RESUMO
The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.
Assuntos
Fibrilação Atrial , Cálcio , Átrios do Coração , Camundongos Knockout , Miócitos Cardíacos , Fatores de Transcrição , Animais , Miócitos Cardíacos/metabolismo , Camundongos , Fibrilação Atrial/metabolismo , Fibrilação Atrial/genética , Cálcio/metabolismo , Átrios do Coração/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Sinalização do Cálcio , Potenciais de Ação , Potenciais da Membrana , MasculinoRESUMO
BACKGROUND: Telomere shortening is strongly associated with cardiovascular aging and disease, and patients with shorter telomeres in peripheral blood leukocytes are at higher risk of cardiovascular diseases such as heart failure and atrial fibrillation (AF). Telomerase reverse transcriptase (TERT) maintains telomere length, and overexpression of TERT has been shown to reduce cardiomyocyte apoptosis and myocardial infarct size, and extend the lifespan of aged mice. However, the specific impact of TERT on the electrophysiology of cardiomyocytes remains to be elucidated. The aims of this study were to evaluate the role of TERT in Ca2+ homeostasis and mitochondrial function in atrial myocytes as well as the underlying mechanisms. METHODS: TERT overexpressed and silenced HL-1 cells were constructed with lentiviruses, and the respective empty lentiviral vectors were used as negative controls. Then the patch clamp technique was used to record the electrophysiological characteristics such as cell action potential duration (APD) and L-type Ca2+ currents (ICa,L), flow cytometry was used to detect intracellular Ca2+ concentration and mitochondrial membrane potential (MMP), and the Seahorse assay was used to measure the oxygen consumption rate (OCR). RESULTS: TERT silencing led to intracellular Ca2+ overload, shortened APD, decreased ICa,L current density, altered Ca2+ gating mechanism, decreased MMP and OCR, and increased reactive oxygen species (ROS), whereas TERT overexpression led to the reverse effects. Additionally, TERT silencing resulted in intracellular Ca2+ overload with decreased expression of the SERCA2a, CaV1.2, and NCX1.1, whereas TERT overexpression had opposing effects. Furthermore, we discovered that TERT could regulate the expression of p53 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The expression of PGC-1α was downregulated by the p53 agonist Tenovin-6 but upregulated by the p53 inhibitor PFTα. The effects of the PGC-1α inhibitor SR-18292 on intracellular Ca2+ and cell electrophysiology were similar to those of silencing TERT, whereas the PGC-1α agonist ZLN005 produced comparable outcomes to TERT overexpression. CONCLUSIONS: TERT silencing-induced Ca2+ overload and mitochondrial dysfunction may be one mechanism of age-related AF. Overexpression of TERT reduced the basis for arrhythmia formation such as AF, suggesting a favorable safety profile for TERT therapy. TERT regulated intracellular Ca2+ homeostasis and mitochondrial function through the p53/PGC-1α pathway. In addition, PGC-1α might be a novel target for AF, suggesting that intervention for AF should be not limited to abnormal cation handling.
Assuntos
Cálcio , Homeostase , Potencial da Membrana Mitocondrial , Miócitos Cardíacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Telomerase , Proteína Supressora de Tumor p53 , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Cálcio/metabolismo , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Telomerase/metabolismo , Telomerase/genética , Miócitos Cardíacos/metabolismo , Linhagem Celular , Mitocôndrias/metabolismo , Potenciais de Ação , Transdução de SinaisRESUMO
Plants delicately regulate endogenous auxin levels through the coordination of transport, biosynthesis, and inactivation, which is crucial for growth and development. While it is well-established that the actin cytoskeleton can regulate auxin levels by affecting polar transport, its potential role in auxin biosynthesis has remained largely unexplored. Using LC-MS/MS-based methods combined with fluorescent auxin marker detection, we observed a significant increase in root auxin levels upon deletion of the actin bundling proteins AtFIM4 and AtFIM5. Fluorescent observation, immunoblotting analysis, and biochemical approaches revealed that AtFIM4 and AtFIM5 affect the protein abundance of the key auxin synthesis enzyme YUC8 in roots. AtFIM4 and AtFIM5 regulate the auxin synthesis enzyme YUC8 at the protein level, with its degradation mediated by the 26S proteasome. This regulation modulates auxin synthesis and endogenous auxin levels in roots, consequently impacting root development. Based on these findings, we propose a molecular pathway centered on the 'actin cytoskeleton-26S proteasome-YUC8-auxin' axis that controls auxin levels. Our findings shed light on a new pathway through which plants regulate auxin synthesis. Moreover, this study illuminates a newfound role of the actin cytoskeleton in regulating plant growth and development, particularly through its involvement in maintaining protein homeostasis via the 26S proteasome.
