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1.
Int J Biol Sci ; 16(9): 1526-1535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226299

RESUMO

Immune checkpoint blockade-based immunotherapy has become standard of care for multiple cancer types. However, the overall response rates among various cancer types still remain unsatisfactory. There is a pressing clinical need to identify combination therapies to improve efficacy of anticancer immunotherapy. We previously showed that pharmacologic inhibition of PPARγ by GW9662 boosts αPD-L1 and αPD-1 antibody efficacy in treating murine mammary tumors. In addition, we defined sexually dimorphic αPD-L1 efficacy in B16 melanoma. Here, we show a sexually dimorphic response to the combination of GW9662 and αPD-L1 immunotherapy in B16 melanoma. Combination effects were observed in female, but not male hosts. Neither female oöphorectomy impairs, nor does male castration rescue the combination effects, suggesting a sex hormone-independent response to this combination therapy. In diet-induced obese females, melanoma growth remained responsive to the combination treatment, albeit less robustly than lean females. These findings are informative for future design and application of immunotherapy-related combination therapy for treating human melanoma patients by taking gender and obesity status into consideration.

2.
Plant J ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32133712

RESUMO

Intron-containing genes have the ability to generate multiple transcript isoforms by splicing, thereby greatly expanding eukaryotic transcriptome and proteome. In eukaryotic cells, precursor mRNA (pre-mRNA) splicing is performed by a mega-macromolecular complex defined as a spliceosome. Among its splicing components, U1 small nuclear ribonucleoprotein (U1 snRNP) is the smallest subcomplex involved in early spliceosome assembly and 5'-splice site recognition. Its central component, named as U1-70K, has been extensively characterized in animals and yeast. However, very few investigations on U1-70K genes have been conducted in plants. To this end, we performed a comprehensive study to systematically identify 115 U1-70K genes from 67 plant species, ranging from algae to angiosperms. Phylogenetic analysis suggested that expansion of plant U1-70K gene family was likely driven by whole genome duplications. Subsequent comparisons of gene structures, protein domains, promoter regions and conserved splicing patterns indicated that plant U1-70Ks are likely to preserve their conserved molecular function across plant lineage, and play an important functional role in response to environmental stresses. Furthermore, genetic analysis by using T-DNA insertion mutants suggested that Arabidopsis U1-70K may be involved in response to osmotic stress. Our results provide a general overview of this gene family in Viridiplantae and will act as a reference source to carry out future mechanistic studies on this U1 snRNP-specific splicing factor.

3.
Environ Pollut ; 263(Pt A): 114102, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32203844

RESUMO

The complexation with extracellular polymeric substances (EPS) greatly reduces the toxicity of heavy metals towards organisms in the environment. However, the molecular mechanism of EPS-metal complexation remains unclear owing to the limitation of precise analysis for key fractions and functionalities in EPS that associate with metals. Herein, we explored the EPS-Cd (II) complexation by fluorescence excitation emission matrix coupled with parallel factor (EEM-PARAFAC), two-dimensional Fourier transform infrared correlation spectroscopy (2D-FTIR-COS) and X-ray photoelectron spectroscopy (XPS), attempting to explain the mechanisms of EPS in alleviating Cd (II) toxicity toward a green alga Chlorella vulgaris (C. vulgaris). When the algal EPS were removed, the cell internalizations of Cd (II), growth inhibition rate and chlorophyll autofluorescence increased, but the surface adsorption and esterase activities decreased, indicating that the sorption of Cd (II) by EPS was crucial in alleviating the algal toxicity. Moreover, the complexation with proteins in EPS controlled the sorption of Cd (II) to algal EPS, resulting in the chemical static quenching of the proteins fluorescence by 47.69 ± 2.37%. Additionally, the complexing capability of the main functionalities, COO- and C-OH in proteins with Cd (II) was stronger than that of C-O(H) and C-O-C in polysaccharides or C-OH in the humus-related substances. Oxygen atom in protein carboxyl C-O might be the key site of EPS-Cd (II) complexation, supported by the modified Ryan-Weber complexation model and the obvious shift of oxygen valence-electron signal. These findings provide deep insights into understanding the interaction of EPS with heavy metals in aquatic environment.

