c gene to inhibit the synthesis of triglycerides and cholesterol in T2DM mice. Lipid accumulation in mice can alleviate glucose and lipid metabolism disorders and play an effective role in regulating blood glucose at liver tissue targets. This study suggested that the GABA-rich adzuki bean can improve hyperglycemia in type 2 diabetic mice by activating the IRS/PI3K/AKT signaling pathway in the liver.

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BACKGROUND AND AIMS: Endosialin, also known as tumor endothelial marker1 or CD248, is a transmembrane glycoprotein that is mainly expressed in cancer-associated fibroblasts (CAFs) in hepatocellular carcinoma (HCC). Our previous study has found that endosialin-positive CAFs could recruit and induce the M2 polarization of macrophages in HCC. However, whether they may regulate other types of immune cells to promoting HCC progression is not known. APPROACH AND RESULTS: The growth of both subcutaneous and orthotopic HCC tumors was significantly inhibited in endosialin knockout (ENKO) mice. Single-cell sequencing and flow cytometry analysis showed that tumor tissues from ENKO mice had increased CD8+ T cell infiltration. Mixed HCC tumor with Hepa1-6 cells and endosialin knockdown fibroblasts also showed inhibited growth and increased CD8+ T cell infiltration. Data from in vitro co-culture assay, chemokine array and antibody blocking assay, RNA-seq and validation experiments showed that endosialin inhibits the phosphorylation and nuclear translocation of STAT1 in CAFs. This inhibition leads to a decrease in CXCL9/10 expression and secretion, resulting in the suppression of CD8+ T cell infiltration. High level of endosialin protein expression was correlated with low CD8+ T infiltration in the tumor tissue of HCC patients. The combination therapy of endosialin antibody and PD-1 antibody showed synergistic antitumor effect compared with either antibody used individually. CONCLUSIONS: Endosialin could inhibit CD8+ T cell infiltration by inhibiting the expression and secretion of CXCL9/10 in CAFs, thus promote HCC progression. Combination therapy with endosialin antibody could increase the antitumor effect of PD-1 antibody in HCC, which may overcome the resistance to PD-1 blockade.

Asunto(s)

Linfocitos T CD8-positivos , Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Animales , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Antígenos CD/metabolismo , Progresión de la Enfermedad , Línea Celular Tumoral , Quimiocina CXCL9/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Noqueados , Microambiente Tumoral , Factor de Transcripción STAT1/metabolismo , Quimiocina CXCL10/metabolismo , Masculino , Antígenos de Neoplasias , Proteínas de Neoplasias

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PURPOSE: To investigate the effectiveness of anti-vascular endothelial growth factor (VEGF) therapy on post-vitrectomy macular edema (PVME) and determine the risk factors for PVME recovery. METHODS: This retrospective study included 179 eyes of 179 patients who underwent pars plana vitrectomy for proliferative diabetic retinopathy and developed PVME within 3 months after surgery. Eyes were grouped according to postoperative anti-VEGF treatment. RESULTS: Central retinal thickness (CRT) decreased significantly from baseline to 3-month follow-up in groups with (509.9 ± 157.2 µm vs. 401.2 ± 172.1 µm, P < 0.001) or without (406.1 ± 96.1 µm vs. 355.1 ± 126.0 µm, P = 0.008) postoperative anti-VEGF treatment. Best-corrected visual acuity (BCVA) did not differ between the two groups during follow-up. In the group not receiving anti-VEGF therapy, BCVA was significantly improved at 1, 2, and 3 months (P = 0.007, P < 0.001, and P < 0.001, respectively), while in the anti-VEGF group, BCVA was significantly improved at 1 and 3 months (P = 0.03 and P < 0.001). A thicker baseline CRT (ß = 0.44; 95% confidence interval, 0.26-0.61; P < 0.001) was significantly associated with decreasing CRT. CONCLUSION: PVME tends to spontaneously resolve in the early postoperative period. The effect of anti-VEGF therapy in the first 3 months after diagnosis appears to be limited.

