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1.
J Nanosci Nanotechnol ; 20(2): 1008-1012, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31383098

RESUMO

Institute of Materials, Chinese Academy of Engineering Physics, Jiangyou 621908, P. R. China To improve the stability of organic-inorganic hybrid perovskite, cesium-containing methylammonium lead iodide perovskite have been synthesized by one-step solution deposition. With the increasing of Cs+ doping concentration, direct optical band gap of perovskite was increases, while defects and roughness of perovskite thin films were gradually augmented. A certain amount of Cs+ incorporated in perovskite absorb layer could improve power conversion efficiency through the enhancing of open circuit voltage and fill factor. However, excessive Cs+ doping concentration results in the reduced of short-circuit current and fill factor, which reduced power conversion efficiency. The optimized ratio 10% Cs+ doping achieved the highest power conversion efficiency (16.84%).

2.
J Med Virol ; 92(1): 96-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31469179

RESUMO

Epstein-Barr virus (EBV) infection is one of the causes of gastric cancer (GC). Besides, previous studies have demonstrated that EBV-encoded latent membrane protein 2A (LMP2A) influences the pathogenesis of EBV-associated gastric cancer (EBVaGC) through regulating several key pathways. In this study, the expression level of Smad2 was observed, which was reduced in EBVaGC cell lines, especially in the presence of LMP2A. Meanwhile, we found that LMP2A promoted the expression of miR-155-5p by activated nuclear factor-κB (NF-κB) signaling. After being treated with NF-κB inhibitor (BAY 11-7082), miR-155-5p sharply decreased. Western blot analysis proved that the overexpression of miR-155-5p could inhibit Smad2. Functional studies showed that the role of miR-155-5p might lead to good prognosis in EBV-positive GC through promoting cell apoptosis and cell cycle arrest, as well as inhibiting tumor proliferation. In addition, p-Smad2 protein was also reduced or induced by overexpression or knockdown, respectively, of miR-155-5p. Immunofluorescence analysis further indicated that LMP2A prevented p-Smad2 from transferring to the nucleus, which played a crucial role in transforming growth factor-ß (TGF-ß) signaling. In summary, our findings confirmed the relationship between LMP2A and Smad2 and provided a potential regulation of the TGF-ß pathway in EBVaGC.

3.
Nanotechnology ; 31(2): 02LT01, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31550691

RESUMO

Self-catalyzed metal organic chemical vapor deposition (MOCVD) growth of Ga2O3 nanowires on GaN layers prepared on a sapphire substrate has been studied. Nanowire orientations are found to be growth temperature dominated. The vertical yields over total (VOT) curve shows a maximum peak beyond 70% around 480 °C, based on scanning electron microscope observations. X-ray diffraction patterns revealed a primary ß-(-201) normal orientation of as grown nanowires all over the studied temperature interval. Further transmission electron microscopy characterization had confirmed ß-(-201) normal axial orientation of these vertical nanowires, which have well crystallinity. The ß-(010)//GaN(110) in-plane epitaxial relationship is consistent with reported Ga2O3 film/nanowire growth. Nanowires crystallized in ß-[001] axial orientation were considered to be the inclined ones. Based on contrast experiments, the temperature dominated growth behavior is considered a thermodynamic process. The two observed crystalline orientation might have distinguishable but similar system energy, which results in coexistence of multi orientation nanowires over a large temperature span and an optimum temperature window for vertical ß-(-201) normal orientation. The presented optimized ß-Ga2O3 nanowire arrays with highest VOT close to 90% should effectively promote development of reliable high performance devices based on Ga2O3 nanowires.