4.
Aging (Albany NY) ; 12(2): 1656-1684, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32003759

RESUMO

Immune cell infiltration mediates therapeutic response to immune therapies. The investigation on the genes regulating leukocyte migration may help us to understand the mechanisms regulating immune cell infiltration in tumor microenvironment. Here, we collected the data from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) to analyze the expression of leukocyte migration related genes in glioblastoma (GBM). Lymphocyte specific protein 1 (LSP1) was identified as the only gene in this family which not only has an elevated expression, but also serve as an independent predictive factor for progressive malignancy in glioma. We further confirmed these results in clinical glioma samples by quantitative PCR, immunofluorescence, immunohistochemistry, and western blot. Moreover, LSP1 expression was closely related to the response to radio- and chemotherapy in GBM, and positively correlated with immunosuppressive cell populations, including M2 macrophages, neutrophil, and regulatory T cell. Additionally, elevated LSP-1 expression enhanced the expression of immunosuppression related genes like programmed cell death 1 (PD1) and leukocyte associated immunoglobulin like receptor 1 (LAIR1) in macrophages. LSP1 also promoted the migration of macrophages. Together, our study suggests a novel role of LSP1 contributing to immunosuppressive microenvironment in GBM and serving as a potential therapeutic target for it.

5.
Dalton Trans ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32057042

RESUMO

Efficient and low-cost catalysts for catalytic wet air oxidation (CWAO) under ambient conditions are of great significance for the degradation of hydrophobic organic contaminants. In this study, four LDH catalysts were prepared and their catalytic performance was studied by the degradation of nitrobenzene. The CuCoFe-LDH shows the best catalytic activity with an NB removal efficiency of 41.2%. The CuCoFe-LDH exhibited a typical layer structure, with a specific surface area of 167.32 m2 g-1, and Cu2+, Co2+ and Fe3+ were evenly dispersed on the crystal. The NB removal efficiency was increased by 12.5% through adding formic acid. After five recycling processes, the NB removal efficiency was 18.9% because 3.8 mg g-1 of Co was leached out of the LDH. In the CWAO process, H2O2, ˙OH, ˙O2- and 1O2 were successfully formed through activated oxygen by the CuCoFe-LDH catalyst under ambient conditions. This work further broadens the application scope of layered double hydroxides (LDHs) in the degradation of organic pollutants by CWAO under ambient conditions.

6.
Virus Genes ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32107672

RESUMO

An avian-origin canine influenza virus (CIV) has recently emerged in dogs and is spreading in China. Given that humans have frequent contact with dogs, this has prompted an increased emphasis on biosafety. In this study, we collected 693 nasal swab samples and 800 blood samples from stray dogs in animal shelters to survey canine influenza epidemiology and characterize the evolution of CIV H3N2 in Shanghai. We tested samples for canine influenza antibodies and canine influenza RNA in January-May, 2019, and the results showed that the positive rate was 17.62% by ELISA, 15.75% by microneutralization (MN) assay, and 18.51% by real time RT-PCR, respectively. We also performed phylogenetic and genomic analysis on six H3N2 CIV isolates. The H3N2 viruses which prevailed in Shanghai originated from Beijing and Jiangsu isolates. Phylogenetic analysis showed that the sequences of CIV isolates have multiple amino acid antigenic drifts, deletions, and substitutions. The time of the most recent common ancestor (TMRCA) of HA and NA was 2004 and 2005, respectively. Notably, the substitution, 146S, in hemagglutinin and the deletion in the neuraminidase (NA) stalk region we found in this study warrant attention because they have frequently been identified in human influenza viruses. The potential adaptation of this CIV H3N2 clade to mammals and its public health threat should be further evaluated.

