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Bladder cancer (BCa) poses a significant medical burden worldwide. However, the epidemiological pattern of the global smoking-induced BCa burden is unclear. Our analysis of the 2019 Global Burden of Disease (GBD) database showed a significant increase in the number of BCa cases worldwide from 1990 to 2019, with a clear upward trend in both age-standardized prevalence and incidence. In contrast, age-standardized rates of mortality (ASMR) and disability-adjusted life-years (ASDR) showed a downward trend, despite an increase in the absolute number of death and disability-adjusted life years. The burden of BCa caused by smoking is greater in males, middle-aged and older adults, and people in countries with high-middle socio-demographic indices (SDI). The study highlights the continuing global health challenge posed by smoking-related BCa. Targeted health policies and interventions are critical, especially in areas with high smoking rates and low socioeconomic status.
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Volatile halogenated hydrocarbons (VHHs) are annually produced and released into the environment, posing a threat to public health. In this study, a simple, rapid, sensitive and automated method based on headspace and gas chromatography (GC) with electron-capture detection was described for the determination of VHHs in different concentration levels in water samples. The proposed headspace GC method was initially optimized, and the optimum experimental conditions found were 10-mL water sample containing 20% w/v sodium chloride placed in a 20-mL vial and stirred at 60°C for 35 min, and then 14 VHHs were well separated on DB-35 MS capillary column with a split ratio of 12.5: 1. The limits of detection were in the low µg/L level, ranging between 0.01 and 0.6 µg/L. Finally optimized method was applied for determination 14 VHHs in drinking and environmental waters. The total mean concentrations of VHHs were 34.962, 26.183, 3.228 and 647.344 µg/L in tap water, purified water with 1-year-old filter element, seawater and effluents, respectively. However, no VHHs was detected in purified water with a new filter element. The main composition is different among different water matrix, which may be attributed to their different sources.
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Maternal age is one of the most important factors affecting the success of maternal pregnancy. Uterine aging is the leading cause of pregnancy failure in older women. However, how uterine aging affects uterine receptivity and decidualization is unclear. In this study, naturally aged one-year-old female mice were used to investigate effects of maternal age on embryo implantation during early pregnancy. In our study, we found abnormal uterine receptivity in aged mice. Aged mouse uterus indicates a decrease in nuclear LAMIN A, and an increase in PRELAMIN A and PROGERIN. In aged mouse uterus, double-stranded DNA (dsDNA) in cytoplasmic fraction is significantly increased. PROGERIN overexpression in mouse uterine epithelial cells and epithelial organoids leads to nuclear DNA leakage and impaired uterine receptivity. DNase I, DNase II, and TREX1 are obviously reduced in aged mouse uterus. Treatments with foreign DNA or STING agonist significantly downregulate uterine receptivity markers and activate cGAS-STING pathway. Uterine estrogen (E2) concentration is significantly increased in aged mice. After ovariectomized mice are treated with a high level of E2, there are significant increase of PROGERIN and cytoplasmic DNA, and activation of cGAS-STING pathway. CD14 is significantly increased in aged uterus. Intrauterine CD14 injection inhibits embryo implantation. In vitro CD14 treatment of cultured epithelial cells or epithelial organoids decreases uterine receptivity. Uterine abnormality in aged mouse can be partially rescued by STING inhibitor. In conclusion, uterine PROGERIN increase in aged mouse uterus results in cytoplasmic DNA accumulation and cGAS-STING pathway activation. CD14 secretion in aged uterus impairs uterine receptivity.