4.
J Cell Biochem ; 121(1): 443-457, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31231887

RESUMO

Accumulating findings reveal that long noncoding RNAs (lncRNAs) as crucial regulatory molecules serve vital functions in the progression of hepatocellular carcinoma (HCC). This study aims to investigate the biological roles and mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in HCC cells based on transcriptome analysis. The Cancer Genome Atlas data analysis and experimental validation showed that HOXD-AS1 was increased in HCC tissues/cell lines and positively relevant to histologic grade. The subcellular localization results indicated HOXD-AS1 was dispersed both in the nucleus as well as the cytoplasm of HCC cells. In vitro loss-of-function experiments revealed that silencing of HOXD-AS1 could dramatically suppress the proliferation, migration, and invasion, and induce S or/and G2/M phase cell cycle arrest as well as apoptosis of Bel-7402 and MHCC97H cells accompanying the changes in expression levels of cyclin B1, cyclin D1, BCL-2, BAX, and MMP2. In vivo assay also showed that HOXD-AS1 silencing could markedly reduce xenograft tumor volume and weight of HCC cells. Transcriptome and bioinformatic analysis indicated that a total of 1103 genes were significantly altered by HOXD-AS1 silencing, of which 132 genes exhibited a significant correlation with HOXD-AS1 expression in HCC tissues. Gene Ontology (GO) enrichment analysis revealed differentially expressed genes were remarkably enriched in several cancer-related biological processes (cell proliferation, cell cycle, apoptosis, migration, angiogenesis, and hypoxic response). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that HOXD-AS1 has the potential to affect p53, tumor necrosis factor (TNF), mitogen-activated protein kinase (MAPK) pathway, and Western blot results further validated that HOXD-AS1 silencing could inhibit the MEK/ERK pathway in Bel-7402 cells. Collectively, HOXD-AS1, as an oncogenic lncRNA, might exert crucial functions in HCC progression and serve as a potential diagnostic biomarker and therapeutic target for HCC.

5.
J Hazard Mater ; 382: 121090, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476718

RESUMO

Fenton reaction is widely used for hazardous pollutant degradation. Reducing agents (RAs) have been proven to be efficient in promoting the generation of HO• in Fenton reaction by accelerating the redox cycle of Fe3+/Fe2+. However, the roles of different RAs in Fenton reaction remain unrevealed. In this work, the catalytic activity of three RAs, i.e., hydroxylamine (NH2OH), ascorbic acid (AA) and cysteine (Cys), on the degradation of benzoic acid (BA) and the hydroxyl radical formation in the Fenton-RAs system were investigated. Results show the catalytic performance of RAs in BA degradation by Fenton reaction followed an order of NH2OH > AA > Cys. Compared with the conventional Fenton system, the effective pH range in the Fenton-NH2OH system extended from 3.0 to 5.0, while the optimal pH in the Fenton-AA and Fenton-Cys systems ranged from 3.0 to 4.0. The Fenton-AA system exhibited a two-stage reaction toward BA degradation, which was different from the Fenton-NH2OH and Fenton-Cys systems. Furthermore, the dosing manner of AA was found to be a key factor governing its role in the Fenton-AA system. This observation suggests the different mechanisms behind the enhancement of the three RAs in Fenton system. Different from NH2OH and Cys, AA would inhibit the generation of HO•, especially at the fast stage of degradation process, where Fe3+ has not accumulated yet. In addition, the economic analysis using the electrical energy per order indicates Fenton-NH2OH system was economically feasible with the lowest energy input, compared to Fenton-AA and Fenton-Cys systems. These results are useful to better understand the roles of RAs in Fenton system, and also provide guidance about the selection and dosing manner of suitable RAs in the advanced oxidation processes.

6.
Chemosphere ; 240: 124979, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31726597

RESUMO

Activation of peroxymonosulfate (PMS) and persulfate (PS) by Fe2+ is widely used for oxidizing organic pollutants. However, their application is limited by the slow conversion rate of Fe3+ to Fe2+ and the accumulation of Fe3+. Here, we introduce commercial molybdenum disulfide (MoS2) to promote the activation of PMS and PS by Fe2+, and explore the mechanism of this promotion using experimental and theoretical methods. The Fe2+/PMS/MoS2 and Fe2+/PS/MoS2 systems achieved faster rate of PMS and PS conversion and also higher degradation efficiency toward pollutants. About 94.7% and 87.6% of rhodamine B (RhB) could be degraded in Fe2+/PMS/MoS2 (54 µM Fe2+, 1 mM PMS) and Fe2+/PS/MoS2 (54 µM Fe2+, 0.25 mM PS) system, respectively. MoS2 addition simultaneously promoted the Fe3+/Fe2+ cycle, the PMS and PS conversion, and the RhB mineralization. As a co-catalyst, MoS2 exhibited excellent stability for eight successive cycles of use. The predominant oxidant was identified as SO4- in Fe2+/PMS/MoS2 and Fe2+/PS/MoS2 systems. Theoretical calculations and a kinetic model were employed to evaluate the catalytic performance of the systems. These novel findings indicate that the combination of a commercially available MoS2 catalyst with a low dosage of Fe2+ is a promising and effective approach for efficient activation of PMS and PS to produce SO4- and OH.

