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1.
Gene ; : 144582, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32173543

RESUMO

As the main energy source for generating ATP during plant growth and development, sugars are synthesized in leaves, while sugar allocation depends on both intracellular transport between different organelles and source-to-sink transport. However, sugar transport related research is limited in pear. Here, a sugar transporter PbSWEET4 was identified that control sugar content and senescence in leaf. Phylogenetic analysis and multiple sequence alignment results indicated that PbSWEET4 was homologous to AtSWEET15, which contained two conserved domains and could promote senescence. The qRT-PCR and transcriptome database result showed that the expression of PbSWEET4 was positively correlated with leaf development, especially highly expressed in older leaves. Furthermore, the evaluation of promoter-GUS activity also indicated that PbSWEET4 exhibited the highest expression level in older leaves. The subcellular localization revealed that the PbSWEET4 localized in the plasma membrane. Finally, overexpression of the PbSWEET4 in strawberry plants could reduce leaf sugar content and chlorophyll content, while accelerate leaf senescence, which might be due to enhanced export of sugars from leaves. These results enrich the knowledge about the function of sugar exporter in regulating the fruit species development, and provide a novel genetic resource for future improvement in carbohydrate partitioning for pear and other fruit trees.

2.
J Sep Sci ; 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32187438

RESUMO

Oroxylin A, obtained from the root of Scutellaria baicalensis Georgi, is a flavonoid with anti-tumor and other pharmacological activities. Our previous studies showed for the first time that it is mainly metabolized to Oroxylin A sodium sulfonate by sulfotransferase enzymes in beagle dogs. In this study, rapid, universal, selective, and robustly ultra-high performance liquid chromatography/tandem mass spectrometry methods were established and fully validated to quantitatively detect Oroxylin A, Oroxylin A 7-O-glucuronide, and Oroxylin A sodium sulfonate in beagle dog plasma. The quantitative analysis for Oroxylin A sodium sulfonate was reported for the first time. Plasma samples were processed with acetonitrile, a universal protein precipitant. Gradient elution was performed to resolve carryover effects and to achieve separation efficiency and sufficient chromatographic retention. The linear relationships of Oroxylin A, Oroxylin A 7-O-glucuronide, and Oroxylin A sodium sulfonate in plasma were in the range of 2.0∼500.0 ng/mL, 5.0∼500.0 ng/mL, and 1.881∼940.5 ng/mL, respectively. The assay method was successfully applied to pharmacokinetic study. This is the first paper that reveals the pharmacokinetic profile of Oroxylin A, Oroxylin A 7-O-glucuronide, and Oroxylin A sodium sulfonate after single-dose intravenous and oral administration of Oroxylin A in beagle dogs. This article is protected by copyright. All rights reserved.

3.
Nat Methods ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32203386

RESUMO

Isobaric labeling empowers proteome-wide expression measurements simultaneously across multiple samples. Here an expanded set of 16 isobaric reagents based on an isobutyl-proline immonium ion reporter structure (TMTpro) is presented. These reagents have similar characteristics to existing tandem mass tag reagents but with increased fragmentation efficiency and signal. In a proteome-scale example dataset, we compared eight common cell lines with and without Torin1 treatment with three replicates, quantifying more than 8,800 proteins (mean of 7.5 peptides per protein) per replicate with an analysis time of only 1.1 h per proteome. Finally, we modified the thermal stability assay to examine proteome-wide melting shifts after treatment with DMSO, 1 or 20 µM staurosporine with five replicates. This assay identified and dose-stratified staurosporine binding to 228 cellular kinases in just one, 18-h experiment. TMTpro reagents allow complex experimental designs-all with essentially no missing values across the 16 samples and no loss in quantitative integrity.

