ABSTRACT
Innovative surface-protecting ligands are in constant demand due to their crucial role in shaping the configuration, property, and application of gold nanoclusters. Here, the unprecedented O-ethyl dithiocarbonate (DTX)-stabilized atomically precise gold nanoclusters, [Au25(PPh3)10(DTX)5Cl2]2+ (Au25DTX-Cl) and [Au25(PPh3)10(DTX)5Br2]2+ (Au25DTX-Br), were synthesized and structurally characterized. The introduction of bidentate DTX ligands not only endowed the gold nanocluster with unique staggered Au25 nanorod configurations but also generated the symmetry breaking from the D5d geometry of the Au25 kernels to the chiral D5 configuration of the Au25 molecules. The chirality of Au25 nanorods was notably revealed through single-crystal X-ray diffraction, and chiral separation was induced by employing chiral DTX ligands. The staggered configurations of Au25 nanorods, as opposed to eclipsed ones, were responsible for the large red shift in the emission wavelengths, giving rise to a promising near-infrared II (NIR-II, >1000 nm) phosphorescence. Furthermore, their performances in photocatalytic sulfide oxidation and electrocatalytic hydrogen evolution reactions have been examined, and it has been demonstrated that the outstanding catalytic activity of gold nanoclusters is highly related to their stability.
ABSTRACT
Rheumatoid arthritis (RA) progression involves multiple cell types, and sequential drug action on target cells is necessary for RA treatment. Nanocarriers are widely used for RA treatment; however, the targeted delivery and on-demand release of multiple drugs remains challenging. Therefore, in this study, a dual-sensitive polymer is developed using chondroitin sulfate (CS) for the co-delivery of the cartilage repair agent, glucosamine (GlcN), and anti-inflammatory drug, tofacitinib (Tof). In the joint cavity, acidic pH facilitates the cleavage of GlcN from CS polymer to repair the cartilage damage. Subsequently, macrophage uptake via CS-CD44 binding and intracellular reactive oxygen species (ROS) mediate conversion of (methylsulfanyl)propylamine to a hydrophilic segment jointly triggered rapid Tof/GlcN release via micelle disassembly. The combined effects of Tof, GlcN, and ROS depletion promote the M1-to-M2 polarization shift to attenuate inflammation. The synergistic effects of these agents against RA are confirmed in vitro and in vivo. Overall, the dual pH/ROS-sensitive CS nanoplatform simultaneously delivers GlcN and Tof, providing a multifunctional approach for RA treatment with synergistic drug effects.
Subject(s)
Arthritis, Rheumatoid , Glucosamine , Piperidines , Pyrimidines , Reactive Oxygen Species , Reactive Oxygen Species/metabolism , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Piperidines/chemistry , Piperidines/pharmacology , Hydrogen-Ion Concentration , Glucosamine/chemistry , Animals , Pyrimidines/chemistry , Pyrimidines/pharmacology , Mice , Drug Carriers/chemistry , Drug Delivery Systems/methods , Drug Synergism , Nanoparticles/chemistry , RAW 264.7 Cells , HumansABSTRACT
Abnormal activation of lung fibroblasts contributes to the initiation and progression of idiopathic pulmonary fibrosis (IPF). The objective of the present study was to investigate the role of fetal-lethal noncoding developmental regulatory RNA (FENDRR) in the activation of lung fibroblasts. Dysregulated long noncoding RNAs in IPF lungs were identified by next-generation sequencing analysis from the two online datasets. FENDRR expression in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis was determined by quantitative real-time PCR. IRP1 (iron-responsive element-binding protein 1), a protein partner of FENDRR, was identified by RNA pulldown-coupled mass spectrometric analysis and confirmed by RNA immunoprecipitation. The interaction region between FENDRR and IRP1 was determined by cross-linking immunoprecipitation. The in vivo role of FENDRR in pulmonary fibrosis was studied using adenovirus-mediated gene transfer in mice. The expression of FENDRR was downregulated in fibrotic human and mouse lungs as well as in primary lung fibroblasts isolated from bleomycin-treated mice. TGF-ß1 (transforming growth factor-ß1)-SMAD3 signaling inhibited FENDRR expression in lung fibroblasts. FENDRR was preferentially localized in the cytoplasm of adult lung fibroblasts and bound IRP1, suggesting its role in iron metabolism. FENDRR reduced pulmonary fibrosis by inhibiting fibroblast activation by reducing iron concentration and acting as a competing endogenous RNA of the profibrotic microRNA-214. Adenovirus-mediated FENDRR gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that FENDRR is an antifibrotic long noncoding RNA and a potential therapeutic target for pulmonary fibrosis.