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BACKGROUND: Changes in the oxidative stress and lipid metabolism (OSLM) pathways play important roles in polycystic ovarian syndrome (PCOS) pathogenesis and development. Consequently, a systematic analysis of genes related to OSLM was conducted to identify molecular clusters and explore new biomarkers that are helpful for the diagnostic of PCOS. METHODS: Gene expression and clinical data from 22 PCOS women and 14 normal women were obtained from the GEO database (GSE34526, GSE95728, and GSE106724). Consensus clustering identified OSLM-related molecular clusters, and WGCNA revealed co-expression patterns. The immune microenvironment was quantitatively assessed utilizing the CIBERSORT algorithm. Multiple machine learning models and connectivity map analyses were subsequently applied to explore potential biomarkers for PCOS, and nomograms were employed to develop a predictive multigene model of PCOS. Finally, the OSLM status of PCOS and the hub genes expression profiles were preliminarily verified using TUNEL, qRTâPCR, western blot, and IHC assays in a PCOS mouse model. RESULTS: 19 differential expression genes (DEGs) related to OSLM were identified. Based on 19 DEGs that were strongly influenced by OSLM, PCOS patients were stratified into two distinct clusters, designated Cluster 1 and Cluster 2. Distinct differences in the immune cell proportions existed in normal and two PCOS clusters. The random forest showed the best results, with the least cross-entropy and the utmost AUC (cross-entropy: 0.111 AUC: 0.960). Among the 19 OSLM-related genes, CXCR1, ACP5, CEACAM3, S1PR4, and TCF7 were identified by a Bayesian network and had a good fit with PCOS disease risk by the nomogram (AUC: 0.990 CI: 0.968-1.000). TUNEL assays revealed more severe DNA damage within the ovarian granule cells of PCOS mice than in those of normal mice (P < 0.001). The RNA and protein expression levels of the five hub genes were significantly elevated in PCOS mice, which was consistent with the results of the bioinformatics analyses. CONCLUSION: A novel predictive model was constructed for PCOS patients and five hub genes were identified as potential biomarkers to offer novel insights into clinical diagnostic strategies for PCOS.
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Metabolismo dos Lipídeos , Estresse Oxidativo , Síndrome do Ovário Policístico , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/imunologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Estresse Oxidativo/genética , Camundongos , Animais , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Regulação da Expressão Gênica , Biomarcadores/metabolismo , Modelos Animais de Doenças , NomogramasRESUMO
Observational studies suggest dyslipidemia as an atopic dermatitis (AD) risk factor and posit that lipid-lowering drugs may influence AD risk, but the causal link remains elusive. Mendelian randomization was applied to elucidate the causal role of serum lipids in AD and assess the therapeutic potential of lipid-lowering drug targets. Genetic variants related to serum lipid traits and lipid-lowering drug targets were sourced from the Global Lipid Genetics Consortium GWAS data. Comprehensive AD data were collated from the UK Biobank, FinnGen, and Biobank Japan. Colocalization, Summary-data-based Mendelian Randomization (SMR), and mediation analyses were utilized to validate the results and pinpoint potential mediators. Among assessed targets, only Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) was significantly linked to a reduced AD risk, corroborated across three separate AD cohorts. No association between serum lipid concentrations or other lipid-lowering drug targets and diminished AD risk was observed. Mediation analysis revealed that beta nerve growth factor (b-NGF) might mediate approximately 12.8% of PCSK9's influence on AD susceptibility. Our findings refute dyslipidemia's role in AD pathogenesis. Among explored lipid-lowering drug targets, PCSK9 stands out as a promising therapeutic agent for AD.
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Dermatite Atópica , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9 , Humanos , Dermatite Atópica/genética , Dermatite Atópica/tratamento farmacológico , Pró-Proteína Convertase 9/genética , Lipídeos/sangue , Predisposição Genética para Doença , Hipolipemiantes/uso terapêutico , Dislipidemias/genética , Dislipidemias/tratamento farmacológico , Feminino , MasculinoRESUMO
Introduction: Cigar wrapper leaves (CWLs) plays a crucial role in reflecting cigar overall quality. Originating from the Qinba region of China, Fangxian Huangjiu (FHJ) is distinctive from other varieties of Huangjiu. Methods: To investigate the effects of FHJ on enhancing the aroma and quality of CWLs, as well as the consequent alterations in microbial communities, Gas Chromatography-Mass Spectrometry (GC-MS) coupled with Odor Active Value (OAV) analysis was utilized to evaluate the volatile aroma components of CWLs. Results and Discussion: The results indicated that the total amount of aroma compounds in CWLs reached 3,086.88 ug/g, increasing of 270.50% and 166.31% compared to the unfermented and naturally fermented groups, respectively. Among them, ß-ionone and 4,7,9-megastigmatrien-3-one from the FHJ fermentation group significantly influenced the sensory characteristics of CWLs. Metagenomic results demonstrated that FHJ fermentation enriched the abundance of both shared and unique microbial species in CWLs, while also increased the diversity of differential microbial species. Addition of FHJ effectively altered the microbial community structure of CWLs from a dominance of Staphylococcus to a prevalence of Staphylococcus, Aspergillus, Pseudomonas, and Acinetobacter. The interactions among these diverse microorganisms collectively contribute to the enhancement of the intrinsic quality of CWLs. This paper provides a theoretical basis for improving the quality of CWLs by FHJ and exploring the changes of microbial community structure and interaction between CWLs and FHJ.