Asunto(s)

Inhibidores de la Angiogénesis , Retinopatía Diabética , Edema Macular , Factor A de Crecimiento Endotelial Vascular , Vitrectomía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/cirugía , Estudios de Seguimiento , Inyecciones Intravítreas , Edema Macular/etiología , Edema Macular/tratamiento farmacológico , Edema Macular/diagnóstico , Complicaciones Posoperatorias , Ranibizumab/administración & dosificación , Ranibizumab/uso terapéutico , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual , Vitrectomía/métodos

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Histopathology image evaluation is indispensable for cancer diagnoses and subtype classification. Standard artificial intelligence methods for histopathology image analyses have focused on optimizing specialized models for each diagnostic task1,2. Although such methods have achieved some success, they often have limited generalizability to images generated by different digitization protocols or samples collected from different populations3. Here, to address this challenge, we devised the Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model, a general-purpose weakly supervised machine learning framework to extract pathology imaging features for systematic cancer evaluation. CHIEF leverages two complementary pretraining methods to extract diverse pathology representations: unsupervised pretraining for tile-level feature identification and weakly supervised pretraining for whole-slide pattern recognition. We developed CHIEF using 60,530 whole-slide images spanning 19 anatomical sites. Through pretraining on 44 terabytes of high-resolution pathology imaging datasets, CHIEF extracted microscopic representations useful for cancer cell detection, tumour origin identification, molecular profile characterization and prognostic prediction. We successfully validated CHIEF using 19,491 whole-slide images from 32 independent slide sets collected from 24 hospitals and cohorts internationally. Overall, CHIEF outperformed the state-of-the-art deep learning methods by up to 36.1%, showing its ability to address domain shifts observed in samples from diverse populations and processed by different slide preparation methods. CHIEF provides a generalizable foundation for efficient digital pathology evaluation for patients with cancer.

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Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell. The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties (t 1/2 = 1.93 ± 0.91 h, F = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the "Induced-fit" allosteric model in favor to the discovery of potent DOT1L candidates.

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Background: Health literacy is an important means to improve health outcomes and reduce health disparities. It plays an important role in promoting multiple health-related behaviors of individuals. Numerous studies have demonstrated a number of sociodemographic and school characteristics, and family related factors were related to health literacy among college students. However, these characteristics and factors were relatively unchangeable. Research on the relationship between factors, that can be intervened, and health literacy remains scarce. This study aims to explore the association between personal and changeable environmental factors, and the level of health literacy in college students. Methods: A cross-sectional study, which used a stratified random sampling method, was conducted at a university in Wuhan (N = 447). The survey questionnaire included sociodemographic characteristics, the School Environment Questionnaire, the Family Environment Questionnaire, the General Self-Efficacy Scale Questionnaire, and the Health Literacy Questionnaire. We used Spearman correlation tests, and Student's tests or analyses of variance to describe the relationship among continuous variables. In addition, we employed linear regression analysis to test the mediating effect based on the bias-corrected nonparametric percentile Bootstrap method. Results: Factors related to socioeconomic status, such as living costs (p = 0.011), residential area (p = 0.003), annual household income (p = 0.001), and parents' education level (fathers: p = 0.001; mothers: p = 0.01) and occupation type (fathers: p < 0.001; mothers: p = 0.044), had close correlations with health literacy. School and family environments and self-efficacy had a positive impact on college students' health literacy (ß = 0.235, p < 0.001; ß = 0.323, p < 0.001; ß = 0.489, p < 0.001). Self-efficacy had a mediating effect on the relationship between school and family environments, as well as health literacy. The total, direct, and indirect effects of the school environment on health literacy were 0.235, 0.157, and 0.078, respectively. The total, direct, and indirect effects of the family environment on health literacy were 0.323, 0.189, and 0.134, respectively. Conclusion: This study confirms that improving school and family environments could directly or indirectly increase college students' health literacy through promoting their self-efficacy. Socioeconomic status has a significant impact on their health literacy. Moreover, other factors that affect students' health literacy and relationships among self-efficacy, surrounding environments, and health literacy may need to be explored in the future.