Subject(s)
Idiopathic Pulmonary Fibrosis/genetics , RNA, Long Noncoding/genetics , Animals , Bleomycin/pharmacology , Cells, Cultured , Down-Regulation/drug effects , Down-Regulation/genetics , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Lung/drug effects , Lung/metabolism , Mice , Mice, Inbred C57BL , MicroRNAs/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Smad3 Protein/genetics , Transforming Growth Factor beta1/geneticsABSTRACT
Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF). However, the mechanisms responsible for the proliferation and activation of fibroblasts are not fully understood. The objective of this study was to investigate the role of miR-101 in the proliferation and activation of lung fibroblasts. miR-101 expression was determined in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis. The regulation of miR-101 and cellular signaling was investigated in pulmonary fibroblasts in vitro The role of miR-101 in pulmonary fibrosis in vivo was studied using adenovirus-mediated gene transfer in mice. The expression of miR-101 was down-regulated in fibrotic lungs from patients with IPF and bleomycin-treated mice. The down-regulation of miR-101 occurred via the E26 transformation-specific (ETS) transcription factor. miR-101 suppressed the WNT5a-induced proliferation of lung fibroblasts by inhibiting NFATc2 signaling via targeting Frizzled receptor 4/6 and the TGF-ß-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-ß receptor 1. Adenovirus-mediated miR-101 gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that miR-101 is an anti-fibrotic microRNA and a potential therapeutic target for pulmonary fibrosis.
Subject(s)
Cell Proliferation , Down-Regulation , Fibroblasts/metabolism , MicroRNAs/biosynthesis , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/adverse effects , Bleomycin/pharmacology , Disease Models, Animal , Female , Fibroblasts/pathology , Frizzled Receptors/genetics , Frizzled Receptors/metabolism , Humans , Male , Mice , MicroRNAs/genetics , NFATC Transcription Factors/genetics , NFATC Transcription Factors/metabolism , Proto-Oncogene Proteins c-ets/genetics , Proto-Oncogene Proteins c-ets/metabolism , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/therapy , Signal Transduction/drug effects , Signal Transduction/genetics , Smad2 Protein/genetics , Smad2 Protein/metabolism , Smad3 Protein/genetics , Smad3 Protein/metabolismABSTRACT
BACKGROUND: MicroRNAs are a group of small RNAs that regulate gene expression at the posttranscriptional level. They regulate almost every aspect of cellular processes. In this study, we investigated whether miR-27b regulates pulmonary fibroblast activation. RESULTS: We found that miR-27b was down-regulated in fibrotic lungs and fibroblasts from an experimental mouse model of pulmonary fibrosis. The overexpression of miR-27b with a lentiviral vector inhibited TGFß1-stimulated mRNA expression of collagens (COL1A1, COL3A1, and COL4A1) and alpha-smooth muscle actin, and protein expression of Col3A1 and alpha-smooth muscle actin in LL29 human pulmonary fibroblasts. miR-27b also reduced contractile activity of LL29. TGFß receptor 1 and SMAD2 were identified as the targets of miR-27b by 3'-untranslated region luciferase reporter and western blotting assays. CONCLUSIONS: Our results suggest that miR-27b is an anti-fibrotic microRNA that inhibits fibroblast activation by targeting TGFß receptor 1 and SMAD2. This discovery may provide new targets for therapeutic interventions of idiopathic pulmonary fibrosis.