7.
Dev Comp Immunol ; 103: 103501, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31634519

RESUMO

Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, participates in both innate and adaptive immunity and regulates the apoptotic process. In this study, we observed that an ortholog of TRAF6 could inhibit the activity of p53 and suppress the apoptotic process in the Hong Kong oyster, Crassostrea hongkongensis. To investigate the possible molecular mechanism of the ChTRAF6-induced antiapoptotic effect, a GST pull-down screening assay was conducted, and ChPellino was found to physically interact with ChTRAF6. In addition, the interaction between them was confirmed by Co-immunoprecipitation. Furthermore, western blotting revealed that the phosphorylation level of ChPellino was decreased after the RNAi of ChTRAF6, demonstrating that ChTRAF6 may be an upstream regulator of Pellino activation. Furthermore, the apoptosis level of hemocytes increased after ChPellino knockdown, and ChPellino overexpression suppressed ChTRAF6-dependent p53 activation. Taken together, these results indicate that ChPellino plays a critical role in suppressing ChTRAF6-dependent anti-apoptosis in the hemocytes of Crassostrea hongkongensis.

8.
Sci Total Environ ; 698: 134298, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31505343

RESUMO

Many studies have examined the acute toxicity of nanoparticles (NPs) towards model bacteria. In this study, we report the time-dependent effects of ZnO NPs on native, selected Zn-resistant and dominant bacteria in estuarine waters. An initial inhibition of bacterial growth followed by a recovery at 24 h was observed, and this rebound phenomenon was particularly notable when the raw water samples were treated with relatively high ZnO NP concentrations (1 and 10 mg/L).By comparing the groups treated with Zn2+, Zn2+ was shown to largely explain the acute cytotoxic effect of ZnO NPs on bacteria in raw waters. Furthermore, similar to the native bacteria, especially the dominant bacteria, the viability of Escherichia coli (E. coli) decreased with the increasing treatments time and the concentrations of ZnO NPs in water with different salinities. Moreover, the expression of Zn-resistance genes including zntA and zntR in E. coli suggested that the Zn-resistance system in E. coli can be activated to defend against the stress of Zn2+ released from ZnO NPs, and salinity may promote this process in estuarine aquatic systems. Thus, the effect of ZnO NPs on bacteria in estuarine water bodies is likely determined by the synergistic effect of environmental salinity and dissolved Zn ions. As such, our findings are of high relevance and importance for understanding the ecological disturbances caused by anthropogenic NPs in estuarine environments.

9.
J Nanosci Nanotechnol ; 20(6): 3568-3575, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748053

RESUMO

Ultrafine nanoporous copper (UNP Cu) with a characteristic pore size of about 12 nm and a ligament size of about 14 nm was fabricated from amorphous Mg65Cu25Y10 precursor alloys after dealloying in a 0.1 M H2SO4 solution modified by poly(vinyly alcohol) polymers with a molecular weight of 105000 g/mol (PVA-124). The suppression of the surface diffusion from PVA-124 reduced the size of the nanopores and ligaments to 20 nm when the concentration of the added PVA-124 exceeded 0.1 g L-1. When the concentration of the added PVA-124 exceeded 2 g L-1, PVA-124 triggered the polymerization process. The resultant polymer surface layer on the fcc Cu ligaments was shown to reduce the rate of selective dissolution. It was also shown that extending the immersion time resulted in a suppression of coarsening. The introduction of PVA-124 polymer into acids resulted in a higher viscosity of the dealloying solutions, particularly when the concentration of PVA-124 was higher than 1.0 g L-1. This viscosity was shown not only to reduced rate of diffusion of Cu adatoms in PVA-124 solutions, but also forced the accumulation of Cu adatoms to form small scale UNP Cu.