Asunto(s)

Alfabetización en Salud , Instituciones Académicas , Autoeficacia , Estudiantes , Humanos , Femenino , Alfabetización en Salud/estadística & datos numéricos , Masculino , Estudios Transversales , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Universidades , Encuestas y Cuestionarios , Adulto Joven , China , Adulto , Adolescente , Factores Socioeconómicos

RESUMEN

Enhanced dielectric constant and high breakdown strength offers immense promise for excellent energy storage performance, which is of critical significance in modern electronics and power systems. However, polymer nanocomposites with traditional routes have to balance between dielectric constant and breakdown strength, hence hindering substantive increases in energy density. Herein, a sandwiched polymer nanocomposite film has been constructed to take full advantage of the individual component layers. BaTiO3 nanoparticles are coated with a fluoropolymer to form core-shell structures and then introduced into a polymer as the top and the bottom layers of a sandwich film for enhancing polarization. Moreover, boron nitride nanosheets (BNNSs) in the middle layer of the sandwich film exert positive effects on the inhibition of current leakage for high breakdown resistance. The breakdown strength increases from 480 MV m-1 of the neat polymer to 580 MV m-1 of the sandwiched film. Additionally, the film exhibits a higher dielectric constant in comparison with the neat polymer. The sandwiched film displays a superior energy density (15.75 J cm-3), which is about 1.9 times that of the neat polymer. This work proposes a feasible route to achieve excellent energy storage of polymer dielectrics by synergistically introducing insulating fillers and additional dipoles in a sandwiched polymer nanocomposite film.

RESUMEN

Dissolved organic matter (DOM) can affect the transformation of pollutants through photosensitization, but most current research focuses on hydrophilic pollutants, making it such that less attention is paid to hydrophobic pollutants. In this paper, the effect and action mechanism of coexisting DOM on the photodegradation of decachlorobiphenyl (PCB-209) on suspended particles collected from the Yellow River were systematically investigated in a heterogeneous system using DOM standards and model compounds. Through molecular probe experiments, mass spectrometry analysis and theoretical calculations, we found that the excited triplet state of DOM (3DOM*) could excite PCB-209 to undergo dechlorination reaction. Due to the different modes of electron transition, the presence of carbonyl groups decreased the energy of 3DOM*, whereas the electron-donating groups made the energy of 3DOM* higher. DOM containing phenolic hydroxyl groups led to a higher steady-state concentration of •OH, and DOM containing phenyl ketone structures had a stronger ability to produce •O2-. Compared with aqueous •OH, •O2- produced from hydrophobic microregions could react more readily with PCB-209. This study deepens the understanding of the role of different functional groups of DOM in the photosensitized transformation of hydrophobic compounds.

Asunto(s)

Fotólisis , Bifenilos Policlorados/química , Contaminantes Químicos del Agua/química

RESUMEN

Viruses are the most abundant yet understudied members that may influence microbial metabolism in activated sludge treating antibiotic production wastewater. This study comprehensively investigated virome community characteristics under the selection pressure of nine types and different concentrations of antibiotics using a metagenomics approach. Of the 15,514 total viral operational taxonomic units (tOTUs) recovered, only 37.5 % were annotated. Antibiotics altered the original viral community structure in activated sludge. The proportion of some pathogenic viral families, including Herpesviridae_like, increased significantly in reactors treating erythromycin production wastewater. In total, 16.5 % of the tOTUs were associated with two or more hosts. tOTUs rarely carried antibiotic resistance genes (ARGs), and the ARG types in the tOTUs did not match the ARGs carried by the bacterial hosts. This suggests that transduction contributes little to the horizontal ARG transfer. Auxiliary metabolic genes (AMGs) were prevalent in tOTUs, and those involved in folate biosynthesis were particularly abundant, indicating their potential to mitigate antibiotic-induced host damage. This study provides comprehensive insights into the virome community in activated sludge treating antibiotic production wastewater and sheds light on the potential role of viral AMGs in mitigating antibiotic-induced stress.

Asunto(s)

Antibacterianos , Reactores Biológicos , Aguas del Alcantarillado , Aguas Residuales , Aguas del Alcantarillado/virología , Eliminación de Residuos Líquidos , Farmacorresistencia Microbiana/genética , Virus/genética