4.
Brain Imaging Behav ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125618

RESUMO

Executive function is a complex involving multiple advanced brain functions like planning, working memory, mental flexibility and psychomotor. Previous researches indicated that executive function may be impaired after acute or chronic high-altitude exposure, while the underlying neurobiological mechanism has not been totally clarified. In the present study, based on 69 young healthy volunteers immigrating to high-altitude, Stroop test was utilized to identify the potential impairment of executive function after two-year high-altitude exposure while resting-state functional MRI (rs-fMRI) technology was employed to observe the alteration of resting-state networks. Stroop test indicated that the subjects experienced significantly lower accuracies and prolonged responding time after two-year exposure. Resting-state network analysis displayed a significantly decreased degree of co-activation within the left/right frontoparietal network, sensorimotor network, and auditory network after exposure. In the frontoparietal network, decreased co-activation intensity was found in left angular gyrus, while in the right frontoparietal network, decreased co-activation intensity was found in left precentral gyrus and postcentral gyrus. Similarly, as for sensorimotor and auditory network, left middle frontal gyrus and left superior temporal gyrus was identified to have decreased co-activation, respectively. Moreover, the responding delays in ST (part II) were negatively correlated with the signal intensity alteration of the right frontoparietal network. All these evidences indicated that the high-altitude exposure induced alteration in above resting state networks may be the functional basis of executive control impairment.

5.
Cell ; 180(5): 968-983.e24, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109415

RESUMO

Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology in vivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo. We use Oximouse to establish several paradigms of physiological redox signaling. We define and validate cysteine redox networks within each tissue that are tissue selective and underlie tissue-specific biology. We describe a common mechanism for encoding cysteine redox sensitivity by electrostatic gating. Moreover, we comprehensively identify redox-modified disease networks that remodel in aged mice, establishing a systemic molecular basis for the long-standing proposed links between redox dysregulation and tissue aging. We provide the Oximouse compendium as a framework for understanding mechanisms of redox regulation in physiology and aging.

6.
Org Lett ; 22(5): 2017-2021, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32077299

RESUMO

Herein we report a redox cyclization of amides and sulfonamides with nitrous oxide (N2O) for the direct synthesis of heterocycles. Various amides and sulfonamides could undergo directed ortho metalation (DoM) by treatment with BuLi, and the lithium intermediate could be trapped by N2O gas to achieve redox cyclization. N2O serves as a N-atom donor to mediate the intramolecular coupling of lithium species toward heterocycle formation with free external oxidant. This protocol offers a direct synthesis of heterocycles with features of readily available starting materials, simple operation, and a broad substrate scope.

7.
Eur J Med Chem ; 191: 112143, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078865

RESUMO

Herein, we communicate our recent medicinal chemistry efforts which have culminated in a series of PI3Kδ/γ dual inhibitors structurally featuring a seven-membered spirocyclic spacer. Compound 26, the most potent one among them, exhibited superior PI3Kδ inhibitory activity (IC50 = 1.0 nM) to that of the approved PI3Kδ inhibitor Idelalisib. Besides, it exerted remarkable anti-proliferative efficacy against human malignant B-cell line SU-DHL-6 with GI50 value of 33 nM. The biochemical assay against the other three class I PI3K isoforms identified compound 26 as a potent PI3Kδ/γ dual inhibitor with considerable selectivity over PI3Kα and PI3Kß. In SU-DHL-6 cells, a dramatic down-regulation of PI3K signaling was observed following compound 26-treatment at the concentration as low as 10 nM. Inspiringly, the pharmacokinetic (PK) study in Sprague-Dawley (SD) rats revealed it was orally available with a favorable bioavailability (F = 87.5%). Overall, compound 26, a promising PI3Kδ/γ dual inhibitor, has the potential to emerge as a clinical candidate for the treatment of leukocyte-mediated malignancies after extensive functional investigation.