RESUMO
BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15â mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.
Assuntos
LDL-Colesterol , Hiperlipoproteinemia Tipo II , Humanos , Feminino , Masculino , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Adulto , LDL-Colesterol/sangue , Pessoa de Meia-Idade , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Criança , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , HomozigotoRESUMO
Fluorene-9-bisphenol (BHPF) is an emerging contaminant. Presently, there is no report on its interaction with G protein-coupled estrogen receptor 1 (GPER). By using an integrated toxicity research scenario that combined theoretical study with experimental methods, BHPF was found to inhibit the GPER-mediated effect via direct receptor binding. Molecular dynamics simulations found that Trp2726.48 and Glu2756.51 be the key amino acids of BHPF binding with GPER. Moreover, the calculation indicated that BHPF was a suspected GPER inhibitor, which neither can activate GPER nor is able to form water channels of GPER. The role of two residues was successfully verified by following gene knockout and site-directed mutagenesis assays. Further in vitro assays showed that BHPF could attenuate the increase in intracellular concentration of free Ca2+ induced by G1-activated GPER. Besides, BHPF showed an enhanced cytotoxicity compared with G15, indicating that BHPF might be a more potent GPER inhibitor than G15. In addition, a statistically significant effect on the mRNA level of GPER was observed for BHPF. In brief, the present study proposes that BHPF be a GPER inhibitor, and its GPER molecular recognition mechanism has been revealed, which is of great significance for the health risk and assessment of BHPF.
Assuntos
Apoptose , Humanos , Apoptose/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Linhagem Celular Tumoral , Fluorenos , Fenóis/farmacologia , Fenóis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
OBJECTIVE: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. RESEARCH AND DESIGN METHODS: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. RESULTS: Between the baseline and 12-month time point, plasma IL-1B was reduced (- 1.8 pg/mL, P = 0.003) while ketones were increased (0.26 mM, P = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (- 158.9 pmole/min/106 cells, P = 0.0497 vs. - 5.2 pmole/min/106 cells, P = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. GOV REGISTRATION: NCT03782259.
Assuntos
Compostos Benzidrílicos , Biomarcadores , Diabetes Mellitus Tipo 2 , Glucosídeos , Mediadores da Inflamação , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Glucosídeos/uso terapêutico , Glucosídeos/efeitos adversos , Feminino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Mediadores da Inflamação/sangue , Biomarcadores/sangue , Fatores de Tempo , Anti-Inflamatórios/uso terapêutico , Fibrose , Inflamação/tratamento farmacológico , Inflamação/sangue , Inflamação/diagnóstico , Método Duplo-Cego , Miocárdio/patologia , Miocárdio/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/sangueRESUMO
Objective: Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. Research and Design Methods: This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); cardiac tissue inflammation was assessed by T2 mapping. Results: Between the baseline and 12-month time point, plasma IL-1B was reduced (-1.8 pg/mL, P=0.003) while ketones were increased (0.26 mM, P=0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (-158.9 pmole/min/106cells, P=0.0497 vs -45.2 pmole/min/106cells, P=0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. ECV and T2 relaxation time did not change in both study groups. Conclusion: This study demonstrates that 12 months of dapagliflozin reduces IL-1B mediated systemic inflammation but affect cardiac fibrosis in T2D. Clinical Trialgov Registration: NCT03782259.