RESUMEN

A hydrophobic Cu2O cathode (CuxO-L) was designed to solve the challenge of low oxidation ability in electro-Fenton (EF) for treating emerging pollutants. This fabrication process involved forming Cu(OH)2 nanorods by oxidizing copper foam (Cu-F) with (NH4)2S2O8, followed by coating them with glucose via hydrothermal treatment. Finally, a self-assembled monolayer of 1-octadecanethiol was introduced to create a low-surface-energy, functionalized CuxO-L cathode. Results exhibited an approximately 7.9-fold increase in hydroxyl radical (·OH) generation compared to the initial Cu-F. This enhancement was attributed to two key factors: (Ⅰ) the superior O2-capturing ability of CuxO-L cathode, which led to high H2O2 production due to a 2 nm thick hydrophobic gas layer facilitated O2-capturing; (Ⅱ) a relative high concentration of Cu+ at the CuxO-L cathode promoted the activation of H2O2 into·OH. In addition, the performance of EF with the CuxO-L cathode using sulfathiazole (STZ) as a model pollutant was evaluated. This study offers valuable insights into the design of O2-capturing cathodes in EF processes, particularly for treating emerging organic pollutants.

RESUMEN

Herein, high-efficiency green fluorescence nitrogen doped CDs (G-CDs) were prepared using acetaminophen and ethylenediamine as precursors. The G-CDs exhibited good anti-photobleaching, salttolerance and low cytotoxicity. Interestingly, the G-CDs revealed excellent fluorescence stability in the pH range of 6-12, however, the intensity of the G-CDs was almost completely quenched in other pH values. The MnO4- demonstrated strong fluorescence quenching capability on our G-CDs with the mechanism involving dynamic quenching caused by energy transfer. G-CDs exhibited a strong linear relationship with MnO4- concentration in the range of 0-75 µmol/L, with a low limit detection of 7.6 nmol/L. What was even more interesting was that the G-CDs displayed bright green solid-state fluorescence, and exhibited potential application in anti-counterfeiting.

RESUMEN

An integrated process of sludge in-situ fermentation, biological phosphorus removal and endogenous denitrification (ISFPR-ED) was developed to treat low ratio of chemical oxygen demand to nitrogen (COD/N) wastewater and waste activated sludge (WAS) in a single reactor. Nutrient removal and WAS reduction were achieved due to Tetrasphaera-dominated sludge fermentation provided organic carbon in extending the anaerobic duration. The WAS reduction efficiency, effluent orthophosphate (PO43--P) and total inorganic nitrogen reached 28.1 %, less than 0.4 and 7.2 mg/L, respectively. While organic carbon was reduced by 67 %. Tetrasphaera, conventional polyphosphate accumulating organisms (PAOs) stored glycogen, amino acids, and PHA for nutrient removal. Excess energy from fermentation enhanced anaerobic PO43--P uptake by Tetrasphaera. Tetrasphaera was the dominant PO43--P removal and fermentation bacteria, working synergistically with conventional PAOs and fermenting microorganisms. This integrated process improves nutrient removal efficiency and reduces operating costs for carbon addition and WAS disposal in wastewater treatment.

Asunto(s)

Reactores Biológicos , Carbono , Desnitrificación , Fermentación , Fósforo , Aguas del Alcantarillado , Aguas Residuales , Purificación del Agua , Fósforo/metabolismo , Fósforo/aislamiento & purificación , Aguas del Alcantarillado/microbiología , Carbono/metabolismo , Aguas Residuales/química , Purificación del Agua/métodos , Análisis de la Demanda Biológica de Oxígeno , Nitrógeno/metabolismo , Eliminación de Residuos Líquidos/métodos

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The stability of diabetes formula food for special medical purposes (D-FSMP) was improved by high-pressure homogenization (HPH) at different homogenization pressures (up to 70 MPa) and number of passes (up to 6 times). The process at 60 MPa/4 times was the best. Casein had the highest surface hydrophobicity in this condition. The casein-polysaccharide complexes were endowed with the smallest size (transmission electron microscopy images). The complex particles exhibited nearly neutral wettability (the three-phase contact angle was 90.89°), lower interfacial tension, and the highest emulsifying activity index (EAI) and emulsifying stability index (ESI). The prepared D-FSMP system exhibited the narrowest particle size distribution range, the strongest interfacial deformation resistance and the best storage stability. Therefore, an appropriate intensity of HPH could enhance the stability of D-FSMP by improving the interfacial and emulsifying properties of casein-polysaccharide complexes. This study provides practical guidance on the productions of stable D-FSMP.