8.
Virol J ; 17(1): 12, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000791

RESUMO

BACKGROUND: Influenza A virus (IAV) continues to pose serious threats to public health. The current prophylaxis and therapeutic interventions for IAV requires frequent changes due to the continuous antigenic drift and antigenic shift of IAV. Emerging evidence indicates that the host microRNAs (miRNAs) play critical roles in intricate host-pathogen interaction networks. Cellular miRNAs may directly target virus to inhibit its infection and be developed as potential anti-virus drugs. METHODS: In this study, we established a broad-spectrum anti-IAV miRNA screening method using miRanda software. The screened miRNAs were further verified by luciferase assay, viral protein expression assay and virus replication assay. RESULTS: Five cellular miRNAs (miR-188-3p, miR-345-5p, miR-3183, miR-15-3p and miR-769-3p), targeting 99.96, 95.31, 92.9, 94.58 and 97.24% of human IAV strains recorded in NCBI, respectively, were chosen for further experimental verification. Finally, we found that miR-188-3p downregulated PB2 expression at both mRNA and protein levels by directly targeted the predicted sites on PB2 and effectively inhibited the replication of IAV (H1N1, H5N6 and H7N9) in A549 cells. CONCLUSIONS: This is the first report screening cellular miRNAs that broad-spectrum inhibiting IAV infection. These findings suggested that cellular miR-188-3p could be used for RNAi-mediated anti-IAV therapeutic strategies.

9.
Fitoterapia ; 142: 104480, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31927013

RESUMO

Oroxylin A (OA), as a natural flavonoid extracted from the root of Scutellaria baicalensis Georgi, is a candidate drug with multiple pharmacological activities. However, pharmacokinetic studies of OA have rarely been reported up to now. The present study aim to conduct a systemic evaluation on the pharmacokinetics, tissue distribution and excretion of OA in rats, with quantification of both OA and its two metabolites, Oroxylin A 7-O-glucuronide (OG) and Oroxylin A sodium sulfonate (OS) by the sensitive and rapid UPLC-MS/MS methods. The results show that OA was rapidly eliminated in vivo after a single-dose (2 mg/kg) i.v. administration of OA. The relative bioavailability of OA in all three i.g. administration groups (40, 120, and 360 mg/kg) were <2%. The AUC0-t values of OA, OG, and OS in rats show an apparent dose-proportionality. OA, OG, and OS all underwent a rapid and widespread tissue distribution after i.g. administration (120 mg/kg) of OA. Except for stomach and intestine, the major distribution tissues of OA and its two metabolites in rats were liver, kidney, respectively. And OA was more widely distributed in tissue than its metabolites. After i.g. administration (120 mg/kg) of OA, it was mainly excreted from the feces, and OG mainly excreted from bile and urine, while OS almost free of excretion. This work present a comprehensive pharmacokinetics information for further investigation of OA and its two metabolites.

10.
J Enzyme Inhib Med Chem ; 35(1): 187-198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752552

RESUMO

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
12.
Int Heart J ; 61(1): 178-182, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31875618

RESUMO

Pompe disease (PD) is a rare and fatal neuromuscular disease, which is an autosomal recessive disorder. This is the first study to report a case of the compound heterozygous c.1822C>T and c.2297A>C mutations of the GAA gene in mainland Chinese patient, which led to the classic infantile-onset Pompe disease (IOPD) characterized by hypertrophic cardiomyopathy. This case highlights that the detection of GAA activity in peripheral blood by dried blood spot and GAA gene analysis can clarify the diagnosis of IOPD and provides the genetic counseling to those parents whose children have IOPD for giving birth in the future. Although PD is rare, and universal screening has not yet been established, we suggest that clinicians should consider the possibility of Pompe in the presence of hypertrophic cardiomyopathy.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Doença de Depósito de Glicogênio Tipo II/diagnóstico , alfa-Glucosidases/genética , Feminino , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo II/genética , Heterozigoto , Humanos , Lactente , Mutação Puntual
13.
Org Lett ; 21(24): 10139-10142, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31808699

RESUMO

An enantioselective synthesis of 15-deoxy-Δ12,14-prostaglandin J2 is reported. The synthesis begins with the preparation of enantiopure 3-oxodicyclopentadiene by a lipase-mediated kinetic resolution. A three-component coupling followed by a retro-Diels-Alder reaction provides the C8 stereochemistry of the prostaglandin skeleton with high enantioselectivity. Stereoretentive olefin metathesis followed by a Pinnick oxidation affords 15-deoxy-Δ12,14-prostaglandin J2 in high enantiopurity.