RESUMO
Many viruses, including foot-and-mouth disease virus (FMDV), can promote the degradation of host proteins through macroautophagy/autophagy, thereby promoting viral replication. However, the regulatory mechanism between autophagy and innate immune responses is not fully understood during FMDV infection. Here, we found that the host GTPBP4/NOG1 (GTP binding protein 4) is a negative regulator of innate immune responses. GTPBP4 deficiency promotes the antiviral innate immune response, resulting in the ability of GTPBP4 to promote FMDV replication. Meanwhile, GTPBP4-deficient mice are more resistant to FMDV infection. To antagonize the host's antiviral immunity, FMDV structural protein VP1 promotes the expression of GTPBP4, and the 209th site of VP1 is responsible for this effect. Mechanically, FMDV VP1 promotes autophagy during virus infection and interacts with and degrades YTHDF2 (YTH N6-methyladenosine RNA binding protein F2) in an AKT-MTOR-dependent autophagy pathway, resulting in an increase in GTPBP4 mRNA and protein levels. Increased GTPBP4 inhibits IRF3 binding to the Ifnb/Ifn-ß promoter, suppressing FMDV-induced type I interferon production. In conclusion, our study revealed an underlying mechanism of how VP1 negatively regulates innate immunity through the autophagy pathway, which would contribute to understanding the negative regulation of host innate immune responses and the function of GTPBP4 and YTHDF2 during FMDV infection.Abbreviation: 3-MA:3-methyladenine; ACTB: actin beta; ATG: autophagy related; ChIP:chromatin immunoprecipitation; CQ: chloroquine; DAPI:4',6-diamidino-2-phenylindole; dpi: days post-infection; EV71:enterovirus 71; FMDV: foot-and-mouth disease virus; GTPBP4/NOG1: GTPbinding protein 4; HIF1A: hypoxia inducible factor 1 subunit alpha;hpt:hours post-transfection; IFNB/IFN-ß:interferon beta; IRF3: interferon regulatory factor 3; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAVS: mitochondriaantiviral signaling protein; MOI: multiplicity of infection; MTOR:mechanistic target of rapamycin kinase; m6A: N(6)-methyladenosine;qPCR:quantitativePCR; SIRT3:sirtuin 3; SQSTM1/p62: sequestosome 1; STING1: stimulator ofinterferon response cGAMP interactor 1; siRNA: small interfering RNA;TBK1: TANK binding kinase 1; TCID50:50% tissue culture infectious doses; ULK1: unc-51 like autophagyactivating kinase 1; UTR: untranslated region; WT: wild type; YTHDF2:YTH N6-methyladenosine RNA binding protein F2.
Assuntos
Autofagia , Proteínas do Capsídeo , Vírus da Febre Aftosa , Febre Aftosa , Fator Regulador 3 de Interferon , Proteínas de Ligação a RNA , Replicação Viral , Animais , Humanos , Camundongos , Autofagia/fisiologia , Autofagia/genética , Proteínas do Capsídeo/metabolismo , Febre Aftosa/virologia , Febre Aftosa/metabolismo , Vírus da Febre Aftosa/fisiologia , Células HEK293 , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Suínos , Serina-Treonina Quinases TOR/metabolismo , Replicação Viral/fisiologiaRESUMO
Metal oxides with oxygen vacancies have a significant impact on catalytic activity for the transformation of organic pollutants in waste-to-energy (WtE) incineration processes. This study aims to investigate the influence of hematite surface oxygen point defects on the formation of environmentally persistent free radicals (EPFRs) from phenolic compounds based on the first-principles calculations. Two oxygen-deficient conditions were considered: oxygen vacancies at the top surface and on the subsurface. Our simulations indicate that the adsorption strength of phenol on the α-Fe2O3(0001) surface is enhanced by the presence of oxygen vacancies. However, the presence of oxygen vacancies has a negative impact on the dissociation of the phenol molecule, particularly for the surface with a defective point at the top layer. Thermo-kinetic parameters were established over a temperature range of 300-1000 K, and lower reaction rate constants were observed for the scission of phenolic O-H bonds over the oxygen-deficient surfaces compared to the pristine surface. The negative effects caused by the oxygen-deficient conditions could be attributed to the local reduction of FeIII to FeII, which lower the oxidizing ability of surface reaction sites. The findings of this study provide us a promising approach to regulate the formation of EPFRs.