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Functional modification of inorganic particles is an effective approach to tackle the issue of Li+ transport and the lithium dendrites formation in lithium-ion batteries (LIBs). In this study, PMIA/BiOCl composite separators are prepared by nonsolvent induce phase separation (NIPS) method using P-type semiconductor bismuth oxychloride (BiOCl) functionalized poly (m-phenylene isophthalamide) (PMIA) separators. Compared with the polypropylene (PP) separator, PMIA has superior thermal stability and the addition of BiOCl further enhances its flame retardancy. And the prepared PMIA/BiOCl separator presents improved porosity (66.47 %), enhanced electrolyte uptake rate (863 %) and higher ionic conductivity (0.49 mSâcm-1). Besides, the incorporation of BiOCl can anchor PF6- to the three-dimensional network skeleton of the PMIA/BiOCl separators, enabling the desolvation of Li+ and selectively facilitating Li+ transport (the Li+ transfer number is 0.79). Moreover, the uniform porous structure of the PMIA/BiOCl separators and the efficient transport of Li+ uniformly deposite Li+, and minimize the growth of lithium dendrites. Batteries assembled with PMIA/BiOCl separators have a discharge specific capacity of 124.4 mAhâg-1 and capacity retention of 96.7 % after 200 cycles at 0.2C. Therefore, this work provides an effective route in the design strategy of separators for LIBs.
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OBJECTIVES: A Salmonella enterica subsp. diarizonae (hereafter S. diarizonae) clinical strain S499 demonstrated unique genomic features. The strain S499 was treated with polymyxin B in vitro to investigate the mechanism of resistance. METHODS: S499 was treated with polymyxin B by increasing concentration gradually to obtain a resistant mutant S499V. Whole genomes of the two strains were sequenced using Illumina HiSeq X-10 and PacBio RS II platforms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to compare the gene expression. RESULTS: The chromosome of strain S499 contained a 40-kb DNA region that was replicated after treatment with polymyxin B and generated a triple tandem DNA repeat region in the chromosome of mutant strain S499V. This repeat region in S499V was flanked by IS1 and contained pmrD, pmrG, and arnBCADTEF operon. In comparison to the homologous 40-kb DNA region of strain S499, a few genes in the repeat DNA region of strain S499V contained truncating mutations that generate two open reading frames (ORFs). The expression of pmrD, pmrG, and arnT was significantly upregulated in S499V. CONCLUSION: The duplication and overexpression of pmrD, pmrG, and arnT operon may be responsible for the polymyxin B resistance of mutant strain S499V.
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BACKGROUND: Endometrial cancer (EC) is one of the gynecologic malignancy cancer with increasing incidence and mortality rates, partly due to aging populations and genetic risks. This study explores the associations between biological age accelerations (BAA) and risk of incident EC and assesses the joint effect of genetic factor and BAA. MATERIALS AND METHODS: Based on the UK Biobank cohort, 132,315 women participants were included for primary analysis and 124,119 white participants for genetic risk analysis. Biological age(BA) was calculated using the Klemera-Doubal (KDM) and PhenoAge method based on clinical biomarkers. We calculated two metrics for BAA (including KDM residual and PhenoAge residual) using residual analysis, comparing them against chronological age. The risk of incident EC was evaluated using multivariable Cox proportional-hazards models, adjusting for relevant covariates. Polygenic risk scores (PRS) were computed from known EC-associated SNPs. RESULTS: Both KDM and PhenoAge residual, were significantly associated with increased EC risk. In fully adjusted models, the highest tertile of KDM and PhenoAge residual was significantly associated with incident EC compared with the lowest group, with HRs of 1.278 (P=0.0044) and 1.424 (P<0.0001), repectively. The population-attributable fractions were 7.84% for KDM residual (P=0.0044), 9.78% for PhenoAge residual (P=0.0005), and 8.47% for genetic risk (P=0.0005). Additionally, joint associations of BAA and genetic risk with incident EC was evaluated. Compared with low genetic risk and low BAA, high genetic risk and high BAA was significantly associated with the incidence of EC with HRs of up to 2.172 (95% CI 1.592-2.963) for KDM and 2.226 (95% CI 1.640-3.022) for PhenoAge. Overall, higher levels of PhenoAge residual were consistently associated with an increased risk of incident EC, regardless of genetic risk. CONCLUSION: BAA and genetics both enhance the risk of incident EC. The effect of the PhenoAge residual is greater than that of the investigated genes, which in turn is greater than that of the KDM residual. These findings highlight the importance of considering both BAA and genetic factors in EC prevention.