Subject(s)
Fibroblasts/metabolism , MicroRNAs/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Animals , Base Sequence , Bleomycin , Down-Regulation/genetics , Lung/cytology , Male , Mice, Inbred C57BL , MicroRNAs/genetics , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism , Smad2 Protein/metabolismABSTRACT
Nanosized noble metallic particles enclosed by high-index facets exhibit superior catalytic activity because of their high density of low-coordinated step atoms at the surface, and thus have attracted growing interest over the past decade. In this article, we employed molecular dynamics simulations to investigate the thermodynamic evolution of tetrahexahedral Rh nanoparticles respectively covered by {210}, {310}, and {830} facets during the heating process. Our results reveal that the {210} faceted nanoparticle exhibits better thermal and shape stability than the {310} and {830} faceted ones. Meanwhile, because the {830} facet consists of {210} and {310} subfacets, the stability of the {830} faceted Rh nanoparticle is dominated by the {310} subfacet, which possesses a relatively poor stability. Furthermore, the shape transformation of these nanoparticles occurs much earlier than their melting. Further analyses indicate that surface atoms with higher coordination numbers display lower surface diffusivity, and are thus more helpful for stabilizing the particle shape. This study offers an atomistic understanding of the thermodynamic behaviors of high-index-faceted Rh nanoparticles.
ABSTRACT
Background: Mental illness in China has traditionally been attributed to physical factors and somatization tendencies, which seldom result in stigma. How has this perception changed after decades of social change? Methods: Based on the Chinese General Social Survey database in 2011, this study constructed a structural equation model to analyze the effects of causal attribution and emotional responses on social distance. The causal attributions include dangerousness, controllability, and responsibility. And the emotional responses encompass negative affect, traditional prejudice, treatment carryover, and exclusionary sentiments. In addition, higher scores indicating greater social distance, whereas a low score reflected stronger emotional responses or a greater degree of internal attribution. Results: The results reported a high level of social distance towards people with mental illness. These findings indicated that emotional responses have a direct impact on social distance. Specifically, when negative affect, traditional prejudice, and exclusionary sentiments increase by one standard deviation, the social distance decreases by 0.497, 0.178, and 0.073 standard deviation, respectively. Conversely, as the level of treatment carryover rises, social distance increases by 0.087. Meanwhile, the causal attribution only exerts a significant indirect effect on social distance by the function of emotional causal responses. Conclusion: The results indicated that the public attributes mental illnesses like depression primarily to psychological issues rather than somatic ones. It suggested widespread stereotypes and public stigma towards people with mental illness in China, as well as an arduous task in anti-stigma. In addition, a targeted way to address public stigma lies in changing the stereotype of people with mental illness.
ABSTRACT
Li-rich layered oxides are promising candidates for high-capacity Li-ion battery cathode materials. In this study, we employ first-principles calculations to investigate the effect of F doping on Li-rich Li2MnO3 layered cathode materials. Our findings reveal that both Li2MnO3 and Li2MnO2.75F0.25 exhibit significant volume changes (greater than 10%) during deep delithiation, which could hinder the cycling of more Li ions from these two materials. For Li2MnO3, it is observed that oxygen ions lose electrons to compensate for charge during the delithiation process, leading to a relatively high voltage plateau. After F doping, oxidation occurs in both the cationic (Mn) and anionic (O) components, resulting in a lower voltage plateau at the beginning of the charge, which can be attributed to the oxidation of Mn3+ to Mn4+. Additionally, F doping can somewhat suppress the release of oxygen in Li2MnO3, improving the stability of anionic oxidation. However, the increase of the activation barriers for Li diffusion can be observed after F doping, due to stronger electrostatic interactions between F- and Li+, which adversely affects the cycling kinetics of Li2MnO2.75F0.25. This study enhances our understanding of the impact of F doping in Li2MnO3 based on theoretical calculations.
ABSTRACT
The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.