Assuntos
Compostos Férricos , Oxigênio , Compostos Férricos/química , Radicais Livres/química , Fenóis , Fenol/químicaRESUMO
Organophosphate triesters (tri-OPEs) threaten human health through dietary exposure, but little is known about their feed-to-food transfer and in vivo behavior in farm animals. Herein 135 laying hens were fed with contaminated feed (control group, low-level group and high-level group) to elucidate the bioaccumulation, distribution, and metabolism of the six most commonly reported tri-OPEs. The storage (breast muscle), metabolism and mobilization (liver and blood) and non-invasive (feather) tissues were collected. The exposure-increase (D1â¼14) and depuration-decrease (D15â¼42) trends indicated that feed exposure caused tri-OPE accumulation in animal tissues. Tissue-specific and moiety-specific behavior was observed for tri-OPEs. The highest transfer factor (TF) and transfer rate (TR) were observed in liver (TF: 14.8%â¼82.3%; TR: 4.40%â¼24.5%), followed by feather, breast muscle, and blood. Tris(2-chloroisopropyl) phosphate (TCIPP) had the longest half-life in feather (72.2 days), while triphenyl phosphate (TPhP) showed the shortest half-life in liver (0.41 days). Tri-OPEs' major metabolites (organophosphate diesters, di-OPEs) were simultaneously studied, which exhibited dose-dependent and time-dependent variations following administration. In breast muscle, the inclusion of di-OPEs resulted in TF increases of 735%, 1108%, 798%, and 286% than considering TCIPP, tributyl phosphate, tris(2-butoxyethyl) phosphate and tris(2-ethylhexyl) phosphate alone. Feather was more of a proxy of birds' long-term exposure to tri-OPEs, while short-term exposure was better reflected by di-OPEs. Both experimental and in silico modeling methods validated aryl-functional group facilitated the initial accumulation and metabolism of TPhP in the avian liver compared to other moiety-substituted tri-OPEs.
Assuntos
Galinhas , Retardadores de Chama , Animais , Feminino , Humanos , Bioacumulação , Galinhas/metabolismo , Ésteres/metabolismo , Biotransformação , Organofosfatos/metabolismo , Fosfatos , Retardadores de Chama/análise , China , Monitoramento AmbientalRESUMO
Cancer remains a significant global health concern, with millions of deaths attributed to it annually. Environmental pollutants play a pivotal role in cancer etiology and contribute to the growing prevalence of this disease. The carcinogenic assessment of these pollutants is crucial for chemical health evaluation and environmental risk assessments. Traditional experimental methods are expensive and time-consuming, prompting the development of alternative approaches such as in silico methods. In this regard, deep learning (DL) has shown potential but lacks optimal performance and interpretability. This study introduces an interpretable DL model called CarcGC for chemical carcinogenicity prediction, utilizing a graph convolutional neural network (GCN) that employs molecular structural graphs as inputs. Compared to existing models, CarcGC demonstrated enhanced performance, with the area under the receiver operating characteristic curve (AUCROC) reaching 0.808 on the test set. Due to air pollution is closely related to the incidence of lung cancers, we applied the CarcGC to predict the potential carcinogenicity of chemicals listed in the United States Environmental Protection Agency's Hazardous Air Pollutants (HAPs) inventory, offering a foundation for environmental carcinogenicity screening. This study highlights the potential of artificially intelligent methods in carcinogenicity prediction and underscores the value of CarcGC interpretability in revealing the structural basis and molecular mechanisms underlying chemical carcinogenicity.
Assuntos
Poluentes Atmosféricos , Aprendizado Profundo , Poluentes Ambientais , Neoplasias , Estados Unidos , Humanos , Carcinógenos/químicaRESUMO
Endocrine-disrupting chemicals (EDCs) pose significant environmental and health risks due to their potential to interfere with nuclear receptors (NRs), key regulators of physiological processes. Despite the evident risks, the majority of existing research narrows its focus on the interaction between compounds and the individual NR target, neglecting a comprehensive assessment across the entire NR family. In response, this study assembled a comprehensive human NR dataset, capturing 49,244 interactions between 35,467 unique compounds and 42 NRs. We introduced a cross-attention network framework, "CatNet", innovatively integrating compound and protein representations through cross-attention mechanisms. The results showed that CatNet model achieved excellent performance with an area under the receiver operating characteristic curve (AUCROC) = 0.916 on the test set, and exhibited reliable generalization on unseen compound-NR pairs. A distinguishing feature of our research is its capacity to expand to novel targets. Beyond its predictive accuracy, CatNet offers a valuable mechanistic perspective on compound-NR interactions through feature visualization. Augmenting the utility of our research, we have also developed a graphical user interface, empowering researchers to predict chemical binding to diverse NRs. Our model enables the prediction of human NR-related EDCs and shows the potential to identify EDCs related to other targets.