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The abuse and irrational use of tetracyclines (TCs) in human medicine and animal husbandry has become a serious concern, affecting the ecological environment and human health. The aim of this study was to develop a sensitive and selective method using fully automatic solid-phase extraction coupled with ultra-performance liquid chromatography-tandem mass spectrometry for the determination of twelve TCs in water. Four isotope-labeled internal standards for TCs were used to correct matrix effects. Several parameters affecting extraction efficiency were systematically optimized, and the optimum experimental conditions found were 1.0 L water sample with 0.5 g/L Na2EDTA (pH 3.0) extracted and enriched by CNW HLB cartridge and eluted by 4 mL of acetone:methanol (v/v, 1:1). The enrichment factors were up to 798-1059 but only requiring about 60 min per six samples. Under the optimized conditions, the linearity of the method ranged from 0.2 to 100 µg/L for 12 TCs, the detection limits were as low as 0.01-0.15 ng/L, and the recoveries were in the range of 70%-118%, with relative standard deviations less than 15%. The developed method can be successfully utilized for the determination of 12 TCs in pure water, tap water, river water, and mariculture seawater. In summary, three and six TCs were detected in river water and mariculture seawater, respectively, with total concentrations of 0.074-0.520 ng/L (mean 0.248 ng/L) and 0.792-58.369 ng/L (12.629 ng/L), respectively. Tetracycline (TC) and oxytetracycline (OTC) were the dominant TCs in river water, while doxytetracycline (DXC) and OTC were dominant in mariculture seawater.
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Água Potável , Extração em Fase Sólida , Espectrometria de Massas em Tandem , Tetraciclinas , Poluentes Químicos da Água , Espectrometria de Massas em Tandem/métodos , Extração em Fase Sólida/métodos , Tetraciclinas/análise , Poluentes Químicos da Água/análise , Água Potável/análise , Água Potável/química , Cromatografia Líquida de Alta Pressão/métodos , Limite de DetecçãoRESUMO
A series of tetra-coordinate boron-peptide conjugates has been reported. The incorporation of a photochromic organoboron unit into the gelator endows photoactivity to the supramolecular gels. While the structural transformation of the gelator upon UV irradiation minimally impacts the formed self-assembled structures, it indeed influences their rheological properties.
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The aim of this study was to investigate the anti-cancer effects of resveratrol (RES) against gastric cancer (GC) and explore the potential mechanisms. We first measured the anti-cancer effects of RES on GC cell lines (i.e. AGS and HGC-27). Then protein-protein interaction (PPI) network was constructed, followed by GO and KEGG analysis to screen the possible targets. Molecular docking analysis was given to visualize the pharmacological effects of RES on GC cell lines. For the in vivo experiments, xenograft tumor model was established, and Western blot analysis was performed to determine the expression of protein screened by network pharmacology. Our results showed that RES could promote the apoptosis of GC cells. Five hub targets were identified by network pharmacology, including AKT1, TP53, JUN, ESR1 and MAPK14. GO and KEGG analyses revealed the PI3K/Akt/P53 signaling pathway was the most related signaling pathway. Molecular docking analysis indicated that RES could form 3 hydrogen bonds with AKT1 and 3 hydrogen bonds with TP53. The inhibitory effects of RES on the proliferation and promoting effects of RES on the apoptosis of AGS and HGC-27 cells were significantly reversed when blocking the PI3K-Akt signaling pathway using the LY294002. In vivo results showed that RES induced significant decrease of tumor volume and tumor weight without changing the body weight, or inducing significant cytotoxicities. Western blot analysis proved that RES could induce down-regulation of p-Akt and up-regulation of P53 in vivo. In conclusion, RES showed anti-cancer effects in GC by regulating the PI3K/Akt/P53 signaling pathway.