10.
J Immunol ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685647

RESUMO

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is believed to be driven by a CD4+ T cell response to liver Ags. However, the pathogenic function of CD4+ effector T cells in AIH is not fully understood. To characterize liver-infiltrating lymphocytes in AIH, we determined the cytokine production of infiltrating cells obtained from biopsy material by quantitative RT-PCR and flow cytometry. A cytokine quantitiative RT-PCR array of AIH specimens revealed that TNF was the most strongly upregulated cytokine, as compared with control livers. To confirm this finding, we determined the frequencies of TNF-producing CD4+ T cells in peripheral blood and in liver biopsy specimens in comparison with those of CD4+ T cells producing IFN-γ or IL-17. In AIH, TNF-producing CD4+ T cells were significantly expanded, both in blood and liver, whereas IL-17-producing CD4+ T cells were not. However, the majority of the TNF-producing CD4+ T cells in AIH also produced IFN-γ, suggesting that TNF producers might represent a pathogenic activation state of Th1 cells. Ag-specific stimulation of PBMC from AIH patients with the AIH-associated autoantigen SEPSECS resulted in significant TNF production only in patients manifesting SLA/LP autoantibodies targeting SEPSEC but not in healthy individuals who do not manifest this reactivity. Taken together, our findings indicated that TNF-producing CD4+ T cells are expanded in AIH, both in blood and in liver. TNF-producing CD4+ T cells in AIH seem to be aberrantly activated Th1 cells. Our findings provide a rationale for therapeutic efforts using TNF blockade in AIH.

11.
Pharmacol Rep ; 71(6): 1244-1252, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670061

RESUMO

BACKGROUND: Coumarin and 3,4-dihydroquinolinone nuclei are two heterocyclic rings that are important and widely exploited for the development of bioactive molecules. Here, we designed and synthesized a series of 3,4-dihydroquinolinone and coumarin derivatives (Compounds 8, 9, 11, 14, 15, 18-20, 23, 24 and 28 are new compounds) and studied their antidepressant activities. METHODS: Forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant activity of the target compounds. The most active compound was used to evaluate the exploratory activity of the animals by the open-field test. 5-HT concentration was estimated to evaluate if the compound has an effect on the mouse brain, by using ELISA. A 5-HT1A binding assay was also performed. The biological activities of the compounds were verified by molecular docking studies. The physicochemical and pharmacokinetic properties of the target compounds were predicted by Discovery Studio and ChemBioDraw Ultra. RESULTS: Of all the compounds tested, compound 7 showed the best antidepressant activity, which decreased the immobility time by 65.52 s in FST. However, in the open-field test, compound 7 did not affect spontaneous activity. The results of 5-HT concentration estimation in vivo showed that compound 7 may have an effect on the mouse brain. Molecular docking results indicated that compound 7 showed significant interactions with residues at the 5-HT1A receptor using homology modeling. The results show that compound 7 exhibits good affinity for the 5-HT1A receptor. CONCLUSION: Coumarin and 3,4-dihydroquinolinone derivatives synthesized in this study have a significant antidepressant activity. These findings can be useful in the design and synthesis of novel antidepressants.

12.
Dalton Trans ; 48(44): 16776-16785, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31674607

RESUMO

A novel metal-organic framework with the formula [Zn3(DDB)(DPE)]·H2O (1) (H5DDB = 3,5-di(2',4'-dicarboxylphenyl)benzoic acid and DPE = 1,2-di(4-pyridyl)ethylene) has been solvothermally synthesized by employing a rigid carboxylate ligand H5DDB to assemble with Zn(ii) ions in the presence of a flexible bis(pyridyl) linker DPE. The Zn-MOF is a 3D framework with six-nuclear clusters and possesses remarkable water stability and pH stability. Interestingly, complex 1 can sensitively and selectively sense Fe(iii), Cr(iii), Cr(vi), Mn(vii) and the pesticide 2,6-Dich-4-NA with low detection limits in aqueous solution. Moreover, complex 1 also exhibits selectivity for 2,6-Dich-4-NA detection in real samples including carrot, grape and nectarine extracts, and its detection ability is almost unchanged in the presence of the surfactant sodium dodecyl sulfate (SDS). The possible mechanisms of luminescence quenching have been explained by the weak affinity of nitrogen atoms, resonance energy transfer, and photoinduced electron transfer. To our knowledge, this is the first example of a MOF-based multiresponsive fluorescent probe for the simultaneous detection of Fe(iii), Cr(iii/vi), Mn(vii) and the pesticide 2,6-Dich-4-NA in aqueous solution.

