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1.
Biosens Bioelectron ; 148: 111666, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31698301

RESUMO

As an essential transition-metal ion in organism, zinc ion (Zn2+) plays a significant role in cellular metabolism, apoptosis and neurotransmission. Herein, we reported a new intramolecular charge transfer-based two-photon probe, (E)-1-(6-(4-(2-(2-(2-methoxyethoxy)ethoxy)eth-oxy)-3,5-dimethylstyryl)quinolin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine (TEO-MPVQ), for ratiometric imaging and biosensing of Zn2+ in living cells and larval zebrafish. The maximum two-photon absorption cross-section values (δmax) of the developed probe increased from 115 ±â€¯16 GM to 188 ±â€¯27 GM, after the probe was chelated with Zn2+. The emission spectrum of TEO-MPVQ probe increased and red-shifted about 60 nm, resulting in the ratiometric determination of Zn2+ with high sensitivity and selectivity. The present fluorescent probe also demonstrated good biocompatibility, high spatial resolution and deep penetration depth for Zn2+ detection. Accordingly, TEO-MPVQ was able to track the endogenous Zn2+ release in neurons and also successfully applied for larval zebrafish imaging. By using of this effective probe, it was found that the endogenous Zn2+ was rapidly released from metallothionein under the stimulation of NO in neurons.

2.
Brief Bioinform ; 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31504171

RESUMO

Essential genes are those whose loss of function compromises organism viability or results in profound loss of fitness. Recent gene-editing technologies have provided new opportunities to characterize essential genes. Here, we present an integrated analysis that comprehensively and systematically elucidates the genetic and regulatory characteristics of human essential genes. First, we found that essential genes act as 'hubs' in protein-protein interaction networks, chromatin structure and epigenetic modification. Second, essential genes represent conserved biological processes across species, although gene essentiality changes differently among species. Third, essential genes are important for cell development due to their discriminate transcription activity in embryo development and oncogenesis. In addition, we developed an interactive web server, the Human Essential Genes Interactive Analysis Platform (http://sysomics.com/HEGIAP/), which integrates abundant analytical tools to enable global, multidimensional interpretation of gene essentiality. Our study provides new insights that improve the understanding of human essential genes.

3.
RNA Biol ; 16(8): 1010-1021, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31046554

RESUMO

The study of cancer prognosis serves as an important part of cancer research. Large-scale cancer studies have identified numerous genes and microRNAs (miRNAs) associated with prognosis. These informative genes and miRNAs represent potential biomarkers to predict survival and to elucidate the molecular mechanism of tumour progression. MiRNAs and transcription factors (TFs) can work cooperatively as essential mediators of gene expression, and their dysregulation affects cancer prognosis. A panoramic view of cancer prognosis at the system level, considering the co-regulation roles of miRNA and TF, remains elusive. Here, we establish 12 prognosis-related miRNA-TF co-regulatory networks. The characteristics of prognostic target genes and their regulators in the network are depicted. Although the target genes and co-regulatory patterns exhibit cancer-specific properties, some miRNAs and TFs are highly conserved across cancers. We illustrate and interpret the roles of these conserved regulators by building a model associated with cancer hallmarks, functional enrichment analysis, network community detection, and exhaustive literature research. The elaborated system-level prognostic miRNA-TF co-regulation landscape, including the highlighted roles of conserved regulators, provides a novel and powerful insights into further biological and medical discoveries.

4.
Bioinformatics ; 35(20): 3931-3936, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30860576

RESUMO

MOTIVATION: During development of the mammalian embryo, histone modification H3K4me3 plays an important role in regulating gene expression and exhibits extensive reprograming on the parental genomes. In addition to these dramatic epigenetic changes, certain unchanging regulatory elements are also essential for embryonic development. RESULTS: Using large-scale H3K4me3 chromatin immunoprecipitation sequencing data, we identified a form of H3K4me3 that was present during all eight stages of the mouse embryo before implantation. This 'stable H3K4me3' was highly accessible and much longer than normal H3K4me3. Moreover, most of the stable H3K4me3 was in the promoter region and was enriched in higher chromatin architecture. Using in-depth analysis, we demonstrated that stable H3K4me3 was related to higher gene expression levels and transcriptional initiation during embryonic development. Furthermore, stable H3K4me3 was much more active in blood tumor cells than in normal blood cells, suggesting a potential mechanism of cancer progression. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

5.
Biochem Biophys Res Commun ; 508(3): 986-990, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30545630

RESUMO

Surgery and chemotherapy are the gold-standard treatments for ovarian cancer. The major cause of treatment failure in patients with ovarian cancer is tumoral heterogeneity and drug resistance. Paclitaxel (PTX) is one of the most commonly used first-line drugs for ovarian cancer chemotherapy. Unfortunately, the mechanisms of PTX chemoresistance remain unclear. Here, we examined the effects of post-translational neddylation on the sensitivity of ovarian cancer cells (OCCs) to PTX-induced apoptosis. Disruption of protein neddylation with the first-in-class inhibitor MLN4924 dramatically neutralized PTX-mediated antiproliferative, antimigration, and apoptotic effects in human OCCs. Moreover, MLN4924 treatment interrupted PTX-induced microtubule polymerization. Importantly, two neddylation conjugating E2 enzymes, UBE2M and UBE2F, were found to play essential roles in PTX-induced cytotoxicity and tubulin polymerization in OCCs. In summary, our findings demonstrated that disruption of protein neddylation by MLN4924 conferred resistance to PTX and provided insights into the potential mechanisms of PTX chemoresistance in ovarian cancer.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Ciclopentanos/farmacologia , Microtúbulos/efeitos dos fármacos , Proteína NEDD8/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/uso terapêutico , Pirimidinas/farmacologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Microtúbulos/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimerização/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores
6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(6): 1863-1867, 2018 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-30501735