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Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Resveratrol , Neoplasias Gástricas , Proteína Supressora de Tumor p53 , Animais , Humanos , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Mapas de Interação de Proteínas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resveratrol/farmacologia , Transdução de Sinais , Estilbenos/farmacologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Vertically-ordered mesoporous silica films (VMSF, also named as silica isoporous membranes) have shown tremendous potential in the field of electroanalytical sensors due to their unique features in terms of controllable and ultrasmall nanopores, high molecular selectivity and permeability, and mechanical stability. This review will present the recent progress on the biomedical analytical applications of VMSF, focusing on the small biomolecules, diseases-related biomarkers, drugs and cancer cells. Finally, conclusions with recent developments and future perspective of VMSF in the relevant fields will be envisioned.
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Experimental studies on DNA transposable elements (TEs) have been limited in scale, leading to a lack of understanding of the factors influencing transposition activity, evolutionary dynamics, and application potential as genome engineering tools. We predicted 130 active DNA TEs from 102 metazoan genomes and evaluated their activity in human cells. We identified 40 active (integration-competent) TEs, surpassing the cumulative number (20) of TEs found previously. With this unified comparative data, we found that the Tc1/mariner superfamily exhibits elevated activity, potentially explaining their pervasive horizontal transfers. Further functional characterization of TEs revealed additional divergence in features such as insertion bias. Remarkably, in CAR-T therapy for hematological and solid tumors, Mariner2_AG (MAG), the most active DNA TE identified, largely outperformed two widely used vectors, the lentiviral vector and the TE-based vector SB100X. Overall, this study highlights the varied transposition features and evolutionary dynamics of DNA TEs and increases the TE toolbox diversity.
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Elementos de DNA Transponíveis , Humanos , Elementos de DNA Transponíveis/genética , Engenharia Genética/métodos , Genoma Humano , Animais , Evolução MolecularRESUMO
Family with sequence similarity 135 member B (FAM135B) is a novel driver gene in esophageal squamous cell carcinoma (ESCC). However, little is known regarding its biological functions and mechanisms in ESCC. Here, we identified that the high expression of FAM135B was associated with lymph node metastasis and infiltrating development of ESCC. Elevated FAM135B expression promoted ESCC migration and invasion in vitro and lung metastasis in vivo. Furthermore, epithelial-mesenchymal transition (EMT)-related pathways were enriched in ESCC samples with high levels of FAM135B and FAM135B positively regulated EMT markers. Mechanistically, we observed that FAM135B interacted with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), activating the Wnt/ß-catenin signaling pathway. The facilitation of TNIK on ESCC migration and invasion was reversed by FAM135B siRNA. In addition, the N6-methyladenosine (m6A) modification positively regulated FAM135B expression, with methyltransferase like 3 (METTL3) acting as its substantial m6A writer. The pro-EMT effects of METTL3 overexpression were reversed by silencing FAM135B. Collectively, these findings illustrate the critical role of ABCDE in ESCC progression and provide new insights into the upstream and downstream mechanisms of FAM135B.NEW & NOTEWORTHY This study reveals for the first time that the novel cancer-related gene, FAM135B, promotes ESCC metastasis both in vitro and in vivo. Besides, we substantiate FAM135B's action on the ß-catenin pathway through interacting with TNIK, thereby elucidating the promotional effect of FAM135B on ESCC EMT. Furthermore, we provide initial evidence demonstrating that METTL3-mediated m6A modification upregulates the expression of FAM135B in ESCC cells.