8.
Drug Discov Today ; 25(1): 248-258, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31705979

RESUMO

Undesirable pharmacokinetic (PK) properties or unacceptable toxicity are the main causes of the failure of drug candidates at the clinical trial stage. Since the concept of drug-likeness was first proposed, it has become an important consideration in the selection of compounds with desirable bioavailability during the early phases of drug discovery. Over the past decade, online resources have effectively facilitated drug-likeness studies in an economical and time-efficient manner. Here, we provide a comprehensive summary and comparison of current accessible online resources, in terms of their key features, application fields, and performance for in silico drug-likeness studies. We hope that the assembled toolbox will provide useful guidance to facilitate future in silico drug-likeness research.

9.
J Exp Bot ; 71(4): 1322-1336, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31740933

RESUMO

The plant hormone abscisic acid (ABA) plays a crucial role during the plant life cycle as well as in adaptive responses to environmental stresses. The core regulatory components of ABA signaling in plants are the pyrabactin resistance1/PYR1-like/regulatory component of ABA receptor family (PYLs), which comprise the largest plant hormone receptor family known. They act as negative regulators of members of the protein phosphatase type 2C family. Due to the biological importance of PYLs, many researchers have focused on their genetic redundancy and consequent functional divergence. However, little is understood of their evolution and its impact on the generation of regulatory diversity. In this study, we identify positive selection and functional divergence in PYLs through phylogenetic reconstruction, gene structure and expression pattern analysis, positive selection analysis, functional divergence analysis, and structure comparison. We found the correlation of desensitization of PYLs under specific modifications in the molecular recognition domain with functional diversification. Hence, an interesting antagonistic co-evolutionary mechanism is proposed for the functional diversification of ABA receptor family proteins. We believe a compensatory evolutionary pathway may have occurred.

10.
J Cell Physiol ; 235(4): 3790-3797, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31613009

RESUMO

Acute myelocytic leukemia (AML) is an aggressive malignant tumor and typically fatal without treatment. Identification and development of novel biomarkers could be beneficial for the diagnosis and prognosis of AML patients. Here, we aimed to identify the accurate DNA methylation prognostic signatures for AML patients. The DNA methylation data of AML patients and corresponding clinical information were retrieved from The Cancer Genome Atlas database. CPG sites that correlates closely with the survival of the AML patients were identified and further combined into CPG sites pairs to screen the survival-related pairs. The prognostic signatures were identified by the C-index and forward search algorithms and validated by the verification group. Finally, the functional enrichment analysis was performed on these CPG sites. As a result, a total of 498 CPG sites associated with the overall survival of AML patients was obtained. A prognostic signature composed of 10 CPG sites pairs was obtained and validated. The functional enrichment analysis showed prognostic genes were mainly enriched in tumor protein processing, cell differentiation, blood leukocyte immunity, and platelet growth factor pathways. In summary, we identified two accurate prognostic methylation signatures (NDRG2 and TLR7), which would be served as a novel therapy target for AML.

11.
J Atheroscler Thromb ; 27(1): 71-99, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142690

RESUMO

AIM: Studies have suggested that genetic and environmental factors do not account for all risks and mechanisms of intracranial atherosclerotic stenosis (ICAS). DNA methylation may play a role in the progression of ICAS. METHODS: DNA methylation profiles of peripheral blood leucocytes from 7 patients with early-onset ICAS and 7 perfectly matched controls were interrogated for the first time using the Illumina Infinium Human MethylationEPIC BeadChip. Afterward, functional analysis for differentially methylated genes was conducted. In addition, pyrosequencing verification was performed in an independent cohort comprising 21 patients with early-onset ICAS and 21 age- and gender-matched controls. RESULTS: A total of 318 cytosine-phosphate-guanine sites were found to be differentially methylated based on the established standards. Functional analysis annotated differentially methylated sites to atherosclerosis-related processes and pathways, such as the negative regulation of hydrolase activity (GO 0051346), type II diabetes mellitus (KEGG hsa04930), and the insulin signaling pathway (KEGG hsa04910). In addition, a differentially methylated site was also validated, cg22443212 in gene Rnf213, which showed significant hypermethylation in patients with early-onset ICAS compared with controls 59.56% (49.77%, 88.55%) vs. 44.65% (25.07%, 53.21%), respectively; P=0.010). Receiver operating characteristic curve analysis showed that the area under the curve value of cg22443212 was 0.744 (95% confidence interval, 0.586-0.866; P=0.002). CONCLUSIONS: We revealed that altered DNA methylation may play a role in the occurrence and development of ICAS. These results provided new epigenetic insights into ICAS.