13.
Chemosphere ; 242: 125159, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31677513

RESUMO

One of the main problems in treating high volumes of wastewater is the long startup time required aerobic granular sludge (AGS), and this issue significantly limits the broad application of advanced AGS technology. To promote rapid AGS formation in the startup phase, a method was developed involving the recovery and natural drying of effluent sludge prior to feeding it back into the sequencing batch reactor (SBR). An analysis of the process shows that supplemented naturally dried sludge swiftly promoted sludge aggregation and granular sludge formation in the reactor, and feeding the SBR with naturally dried sludge aggregates (1.75 ±â€¯0.05 g/L seven times) significantly shortened the granulation time in the startup phase by 14 days. In addition, MLSS, SVI30, SVI30/SVI5, and the average granule size of AGS in the reactor were maintained at 4.66 g/L, 47.4 mL/g, 0.93, and 2.8 mm, respectively. When fed back into the bioreactor, the aggregates acted as nuclei/carriers in the rapid granulation and played a significant role in rendering the SBR operation stable. This approach could be used to eliminate the random granules aggregation-disintegration mechanism that occurs in the initial stage of AGS formation. The study results reveal that the removal rate of COD and NH4+-N were above 95% and 96%, respectively. Furthermore, this approach requires less energy and significantly reduces the amount of sludge produced (as the effluent sludge is reused).

14.
DNA Res ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711192

RESUMO

Black rockfish (Sebastes schlegelii) is an economically important viviparous marine teleost in Japan, Korea, and China. It is characterized by internal fertilization, long-term sperm storage in the female ovary and a high abortion rate. For better understanding the mechanism of fertilization and gestation, it is essential to establish a reference genome for viviparous teleosts. Herein, we used a combination of Pacific Biosciences sequel, Illumina sequencing platforms, 10x Genomics and Hi-C technology to obtain a genome assembly size of 848.31 Mb comprising 24 chromosomes, and contig and scaffold N50 lengths of 2.96 Mb and 35.63 Mb, respectively. We predicted 39.98% repetitive elements, and 26,979 protein-coding genes. S. schlegelii diverged from Gasterosteus aculeatus approximately 32.1-56.8 million years ago. Furthermore, sperm remained viable within the ovary for up to 6 months. The glucose transporter SLC2 showed significantly positive genomic selection, and carbohydrate metabolism-related KEGG pathways were significantly up-regulated in ovaries after copulation. In vitro suppression of glycolysis with sodium iodoacetate reduced sperm longevity significantly. The results indicated the importance of carbohydrates in maintaining sperm survivability. Decoding the S. schlegelii genome not only provides new insights into sperm storage; additionally, it is highly valuable for marine researchers and reproduction biologists.

15.
Nat Prod Res ; : 1-6, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31711315

RESUMO

A new phenylpentenol, wortmannine H (1) was isolated from Talaromyces wortmannii LGT-4, an endophytic fungus of Tripterygium wilfordii. The structure of 1 was elucidated by IR, MS, 1D and 2D NMR spectra and comparison of the experimental and calculated optical rotatory dispersion (ORD). Monoamine oxidase (MAO), acetylcholinesterase (AChE) and phosphoinositide 3-kinase (PI3Kα) inhibitory activities of 1 was also tested. The compound did not show good biological activity.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31713833

RESUMO

White-tip nematode, Aphelenchoides besseyi is a kind of widely distributed migratory parasitic nematode that can infect plant shoots. Transcriptome sequencing of plant parasitic nematodes and their host plants is helpful for understanding their interaction relationship. This study first reported expression patterns of defense-related genes in rice, and rice transcriptomes at different periods after infection with A. besseyi. The result showed that the defense response pathways of rice changed obviously in the early stage of A. besseyi infection, including upregulated salicylic acid and jasmonate pathways and a downregulated ethylene pathway. Transcriptome analysis results suggested that A. besseyi infection was associated with the downregulation of multiple genes related to photosynthesis with possible suppression of the photosynthetic activity. It suggested that the photosynthesis system of rice could be suppressed by infections of migratory nematodes, including A. besseyi and Hirschmanniella oryzae, but was stimulated by that of a sedentary nematode, Meloidogyne graminicola, by comparing our study with the reported transcriptome. OS09G0417800 (OsWRKY62) might play an important role in the interaction of migratory nematodes and rice. It also indicated that the infection strategy of both A. besseyi and the reported migratory nematode H. oryzae was similar to that of the fungal pathogen Magnaporthe grisea. These results provided an interesting starting point to elucidate the mechanism of the interaction between rice and A. besseyi, as well as the host and migratory plant nematodes.