Assuntos
Aprendizado Profundo , Disruptores Endócrinos , Humanos , Disruptores Endócrinos/químicaRESUMO
The investigation of pollutant behavior at water interfaces is critical to understand pollution in aquatic systems. Computational methods allow us to overcome the limitations of experimental analysis, delivering valuable insights into the chemical mechanisms and structural characteristics of pollutant behavior at interfaces across a range of scales, from microscopic to mesoscopic. Quantum mechanics, all-atom molecular dynamics simulations, coarse-grained molecular dynamics simulations, and dissipative particle dynamics simulations represent diverse molecular interaction calculation methods that can effectively model pollutant behavior at environmental interfaces from atomic to mesoscopic scales. These methods provide a rich variety of information on pollutant interactions with water surfaces. This review synthesizes the advancements in applying typical computational methods to the formation, adsorption, binding, and catalytic conversion of pollutants at water interfaces. By drawing on recent advancements, we critically examine the current challenges and offer our perspective on future directions. This review seeks to advance our understanding of computational techniques for elucidating pollutant behavior at water interfaces, a critical aspect of water research.
Assuntos
Poluentes Ambientais , Água , Água/química , Simulação de Dinâmica MolecularRESUMO
Investigating soil organic matter's (SOM) microscale assembly and functionality is challenging due to its complexity. This study constructs comparatively realistic SOM models, including diverse components such as Leonardite humic acid (LHA), lipids, peptides, carbohydrates, and lignin, to unveil their spontaneous self-assembly behavior at the mesoscopic scale through microsecond coarse-grained molecular dynamics simulations. We discovered an ordered SOM aggregation creating a layered phase from its hydrophobic core to the aqueous phase, resulting in an increasing O/C ratio and declining structural amphiphilicity. Notably, the amphiphilic lipids formed a bilayer membrane, partnering with lignin to constitute SOM's hydrophobic core. LHA, despite forming a layer, was embedded within this structure. The formation of such complex architectures was driven by nonbonded interactions between components. Our analysis revealed component-dependent diffusion effects within the SOM system. Lipids, peptides, and lignin showed inhibitory effects on self-diffusion, while carbohydrates facilitated diffusion. This study offers novel insights into the dynamic behavior and assembly of SOM components, introducing an effective approach for studying dynamic SOM mechanisms in aquatic environments.
Assuntos
Simulação de Dinâmica Molecular , Solo , Solo/química , Água/química , Lignina , Substâncias Húmicas , Peptídeos/química , Lipídeos , CarboidratosRESUMO
Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016 pM.The mechanism was related to binding with Y453 of RBD deter-mined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quan-tum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)path-ways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
RESUMO
The purpose of this study was to determine the effect of amiodarone (Ami) on hERG-T618I currents in HEK293 cells. A transient transfection method was used to transfer hERG-T618I and hERG wild-type (WT) channel plasmids into HEK293 cells. An extracellular local perfusion method was used for administration. Currents were recorded using the whole-cell patch clamp technique. Ami (10 µM) had a greater retarding effect on the hERG-T618I channel than WT (P < 0.05). The half-inhibitory concentration for the mutant was approximately 1.82 times that of WT (P < 0.05). The WT current inhibition fraction against Ami was significantly greater than T618I in the same cell (P < 0.05). The STEP current of the mutant channel was larger than the WT channel, but the characteristic of inward rectification did not appear. Ami reduced the STEP current of the mutant channel, and the steady-state activation curve indicated that channel activation decreased (P > 0.05). Ami restored partial inactivation of the mutant channel. Ami effectively reduced the current in the phase 2 plateau (P < 0.05), but the phase 3 current did not exhibit the characteristics of a WT current. Ami inhibited hERG-T618I currents on HEK293 cells, but the effect was weaker than WT.
RESUMO
Objective: To understand the situation and risk factors of skin lesions following the eruption of shingles. Methods: We selected 275 patients with shingles who had been diagnosed and treated in the Dermatology Department of Changshu No. 1 People's Hospital between July 2017 and March 2022. Age, gender, skin lesion site, skin lesion type, prodromal pain, history of diabetes, history of hypertension, history of other immune diseases, as well as other pertinent clinical data, were collected. The severity and pain of patients with severe shingles were evaluated, and their fasting blood sugar and plasma albumin were measured for routine antiviral treatment. They were followed up 6 months-the types of skin lesions and pertinent clinical data were compared, and the risk factors for skin lesions were analyzed. Results: There were no statistically significant differences in gender, age, or site among the different types of skin lesions (P > 0.05). The severity of skin lesions, acute pain, history of diabetes, history of scars, low immune function, combined with hypoproteinemia, squeezing and stripping behavior, and post-herpetic neuralgia (PHN) were significantly associated with skin lesions (P < 0.05). The results of multivariate analysis showed that: age ≥60 years old, severe skin injury combined with diabetes, low immune function, scar history, squeezing and stripping were independent risk factors for the development of skin lesions due to shingles. Conclusion: There is no significant difference in age, gender, site, or other characteristics between the types of skin lesions due to shingles. The independent risk factors of skin lesions due to shingles are old age, severe rash, history of scars, diabetes, low immunity, squeezing, and peeling.