Subject(s)
Aging , Aortic Aneurysm , Aortic Dissection , Cellular Senescence , MicroRNAs , Muscle, Smooth, Vascular , Myosin-Light-Chain Kinase , Signal Transduction , Animals , Female , Humans , Male , Mice , Aging/genetics , Aging/metabolism , Angiotensin II/metabolism , Aortic Aneurysm/metabolism , Aortic Aneurysm/genetics , Aortic Aneurysm/pathology , Aortic Dissection/metabolism , Aortic Dissection/genetics , Aortic Dissection/pathology , Calcium-Binding Proteins , Disease Models, Animal , Mice, Inbred C57BL , MicroRNAs/genetics , MicroRNAs/metabolism , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/metabolism , Myosin-Light-Chain Kinase/metabolism , Myosin-Light-Chain Kinase/genetics , Transforming Growth Factor beta/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/geneticsABSTRACT
Macrophages play an essential role in host defense and display remarkable plasticity in switching between classically (pro-inflammatory-M1) and alternatively activated (anti-inflammatory-M2) phenotypes. The molecular mechanisms of macrophage polarization are not fully understood. Long non-coding RNAs (lncRNAs) with a length of > 200 nucleotides have been shown to play diverse roles in biological processes. Aberrant expression of lncRNAs is associated with a variety of pathophysiological conditions such as cancer, diabetes, cardiovascular, pulmonary diseases, and tissue fibrosis. In this study, we investigated the role of lncRNA FENDRR in human and mouse macrophage polarization. Human THP-1 monocytes were activated with phorbol-12-myristate-13-acetate (PMA) and differentiated into M1 macrophages with IFNγ or M2 macrophages with IL4. Real-time PCR analysis revealed that FENDRR was expressed 80-fold higher in M1 macrophages than that in M2 macrophages. Overexpression of FENDRR in PMA-activated THP-1 cells increased the IFNγ-induced expression of M1 markers, including IL1ß and TNFα at both mRNA and protein levels. Knockdown of FENDRR had an opposite effect. Similarly, FENDRR overexpression in primary mouse bone marrow-derived macrophages increased mRNA expression of M1 markers. FENDRR overexpression increased, while FENDRR knock-down decreased, the IFNγ-induced phosphorylation of STAT1 in PMA-activated THP-1 cells. Our studies suggest that FENDRR enhances IFNγ-induced M1 macrophage polarization via the STAT1 pathway.
Subject(s)
Down-Regulation , Interferon-gamma/pharmacology , Monocytes/cytology , RNA, Long Noncoding/genetics , Animals , Cell Polarity , Down-Regulation/drug effects , Gene Knockdown Techniques , Humans , Macrophage Activation , Mice , Monocytes/metabolism , STAT1 Transcription Factor/metabolism , THP-1 CellsABSTRACT
Introducing hollow structures into metallic nanoparticles has become a promising route to improve their catalytic performances. A fundamental understanding of thermal stability of these novel nanostructures is of significance for their syntheses and applications. In this article, molecular dynamics simulations have been employed to offer insights into the thermodynamic evolution of hollow bimetallic core-shell nanoparticles. Our investigation reveals that for hollow Pt-core/Au-shell nanoparticle, premelting originates at the exterior surface, and a typical two-stage melting behavior is exhibited, similar to the solid ones. However, since the interior surface provides facilitation for the premelting initiating at the core, the two-stage melting is also observed in hollow Au-core/Pt-shell nanoparticle, remarkably different from the solid one. Furthermore, the collapse of hollow structure is accompanied with the overall melting of the hollow Pt-core/Au-shell nanoparticle while it occurs prior to that of the hollow Au-core/Pt-shell nanoparticle and leads to the formation of a liquid-core/solid-shell structure, although both of them finally transform into a mixing alloy with Au-dominated surface. Additionally, the existence of stacking faults in the hollow Pt-core/Au-shell nanoparticle distinctly lowers its melting point. This study could be of great importance to the design and development of novel nanocatalysts with both high activity and excellent stability.