12.
Enzyme Microb Technol ; 132: 109428, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31731949

RESUMO

Phenylalanine aminomutase (PaPAM) from Pantoea agglomerans is a member of the MIO (4-methylene-imidazol-5-one) family of enzymes, which isomerizes α-phenylalanine to ß-phenylalanine, and could be used to synthesize unnatural ß-arylalanine. However, the mechanism of isomerization reaction is not clear. To investigate the mechanism, the gene (pam), which encodes PaPAM, was first expressed in E.coli, and recombinant PaPAM was prepared using affinity chromatography. Then, 15N-(2S)-α-phenylalanine, (2S)-(3-2H2)-α-phenylalanine and (2S,3S)-[2,3-2H2]-α-phenylalanine were used as substrates to analyze the mechanism of isomerization reaction. The results of MS and NMR showed that the isomerization reaction was performed through the intramolecular exchange of NH2 with pro-3R hydrogen of α-phenylalanine. The PaPAM shuttles the α-NH2 of α-phenylalanine to ß site to replace the pro-3R hydrogen. Simultaneously, the pro-3R hydrogen is shifted to α site to produce ß-phenylalanine. Furthermore, a key residue, Phe at position 455 in the active site, was determined to control the exchange way using molecular docking and sequence alignment of MIO family enzymes. The results indicated that the key 455 Phe residue is involved in changing the binding orientation of the carboxyl group of the intermediate trans-cinnamic acid to control the NH2-H pair exchange.

13.
J Hazard Mater ; 383: 121063, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539660

RESUMO

Microalgae photosynthesis is sensitive to coexisted contaminates in aquatic environment, thereby causes adverse effect on algal growth and nutrients uptake. Here, we investigated the photosynthetic toxicity mechanism of cetyltrimethyl ammonium chloride (CTAC)-induced on a green microalga Chlorella vulgaris F1068 (C. vulgaris F1068). Results showed that CTAC reduced the algal growth rate, nutrients removal efficiency and weakened the photosynthetic performance. Meanwhile, the efficiency of oxygen evolution complex (OEC) and oxygen evolvement rates stressed by CTAC were significantly declined to 90.48% and 58.48% of the control (without CTAC), respectively. In addition, atomic force microscopy (AFM) detected the damage of PSII-OEC morphology and structure by CTAC. Furthermore, proteomic analysis showed that 41% of proteins were in the chloroplast thylakoid membranes which function in photosynthesis. The activity of oxygen-evolving enhancer protein 2 (OEE2 or PsbP) involved in electron transfer was significantly inhibited by CTAC, which down-regulated 15.14-fold in the presence of 0.6 mg/L CTAC. These results indicated that photosynthetic inhibition of CTAC mainly occurred in the PSII-OEC. This study provided a new perspective of the photosynthetic response in evaluation of environmental bioimpacts of surfactants on microalgae.