14.
DNA Res ; 26(6): 485-494, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883002

RESUMO

Hybridization and polyploidy are pervasive evolutionary features of flowering plants and frequent among some animal groups, such as fish. These processes always lead to novel genotypes and various phenotypes, including growth heterosis. However, its genetic basis in lower vertebrate is still poorly understood. Here, we conducted transcriptome-level analyses of the allopolyploid complex of Carassius auratus red var. (R) (♀) × Cyprinus carpio L. (C) (♂), including the allodiploid and allotetraploid with symmetric subgenomes, and the two allotriploids with asymmetric subgenomes. The gradual changes of gene silencing and novel gene expression suggested the weakening of the constraint of polymorphic expression in genotypic changes. Then, analyses of the direction and magnitude of homoeolog expression exhibited various asymmetric expression patterns, which supported that R incomplete dominance and dosage compensation were co-regulated in the two triploids. Under these effects, various magnitudes of R-homoeolog expression bias were observed in growth-regulated genes, suggesting that they might contribute to growth heterosis in the two triploids. The determination of R incomplete dominance and dosage compensation, which might be led by asymmetric subgenomes and multiple sets of homologous chromosomes, explained why various expression patterns were shaped and their potential contribution to growth heterosis in the two triploids.

15.
Bioorg Med Chem Lett ; 29(24): 126712, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31679973

RESUMO

To improve the anti-inflammatory activity of desloratadine, we designed and synthesized a series of novel desloratadine derivatives. All compounds were evaluated for their anti-inflammatory and H1 antagonistic activities. Among them, compound 2c showed the strongest H1 antagonistic and anti-inflammatory activity. It also exhibited promising pharmacokinetic profiles and low toxicity. All these results suggest that compound 2c as a novel anti-allergic agent is worthy of further investigation.

16.
Cell Rep ; 29(7): 2092-2104.e4, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31722220

RESUMO

Governance of protein phosphorylation by kinases and phosphatases constitutes an essential regulatory network in eukaryotic cells. Network dysregulation leads to severe consequences and is often a key factor in disease pathogenesis. Previous studies revealed multiple roles for protein phosphorylation and pathway structures in cellular functions from different perspectives. We seek to understand the roles of kinases and phosphatases from a protein homeostasis point of view. Using a streamlined tandem mass tag (SL-TMT) strategy, we systematically measure proteomic and phosphoproteomic responses to perturbations of phosphorylation signaling networks in yeast deletion strains. Our results emphasize the requirement for protein normalization for more complete interpretation of phosphorylation data. Functional relationships between kinases and phosphatases were characterized at both proteome and phosphoproteome levels in three ways: (1) Gene Ontology enrichment analysis, (2) Δgene-Δgene correlation networks, and (3) molecule covariance networks. This resource illuminates kinase and phosphatase functions and pathway organizations.

17.
Cell Mol Immunol ; 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31611650

RESUMO

Although PD-L1/PD-1 blockade therapy has been approved to treat many types of cancers, the majority of patients with solid tumors do not respond well, but the underlying reason remains unclear. Here, we studied ovarian cancer (OvCa), a tumor type generally resistant to current immunotherapies, to investigate PD-1-independent immunosuppression. We found that PD-L1 was not highly expressed in the tumor microenvironment (TME) of human OvCa. Instead, B7-H3, another checkpoint molecule, was highly expressed by both tumor cells and tumor-infiltrating antigen-presenting cells (APCs), which correlated with T-cell exhaustion in patients. Using ID8 OvCa mouse models, we found that B7-H3 expressed on tumor cells, but not host cells, had a dominant role in suppressing antitumor immunity. Therapeutically, B7-H3 blockade, but not PD-1 blockade, prolonged the survival of ID8 tumor-bearing mice. Collectively, our results demonstrate that tumor-expressed B7-H3 inhibits the function of CD8+ T cells and suggest that B7-H3 may be a target in patients who are not responsive to PD-L1/PD-1 inhibition, particularly OvCa patients.