17.
Chem Commun (Camb) ; 55(92): 13852-13855, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31670346

RESUMO

An exogenous-oxidant- and catalyst-free electrochemical deoxygenative C2 sulfonylation reaction has been achieved. By employing quinoline N-oxides as the starting materials, the electrochemical C-H sulfonylation of electron-deficient quinolines was indirectly achieved at room temperature and a variety of sulfonylated quinoline derivatives were synthesized in modest to high yield with excellent regioselectivity. Notably, this protocol is the first example for synthesizing sulfonylated electron-deficient heteroarenes/arenes through electrochemistry.

18.
Anal Chem ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31693341

RESUMO

The structural annotation of metabolites now relies heavily on HR-MS/MS information, resulting in ambiguous identities in most cases. More auxiliary evidence is therefore desired to achieve confirmative identification. Herein, we made an attempt to involve retention time (tR) along with optimal collision energy (OCE) as the additionally structural clues, and the applicability validation was conducted via confidence-enhanced metabolite characterization of echinacoside, an antidementia drug candidate within clinical trials. Quantitative structure-retention relationships (QSRR) were modeled via assaying 184 authentic compounds on RPLC, HILIC, and serially coupled RPLC and HILIC (RPLC-HILIC). Online energy-resolved MS was developed to yield breakdown graphs for selected ion transitions, and OCE was demonstrated to be superior to CE50 toward pointedly denoting the bonds-of-interest. Nineteen metabolites (M1-M19) were confidently identified in biological samples from echinacoside-treated rats by analyzing m/z values first to yield empirical formulas and substructures, and tR and OCE subsequently contributed to sift the candidate structures. Structural identification was validated by oral administration of three relevant compounds in parallel and chromatographic purification as well. Above all, the integration of retention and dissociation behaviors enabled promoting one step forward for structural annotation confidences merely relied on HR-MS/MS.

19.
J Biol Chem ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723028

RESUMO

Proteins of nuclear receptor subfamily 4 group A (NR4A), including NR4A1/NGFI-B, NR4A2/Nurr1, and NR4A3/NOR-1, are nuclear transcription factors that play important roles in metabolism, apoptosis, and proliferation. NR4A proteins recognize DNA response elements as monomers or dimers to regulate the transcription of a variety of genes involved in multiple biological processes. In this study, we determined two crystal structures of the NR4A2 DNA-binding domain (NR4A2-DBD) bound to two Nur-responsive elements (NurREs), namely, an inverted repeat and an everted repeat at 2.6-2.8 Å resolutions.  The structures revealed that two NR4A2-DBD molecules bind independently to the everted repeat, whereas two other NR4A2-DBD molecules form a novel dimer interface on the inverted repeat. Moreover, substitution of the interfacial residue Valine 298 to lysine, as well as mutation of DNA bases involved in the interactions, abolished the dimerization. Overall, our structural, biochemical, and bioinformatics analyses provide a molecular basis for the binding of the NR4A2 protein dimers to NurREs and advance our understanding of the dimerization specificity of nuclear receptors.

20.
Arch Med Res ; 50(6): 384-392, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31678897

RESUMO

BACKGROUND: T helper 2 (Th2) lymphocytes and associated interleukin (IL) 4 and IL-13 play crucial roles in asthma pathogenesis. In this study, we explored an adeno-associated virus 5 (AAV5) based gene therapy by delivering truncated IL-4 protein to antagonize IL-4 receptor α chain and interrupt asthmatic signal pathway. RESULTS: A recombinant adeno-associated virus 5 (AAV5) vector harboring a truncated mouse IL-4 gene (AAV5-mIL-4ΔC22) was prepared. Western blotting showed that the IL-4 mutant protein lacking the C-terminal 22 amino acids was expressed well in AAV5-mIL-4ΔC22 infected 16HBE and BEAS-2B cells. AAV5-drivn green fluorescent protein (AAV5-GFP) served as a control. The biodistribution of vector DNA after AAV5 vector aerosol inhalation was examined by PCR and the result showed that foreign DNA was detectable in the lungs but not in other organs including gonads. The aerosol inhalation-mediated delivery of AAV5-expressed antagonistic IL-4 mutant protein improved the lung function of ovalbumin-induced asthma mice. CONCLUSIONS: The inhalation of aerosolized AAV5-mIL-4ΔC22 significantly improved the lung function and modulated the immune cell infiltration and associated cytokine expression in the bronchoalveolar lavage fluid (BALF) of ovalbumin-induced asthma mice.

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