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Movimento Celular , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Metiltransferases , Regulação para Cima , Via de Sinalização Wnt , Humanos , Via de Sinalização Wnt/genética , Transição Epitelial-Mesenquimal/genética , Metiltransferases/genética , Metiltransferases/metabolismo , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/metabolismo , Linhagem Celular Tumoral , Animais , Masculino , Feminino , Camundongos Nus , Camundongos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Invasividade Neoplásica , Camundongos Endogâmicos BALB C , Metástase Linfática , Pessoa de Meia-Idade , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genéticaRESUMO
The prompt and accurate point-of-care test (POCT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infected persons or virus-containing environmental samples is of great importance. The present work reports a highly integrated electrochemiluminescence/electrochemical (ECL/EC) sensor for determination of SARS-CoV-2 pseudoviruses, in which bio-recognition element (SARS-CoV-2 IgG antibody), bifunctional probe (tris (2,2'-bipyridyl) ruthenium (Ru(bpy)32+)), and amplification material (gold nanoparticles (Au NPs)) are designed into bipolar silica nanochannel array (bp-SNA). bp-SNA consisting of homogeneous two-layer mesoporous silica films bears inner silanol groups and outer amino groups, generating a solid "electrostatic nanocage" for stable confinement of Ru(bpy)32+ and Au NPs inside the nanochannels and further providing functional sites for covalent modification of SARS-CoV-2 IgG antibody. Owing to the preconcentration capacity of bp-SNA and amplified effect of Au NPs, ECL or EC signals of Ru(bpy)32+ can be remarkably promoted and thereby increase the analytical performance, which can be diminished by immunorecognization of target SARS-CoV-2 pseudoviruses on the sensing interface. The developed integrated ECL/EC sensor based on Ru@AuNPs/bp-SNA modified solid indium tin oxide electrode enables the sensitive analysis of SARS-CoV-2 pseudoviruses by ECL mode with a linear range of 50 TU mL-1-5000 TU mL-1, as well as the EC mode with a linear range of 100 TU mL-1-5000 TU mL-1. Moreover, the designed sensor showed satisfactory results in the analyses of saliva and pond water samples. When flexible electrode substate (polyethylene terephthalate) is employed, Ru@AuNPs/bp-SNA has great potential to integrate with KN95 face masks for direct detection of SARS-CoV-2 pseudoviruses produced from breathing, talking and coughing processes, which could provide an efficient platform for POCT diagnosis.
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COVID-19 , Técnicas Eletroquímicas , Ouro , Limite de Detecção , Medições Luminescentes , Nanopartículas Metálicas , SARS-CoV-2 , Dióxido de Silício , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/imunologia , Nanopartículas Metálicas/química , Ouro/química , Dióxido de Silício/química , Humanos , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Medições Luminescentes/métodos , COVID-19/diagnóstico , COVID-19/virologia , Técnicas Biossensoriais/métodos , Anticorpos Antivirais/imunologia , Imunoglobulina G/análise , Compostos OrganometálicosRESUMO
The podocyte cytoskeleton determines the stability of podocyte structure and function, and their imbalance plays a pathogenic role in podocyte diseases. However, the underlying mechanism of podocyte cytoskeleton damage is not fully understood. Here, we investigate the specific role of cuproptosis in inducing podocyte cytoskeleton injury. In in vitro and in vivo studies, exposure to high levels of copper and adriamycin (ADR) caused significant increases in copper concentration in intracellular and renal tissue. Moreover, excessive accumulation of copper induced cuproptosis, resulting in the destruction of the podocyte cytoskeleton. However, inhibition of copper accumulation to reduce cuproptosis also significantly alleviated the damage of podocyte cytoskeleton. In addition, inhibition of cuproptosis mitigated ADR-induced mitochondrial damage as well as the production of reactive oxygen species and depolarization of mitochondrial membrane potential, and restored adenosine triphosphate (ATP) synthesis. Among the transcriptome sequencing data, the difference of CXCL5 (C-X-C motif chemokine ligand 5) was the most significant. Both high copper and ADR exposure can cause upregulation of CXCL5, and CXCL5 deletion inhibits the occurrence of cuproptosis, thereby alleviating the podocyte cytoskeleton damage. This suggests that CXCL5 may act upstream of cuproptosis that mediates podocyte cytoskeleton damage. In conclusion, cuproptosis induced by excessive copper accumulation may induce podocyte cytoskeleton damage by promoting mitochondrial dysfunction, thereby causing podocyte injury. This indicates that cuproptosis plays an important role in the pathogenesis of podocyte injury and provides a basis for seeking potential targets for the treatment of chronic kidney disease.NEW & NOTEWORTHY Cuproptosis induced by excessive copper accumulation leads to podocyte cytoskeleton damage by promoting mitochondrial dysfunction, and CXCL5 acts as an upstream signal mediating the occurrence of cuproptosis.