18.
Genome Res ; 29(11): 1805-1815, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31649058

RESUMO

Hybridization drives rapid speciation by shaping novel genotypic and phenotypic profiles. Genomic incompatibility and transcriptome shock have been observed in hybrids, although this is rarer in animals than in plants. Using the newly sequenced genomes of the blunt snout bream (Megalobrama amblycephala [BSB]) and the topmouth culter (Culter alburnus [TC]), we focused on the sequence variation and gene expression changes in the reciprocal intergeneric hybrid lineages (F1-F3) of BSB × TC. A genome-wide transcriptional analysis identified 145-974 expressed recombinant genes in the successive generations of hybrid fish, suggesting the rapid emergence of allelic variation following hybridization. Some gradual changes of gene expression with additive and dominance effects and various cis and trans regulations were observed from F1 to F3 in the two hybrid lineages. These asymmetric patterns of gene expression represent the alternative strategies for counteracting deleterious effects of the subgenomes and improving adaptability of novel hybrids. Furthermore, we identified positive selection and additive expression patterns in transforming growth factor, beta 1b (tgfb1b), which may account for the morphological variations of the pharyngeal jaw in the two hybrid lineages. Our current findings provide insights into the evolution of vertebrate genomes immediately following hybridization.

19.
Genomics ; 111(5): 1097-1107, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31533901

RESUMO

S-type anion channels, which play important roles in plant anion (such as nitrate and chloride) transport, growth and development, abiotic stress responses and hormone signaling. However, there is far less information about this family in Rosaceae species. We performed a genome-wide analysis and identified SLAC/SLAH gene family members in pear (Pyrus bretschneideri) and four other species of Rosaceae. A total of 21 SLAC/SLAH genes were identified from the five Rosaceae species. Based on the structural characteristics and a phylogenetic analysis of these genes, the SLAC/SLAH gene family could be classified into three main groups. Transcriptome data demonstrated that PbrSLAC/SLAH genes were detected in all parts of the pear. PbrSLAC/SLAH genes were only located on the plasma membrane in transient expression experiments in Arabidopsis protoplasts cells. These results provide valuable information that increases our understanding of the evolution, expression and functions of the SLAC/SLAH gene family in higher plants.


Assuntos
Canais Iônicos/genética , Proteínas de Plantas/genética , Pyrus/genética , Ânions/metabolismo , Canais Iônicos/química , Canais Iônicos/metabolismo , Nitratos/metabolismo , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Pyrus/classificação , Transcriptoma
20.
Medchemcomm ; 10(7): 1180-1186, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31391892

RESUMO

A novel series of gardenamide A derivatives was synthesized as potential anti-Alzheimer's disease agents. The neuroprotective effects of these multifunctional agents against oxygen-glucose deprivation (OGD)-induced neurotoxicity in rat cortical neurons, and hydrogen peroxide (H2O2)- and amyloid-ß1-42 (Aß1-42)-induced neurotoxicity in rat hippocampal neurons were evaluated. In vitro studies revealed that these compounds demonstrated moderate to good multifunctional neuroprotective activity. Among the entire series, compounds 10e, 10j, 10n and 10p appeared to be the most active multifunctional neuroprotective agents. Studies indicate that compounds 10e, 10f, 10h, 10i, 10j, 10n and 10p exhibit significant activities against OGD-induced neurotoxicity in rat cortical neurons, and 10e, 10j, 10n and 10p show prominent activities against H2O2- and Aß1-42-induced neurotoxicity in rat hippocampal neurons. Moreover, these derivatives did not exert conspicuous neurotoxicity in rat cortical neurons. Thus, the present study evidently shows that 10e, 10j, 10n and 10p are potent multifunctional neuroprotective agents, which may serve as promising lead candidates for anti-Alzheimer's disease drug development.

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