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Purpose: Lichen sclerosus urethral stricture disease (LS USD) is a refractory and progressive disease primarily affecting the anterior urethra in males. Various potential etiological factors, such as genetics, autoimmunity, infection, and exposure to infectious urine, have been suggested. However, the accurate etiology of LS in the male urethra remains unclear. Patients and Methods: In this study, we conducted single-cell RNA sequencing to identify the transcriptional profiles of three patients with LS USD and three patients with non-LS USD. Immunofluorescence was used to confirm the single-cell sequence results. Results: Our study revealed distinct subsets of vein endothelial cells (ECs), smooth muscle cells (SMCs), and fibroblasts (FBs) with high proportions in LS USD, contributing to the tissue microenvironment primarily involved in proinflammatory and immune responses. In particular, FBs displayed a unique subset, Fib7, which is exclusively present in LS USD, and exhibited high expression levels of SAA1 and SAA2. The accumulation of macrophages, along with the dysregulated ratios of M1/M2-like phenotype macrophages, may be engaged in the pathogenesis of LS USD. Through cell-cell communication analysis, we identified significant interactions involving CXCL8/ACKR1 and CCR7/CCL19 in LS USD. Remarkably, Fib7 exhibited exclusive communication with IL-1B macrophages through the SAA1/FPR2 receptor-ligand pair. Conclusion: Our study provides a profound understanding of the tissue microenvironment in LS USD, which may be valuable for understanding the pathogenesis of LS USD.

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Prostate cancer (PCa) rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAFs) are critical components of the immunologically "cold" tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from pro-tumorigenic to anti-tumor phenotypes and enhance ICB efficacy in PCa. Integration of four PCa single-cell RNA-sequencing datasets defined pro-tumorigenic and anti-tumor CAFs, and RNA-seq, flow cytometry, and a PCa organoid model demonstrated the functions of two CAF subtypes. Extracellular matrix-associated CAFs (ECM-CAF) promoted collagen deposition and cancer cell progression, and lymphocyte-associated CAFs (Lym-CAF) exhibited an anti-tumor phenotype and induced the infiltration and activation of CD8+ T cells. YAP1 activity regulated the ECM-CAF phenotype, and YAP1 silencing promoted switching to Lym-CAFs. NF-κB p65 was the core transcription factor in the Lym-CAF subset, and YAP1 inhibited nuclear translocation of p65. Selective depletion of YAP1 in ECM-CAFs in vivo promoted CD8+ T-cell infiltration and activation and enhanced the therapeutic effects of anti- PD-1 treatment in PCa. Overall, this study revealed a mechanism regulating CAF identity in PCa and highlighted a therapeutic strategy for altering the CAF subtype to suppress tumor growth and increase sensitivity to ICB.

RESUMEN

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, posing a significant global health concern due to its increasing prevalence. Insulin resistance (IR) plays a major role in the development of T2DM and is often linked to factors such as obesity, physical inactivity, and a sedentary lifestyle. Recently, there has been growing interest in exploring the potential of natural products for improving insulin sensitivity and glucose metabolism. Among these, Cynomorium songaricum Rupr., an edible parasitic plant, has shown promising antidiabetic effects. However, research on its beneficial effects on IR is still nascent. Therefore, this study aims to investigate the application of a Cynomorium songaricum flavonoid-enriched fraction (CSF) in the treatment of IR in T2DM, along with elucidating the chemical and biochemical mechanisms involved. METHOD: First, UHPLC/ESI-LTQ-Orbitrap-MS was utilized to perform a chemical profiling of CSF. Subsequently, glycogen synthesis, gluconeogenesis and glucose consumption assays were conducted on HepG2 cells with a high glucose high insulin-induced IR model to illustrate the favorable impacts of CSF on IR. Then, an innovative network pharmacology analysis was executed to predict the potential chemical components and hub genes contributing to CSF's protective effect against IR. To further elucidate molecular interactions, molecular docking studies were performed, focusing on the binding interactions between active constituents of CSF and crucial targets. Additionally, an RNA-sequencing assay was employed to uncover the underlying biochemical signaling pathway responsible for CSF's beneficial effects. To validate these findings, western blot and qPCR assays were employed to verify the pathways related to IR and the potential signaling cascades leading to the amelioration of IR. RESULTS: The UHPLC/ESI-LTQ-Orbitrap-MS analysis successfully identified a total of thirty-six flavonoids derived from CSF. Moreover, CSF was shown to significantly improve glycogen synthesis and glucose consumption as well as inhibit gluconeogenesis in HepG2 cells of IR. An innovative network pharmacology analysis unveiled key hub genes-AKT1 and PI3K-integral to metabolic syndrome-related signaling pathways, which contributed to the favorable impact of CSF against IR. Noteworthy active ingredients including quercetin, ellagic acid and naringenin were identified as potential contributors to these effects. The results of western blot and qPCR assays provided compelling evidence that CSF improved insulin sensitivity by modulating the PI3K-Akt signaling pathway. Subsequent RNA-sequencing analysis, in tandem with western blot assays, delved deeper into the potential mechanisms underlying CSF's advantageous effects against IR, potentially associated with the enhancement of endoplasmic reticulum (ER) proteostasis. CONCLUSION: CSF exhibited a remarkable ability to enhance insulin sensitivity in the IR model of HepG2 cells. This was evident through enhancements in glycogen synthesis and glucose consumption, along with its inhibitory impact on gluconeogenesis. Furthermore, CSF demonstrated an improvement in the insulin-mediated PI3K-Akt signaling pathway. The potential active constituents were identified as quercetin, ellagic acid and naringenin. The underlying biochemical mechanisms responsible for CSF's beneficial effects against IR were closely linked to its capacity to mitigate ER stress, thereby offering a comprehensive understanding of its protective action.