14.
Brief Bioinform ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31799600

RESUMO

Protein dynamics is central to all biological processes, including signal transduction, cellular regulation and biological catalysis. Among them, in-depth exploration of ligand-driven protein dynamics contributes to an optimal understanding of protein function, which is particularly relevant to drug discovery. Hence, a wide range of computational tools have been designed to investigate the important dynamic information in proteins. However, performing and analyzing protein dynamics is still challenging due to the complicated operation steps, giving rise to great difficulty, especially for nonexperts. Moreover, there is a lack of web protocol to provide online facility to investigate and visualize ligand-driven protein dynamics. To this end, in this study, we integrated several bioinformatic tools to develop a protocol, named Ligand and Receptor Molecular Dynamics (LARMD, http://chemyang.ccnu.edu.cn/ccb/server/LARMD/ and http://agroda.gzu.edu.cn:9999/ccb/server/LARMD/), for profiling ligand-driven protein dynamics. To be specific, estrogen receptor (ER) was used as a case to reveal ERß-selective mechanism, which plays a vital role in the treatment of inflammatory diseases and many types of cancers in clinical practice. Two different residues (Ile373/Met421 and Met336/Leu384) in the pocket of ERß/ERα were the significant determinants for selectivity, especially Met336 of ERß. The helix H8, helix H11 and H7-H8 loop influenced the migration of selective agonist (WAY-244). These computational results were consistent with the experimental results. Therefore, LARMD provides a user-friendly online protocol to study the dynamic property of protein and to design new ligand or site-directed mutagenesis.

15.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4272-4276, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872709

RESUMO

In this paper,the case reports on rug-induced liver injury( ADR cases) related to Gukang Capsules containing Psoralea corylifolia( Buguzhi,BGZ) were collected from the adverse reaction monitoring database from January 1,2012 to December 31,2016,and the in-patients cases with drug-induced liver injury admitted to a tertiary Class A liver disease hospital from January 1,2010 to December 31,2016 were also collected. These collected cases were re-evaluated and analyzed. 110 cases with liver injury related to this preparation were collected from adverse reaction monitoring database,and 55 cases of them received the preparation alone,mainly for fracture treatment( 52. 74%). Ninty one cases( 82. 72%) met the standard of the biochemical diagnostic criteria for drug-induced liver injury. 89. 01% of patients were over the age of 41 and women accounted for 60. 9%. The time from administration to liver injury was 1-208 days,with the median of 29 d. The dose of the preparation was 2. 4-4. 8 g per day,with a cumulative dose ranging from 3. 6-699. 6 g. The recovery and improvement rate reached 96. 70% after positive treatment. Seven inpatient cases related to the preparation were collected in a tertiary Class A liver disease hospital,6 females and 1 male. All of them were over 40 years old. Two cases reached the " suspicious diagnosis" standard and 5 cases reached the " clinical diagnosis" standard in Guidelines for the diagnosis and treatment of herb-induced liver injury. Six patients had a good prognosis effect,but another one had liver failure. This preparation is commonly used in fracture,osteoarthritis and other diseases,with remarkable curative effect. However,ADR cases and hospital cases all indicated the risk of liver injury. There was no significant correlation between the time and dose of drug use and the occurrence of liver injury.The induced-liver injury may have immunological heterogeneity,thus regular monitoring of liver function should be taken during clinical use.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Adulto , Bases de Dados Factuais , Feminino , Humanos , Masculino
16.
Animals (Basel) ; 9(12)2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766342

RESUMO

Copy number variation (CNV) is currently accepted as a common source of genetic variation. It is reported that CNVs may influence the resistance to disease and complex economic traits, such as residual feed intake, muscle formation, and fat deposition in livestock. Cell adhesion molecule 2 (CADM2) is expressed widely in the brain and adipose tissue and can regulate body weight through the central nervous system. Growth traits are important economic traits for animal selection. In this study, we aimed to explore the effect of CADM2 gene copy number variants on yak growth traits. Here, two CNVs in the CADM2 gene were investigated using the quantitative polymerase chain reaction (qPCR), and the association of the CNVs with growth traits in yak was analyzed using statistical methods by SPSS software. Differences were considered significant if the p value was < 0.05. Statistical analysis indicated significant association of CADM2-CNV2 with the body weight of the Chinese Ashidan yak. A significant effect of CNV2 (p < 0.05) was found on body weight at 6 months. In CNV2, the gain-type copy number variation exhibited greater performance than the other variants, with greater body weight observed at 6 months (p < 0.05). To the best of our knowledge, this is the first attempt to investigate the function of CADM2-CNVs and their association with growth traits in animals. This may be a useful candidate marker in marker-assisted selection of yaks.