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Cobre , Citoesqueleto , Podócitos , Insuficiência Renal Crônica , Podócitos/metabolismo , Podócitos/patologia , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Animais , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/genética , Cobre/metabolismo , Cobre/toxicidade , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Masculino , Doxorrubicina/toxicidade , Camundongos Endogâmicos C57BL , Potencial da Membrana Mitocondrial , HumanosRESUMO
BACKGROUND: Advanced age is associated with an increased risk of adverse cardiovascular events. The relationship between biological age acceleration (BAA), cardiac size, cardiac function, and heart failure (HF) is not well-defined. METHODS: Utilizing the UK Biobank cohort, we assessed biological age using the Klemera-Doubal and PhenoAge method. BAA was quantified by residual analysis compared to chronological age. Cardiovascular magnetic resonance (CMR) imaging provided detailed insights into cardiac structure and function. We employed multivariate regression to examine links between BAA and CMR-derived cardiac phenotypes. Cox proportional hazard regression models analyses was applied to explore the causative relationship between BAA and HF. Additionally, Mendelian randomization was used to investigate the genetic underpinnings of these associations. RESULTS: A significant correlation was found between increased BAA and deleterious changes in cardiac structure, such as diminished left ventricular mass, lower overall ventricular volume, and reduced stroke volumes across ventricles and atria. Throughout a median follow-up of 13.8 years, participants with greater biological aging showed a heightened risk of HF (26% per standard deviation [SD] increase in KDM-BA acceleration, 95% confidence intervals [CI]: 23%-28%; 33% per SD increase in PhenoAge acceleration, 95% CI: 32%-35%). Mendelian randomization analysis suggests a likely causal link between BAA, vital cardiac metrics, and HF risk. CONCLUSIONS: In this cohort, accelerated biological aging may serve as a risk indicator for altered cardiac dimensions, functionality, and the onset of heart failure among middle-aged and elderly adults. It holds promise as a focal point for evaluating risk and developing targeted interventions.
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Cacumen platycladi (CP) is a frequently used traditional Chinese medicine to treat hair loss. In this study, CP fermented by Lactiplantibacillus plantarum CCFM1348 increased the proliferation of human dermal papilla cells. In an in vivo assay, compared to nonfermented CP, postbiotics (fermented CP) and synbiotics (live bacteria with nonfermented CP) promoted hair growth in mice. The Wnt/ß-catenin signaling pathway plays crucial roles in the development of hair follicles, including growth cycle restart and maintenance. Both postbiotics and synbiotics upregulated ß-catenin, a major factor of the Wnt/ß-catenin signaling pathway. Postbiotics and synbiotics also increased the vascular endothelial growth factor expression and decreased the BAX/Bcl2 ratio in the dorsal skin of mice. These results suggest that fermented CP by L. plantarum CCFM1348 may promote hair growth through regulating the Wnt/ß-catenin signaling pathway, promoting the expression of growth factors and reducing apoptosis.
Assuntos
Cabelo , Via de Sinalização Wnt , Animais , Camundongos , Cabelo/metabolismo , Cabelo/crescimento & desenvolvimento , Cabelo/química , Humanos , Via de Sinalização Wnt/efeitos dos fármacos , Biotransformação , Fermentação , beta Catenina/metabolismo , beta Catenina/genética , Masculino , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Folículo Piloso/metabolismo , Folículo Piloso/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Lactobacillus plantarum/metabolismo , Lactobacillus plantarum/crescimento & desenvolvimentoRESUMO
Enzyme immobilization within metal-organic frameworks (MOFs) is a promising solution to avoid denaturation and thereby utilize the desirable properties of enzymes outside of their native environments. The biomimetic mineralization strategy employs biomacromolecules as nucleation agents to promote the crystallization of MOFs in water at room temperature, thus overcoming pore size limitations presented by traditional postassembly encapsulation. Most biomimetic crystallization studies reported to date have employed zeolitic imidazole frameworks (ZIFs). Herein, we expand the library of MOFs suitable for biomimetic mineralization to include zinc(II) MOFs incorporating functionalized terephthalic acid linkers and study the catalytic performance of the enzyme@MOFs. Amine functionalization of terephthalic acids is shown to accelerate the formation of crystalline MOFs enabling new enzyme@MOFs to be synthesized. The structure and morphology of the enzyme@MOFs were characterized by PXRD, FTIR, and SEM-EDX, and the catalytic potential was evaluated. Increasing the linker length while retaining the amino moiety gave rise to a family of linkers; however, MOFs generated with the 2,2'-aminoterephthalic acid linker displayed the best catalytic performance. Our data also illustrate that the pH of the reaction mixture affects the crystal structure of the MOF and that this structural transformation impacts the catalytic performance of the enzyme@MOF.