RESUMO
The innate immune system is the first line of the host's defense, and studying the mechanisms of the negative regulation of interferon (IFN) signaling is important for maintaining the balance of innate immune responses. Here, we found that the host GTP-binding protein 4 (NOG1) is a negative regulator of innate immune responses. Overexpression of NOG1 inhibited viral RNA- and DNA-mediated signaling pathways, and NOG1 deficiency promoted the antiviral innate immune response, resulting in the ability of NOG1 to promote viral replication. Vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) infection induced a higher level of IFN-ß protein in NOG1 deficient mice. Meanwhile, NOG1-deficient mice were more resistant to VSV and HSV-1 infection. NOG1 inhibited type I IFN production by targeting IRF3. NOG1 was also found to interact with phosphorylated IFN regulatory factor 3 (IRF3) to impair its DNA binding activity, thereby downregulating the transcription of IFN-ß and downstream IFN-stimulated genes (ISGs). The GTP binding domain of NOG1 is responsible for this process. In conclusion, our study reveals an underlying mechanism of how NOG1 negatively regulates IFN-ß by targeting IRF3, which uncovers a novel role of NOG1 in host innate immunity.
Assuntos
Herpes Simples , Infecções por Herpesviridae , Interferon Tipo I , Animais , Camundongos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Expressão Gênica , Imunidade Inata , DNA , Interferon Tipo I/metabolismoRESUMO
There are no planets intermediate in size between Earth and Neptune in our Solar System, yet these objects are found around a substantial fraction of other stars1. Population statistics show that close-in planets in this size range bifurcate into two classes on the basis of their radii2,3. It is proposed that the group with larger radii (referred to as 'sub-Neptunes') is distinguished by having hydrogen-dominated atmospheres that are a few percent of the total mass of the planets4. GJ 1214b is an archetype sub-Neptune that has been observed extensively using transmission spectroscopy to test this hypothesis5-14. However, the measured spectra are featureless, and thus inconclusive, due to the presence of high-altitude aerosols in the planet's atmosphere. Here we report a spectroscopic thermal phase curve of GJ 1214b obtained with the James Webb Space Telescope (JWST) in the mid-infrared. The dayside and nightside spectra (average brightness temperatures of 553 ± 9 and 437 ± 19 K, respectively) each show more than 3σ evidence of absorption features, with H2O as the most likely cause in both. The measured global thermal emission implies that GJ 1214b's Bond albedo is 0.51 ± 0.06. Comparison between the spectroscopic phase curve data and three-dimensional models of GJ 1214b reveal a planet with a high metallicity atmosphere blanketed by a thick and highly reflective layer of clouds or haze.
RESUMO
Despite the fact that coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been disrupting human life and health worldwide since the outbreak in late 2019, the impact of exogenous substance exposure on the viral infection remains unclear. It is well-known that, during viral infection, organism receptors play a significant role in mediating the entry of viruses to enter host cells. A major receptor of SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2). This study proposes a deep learning model based on the graph convolutional network (GCN) that enables, for the first time, the prediction of exogenous substances that affect the transcriptional expression of the ACE2 gene. It outperforms other machine learning models, achieving an area under receiver operating characteristic curve (AUROC) of 0.712 and 0.703 on the validation and internal test set, respectively. In addition, quantitative polymerase chain reaction (qPCR) experiments provided additional supporting evidence for indoor air pollutants identified by the GCN model. More broadly, the proposed methodology can be applied to predict the effect of environmental chemicals on the gene transcription of other virus receptors as well. In contrast to typical deep learning models that are of black box nature, we further highlight the interpretability of the proposed GCN model and how it facilitates deeper understanding of gene change at the structural level.