Asunto(s)

Cynomorium , Diabetes Mellitus Tipo 2 , Flavonoides , Resistencia a la Insulina , Flavonoides/farmacología , Flavonoides/química , Humanos , Células Hep G2 , Cynomorium/química , Cromatografía Líquida de Alta Presión , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Espectrometría de Masa por Ionización de Electrospray/métodos , Gluconeogénesis/efectos de los fármacos , Simulación del Acoplamiento Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Insulina/metabolismo , Glucógeno/metabolismo , Glucosa/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

BACKGROUND: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies. METHODS: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction. RESULTS: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level. CONCLUSION: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Animales , Ratones , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/antagonistas & inhibidores , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/antagonistas & inhibidores , Línea Celular Tumoral , Apoptosis , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica , Femenino

RESUMEN

In this paper, the Fourier spectrum of an image in microsphere-assisted microscopy (MAM) and the wavenumber decomposition of the Poynting vector of the dipole model are compared for the first time to study the super-resolution performance within several wavelengths in MAM. Firstly, an experiment using microsphere-assisted microscopy is performed, and the fast Fourier transformation (FFT) spectra of the images along the distance are studied. Then the Poynting vector in the point dipole field is theoretically investigated based on the spectral decomposition of dyadic Green's function. Our study finds that the result of decomposition of the Poynting vector corresponds with the propagation results of components with different transverse wavenumbers kρ in an experiment. Even when kρ reaches 1.7k0, the waves can still arrive outside one wavelength. Our work is the first effort (to our knowledge) to associate the Fourier spectrum and the decomposition of the Poynting vector together, and it may contribute to the quantitative exploration of super-resolution performance in MAM in the future.

RESUMEN

The ion permeability and selectivity of membranes are crucial in nanofluidic behavior, impacting industries ranging from traditional to advanced manufacturing. Herein, we demonstrate the engineering of ion-conductive membranes featuring angstrom-scale ion-transport channels by introducing ionic polyamidoamine (PAMAM) dendrimers for ion separation. The exterior quaternary ammonium-rich structure contributes to significant electrostatic charge exclusion due to enhanced local charge density; the interior protoplasmic channels of PAMAM dendrimer are assembled to provide additional degrees of free volume. This facilitates the monovalent ion transfer while maintaining continuity and efficient ion screening. The dendrimer-assembled hybrid membrane achieves high monovalent ion permeance of 2.81 mol m-2 h-1 (K+), reaching excellent mono/multivalent selectivity up to 20.1 (K+/Mg2+) and surpassing the permselectivities of state-of-the-art membranes. Both experimental results and simulating calculations suggest that the impressive ion selectivity arises from the significant disparity in transport energy barrier between mono/multivalent ions, induced by the "exterior-interior" synergistic effects of bifunctional membrane channels.