17.
Front Oncol ; 9: 904, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31616629

RESUMO

Background: Glioblastoma (GBM) is the most lethal cancer of the central nervous system. Integrin beta 5 (ITGB5) is thought to be involved in intercellular signal transduction and regulation of tumor initiation and progression. However, the function of ITGB5 in GBM is not known. Methods: To address this question, we evaluated the expression level of ITGB5 in clinical specimens by immunohistochemistry and western blotting, as well as the association between ITGB5 expression and GBM patient survival using data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. The biological function of ITGB5 in GBM was investigated by Gene Ontology, gene set enrichment, and in vitro loss-of-function experiments using glioma cells. Results: Among integrin family members, ITGB5 showed the greatest difference in expression between low-grade glioma and GBM. Elevated ITGB5 expression was highly correlated with glioma progression and a mesenchymal subtype and poor survival in GBM patients. ITGB5 was found to be associated with regulation of the immune response and angiogenesis in GBM, and was required for migration and invasion of glioma cells and tube formation by endothelial cells. Conclusions: These data indicate that ITGB5 can serve as a predictive biomarker for GBM patient survival and is a potential therapeutic target in GBM treatment.

18.
Ecotoxicol Environ Saf ; 184: 109655, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31525561

RESUMO

This study investigated the effects of Cupriavidus sp. strain Cd02-mediated increase on biosorption and bioprecipitation of Cd2+ during the 144-h cultivation time as well as evaluated effectivenesses of changing soil pH and bioavailability of cadmium after bioaugmentation of strain Cd02 into Cd-contaminated paddy soil for 15 days. Results showed that strain Cd02-induced pH increase of the culture medium (from 7.40 to 8.68) facilitated biosorption of Cd2+ on Cd02 cell surface (4.82 mg/mg) and extracellular bioprecipitation in form of cadmium carbonate (3.07 mg/mg). Also, the pH values of Cd-contaminated paddy soil increased by 1.41 units after strain Cd02 was applied for 15 days, which thereby promoted the decrease of exchangeable fraction of Cd2+ by 6.5% in the tested paddy soil. Meanwhile, strain Cd02 could prosperously live in paddy soils after bioaugmentation. These results suggest that strain Cd02 may be applicable for bioremediation of the heavy metal-contaminated soils by bioaugmentation.


Assuntos
Cádmio/análise , Carbonatos/análise , Cupriavidus/metabolismo , Poluentes do Solo/análise , Solo/química , Biodegradação Ambiental , Disponibilidade Biológica , Biomineralização , Cádmio/metabolismo , Carbonatos/metabolismo , Cupriavidus/crescimento & desenvolvimento , Concentração de Íons de Hidrogênio , Oryza/crescimento & desenvolvimento , Poluentes do Solo/metabolismo
19.
J Agric Food Chem ; 67(39): 10844-10852, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525997

RESUMO

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Isoindóis/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Pirazóis/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Isoindóis/química , Cinética , Estrutura Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Pirazóis/química , Relação Estrutura-Atividade
20.
J Headache Pain ; 20(1): 93, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477012

RESUMO

BACKGROUND: Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. METHODS: Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. RESULTS: MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). CONCLUSION: MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.


Assuntos
Tronco Encefálico/patologia , Cerebelo/patologia , Enxaqueca sem Aura/patologia , Anisotropia , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Masculino , Enxaqueca sem Aura/diagnóstico por imagem , Núcleo Espinal do Trigêmeo/diagnóstico por imagem , Núcleo Espinal do Trigêmeo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
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