RESUMO

In recent years, with the development of gene editing technology, the site-specific genome can be modified. The curability of genetic disease may be achieved by the use of gene editing techniques. As the simplicity, high specificity and economical efficiency, much attention has been paid to the CRISPR/Cas9 system, which was been widely used in research of molecular biology and other fields of life science. In this review, the mechanism for CR1SPR/Cas9 system and the progress of gene therapy, such as for hemophilia, betathalassaemia and chronic myeloid leukemia were summarized briefly.

7.
PeerJ ; 6: e5951, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30473937

RESUMO

Transcription factors (TFs) and microRNAs (miRNAs) are well-characterized trans-acting essential players in gene expression regulation. Growing evidence indicates that TFs and miRNAs can work cooperatively, and their dysregulation has been associated with many diseases including cancer. A unified picture of regulatory interactions of these regulators and their joint target genes would shed light on cancer studies. Although online resources developed to support probing of TF-gene and miRNA-gene interactions are available, online applications for miRNA-TF co-regulatory analysis, especially with a focus on cancers, are lacking. In light of this, we developed a web tool, namely CMTCN (freely available at http://www.cbportal.org/CMTCN), which constructs miRNA-TF co-regulatory networks and conducts comprehensive analyses within the context of particular cancer types. With its user-friendly provision of topological and functional analyses, CMTCN promises to be a reliable and indispensable web tool for biomedical studies.

8.
SLAS Discov ; 23(9): 919-929, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30011241

RESUMO

Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation. We developed a novel duplex homogeneous BTK occupancy assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to measure free and total BTK levels in a multiplexed format. The dual-wavelength emission property of terbium-conjugated anti-BTK antibody served as the energy donor for two fluorescent energy acceptors with distinct excitation and emission spectra. The assay was characterized and qualified using full-length purified recombinant human BTK protein and peripheral blood mononuclear cells derived from healthy volunteers and patients with CLL. We demonstrated assay utility using cells derived from lymph node and bone marrow samples from patients with CLL and DLBCL. Our TR-FRET-based BTK occupancy assay provides accurate, quantitative assessment of BTK occupancy in the clinical trial program for tirabrutinib and is in use in ongoing clinical studies.

9.
Zhongguo Zhen Jiu ; 38(7): 695-9, 2018 Jul 12.
Artigo em Chinês | MEDLINE | ID: mdl-30014661

RESUMO

OBJECTIVE: To observe the clinical effects between moxibustion combined with 5-hydroxy tryptamine (5-HT) receptor antagonist and simple 5-HT receptor antagonist in the prevention and treatment of nausea and vomiting caused by cisplatin chemotherapy in patients with lung cancer. METHODS: Fifty-eight patients with lung cancer who were treated with cisplatin chemotherapy were randomly assigned into an observation group and a control group, 29 cases in each one. The patients in the two groups were applied by 5-HT receptor antagonist to prevent nausea and vomiting on the 1st through 3rd days of chemotherapy. Moxibustion at Baihui (GV 20) and Zhongwan (CV 12) was used in the observation group 1-3 days before chemotherapy for 1 course, 3 days as 1 course, 5 cones each acupoint and once a day. Rhodes's index of nausea and vomiting and retching (INVR) was recorded in 0-24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy. The rates of nausea and vomiting, as well as fatigue degree were observed in the above 4 time periods. The safety was assessed. RESULTS: After treatment, the scores of nausea and vomiting in 0-24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy in the observation group were lower than those in the control group (all P<0.01). The nausea rates in the above 4 time periods in the observation group were 37.9% (11/29), 62.1% (18/29), 60.7% (17/28) and 17.4% (4/23), which were lower than 93.1% (27/29), 89.7% (26/29), 89.3% (25/28), 52.0% (13/25) in the control group respectively (all P<0.05). The vomiting rates in the above 4 time periods in the observation group were 10.3% (3/29), 31.0% (9/29), 32.1% (9/28) and 13.0% (3/23), which were better than 37.9% (11/29), 79.3% (23/29), 82.1% (23/28) and 44.0% (11/25) in the control group (all P<0.05). The fatigue scores in the observation group in 0-24 h, 24-48 h, 48-72 h and 72-96 h of chemotherapy were lower than those in the control group (all P<0.01). There was no adverse reactions in the two groups during chemotherapy, such as skin toxicity, diarrhea, fever, allergy, etc. CONCLUSION: Moxibustion combined with 5-HT receptor antagonist can obviously reduce the rates and degrees of nausea and vomiting caused by cisplatin chemotherapy in patients with lung cancer, which are better than simple 5-HT receptor antagonist, without apparent adverse reactions.

10.
Brief Bioinform ; 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29617727

RESUMO

The Cancer Genome Atlas (TCGA) is a publicly funded project that aims to catalog and discover major cancer-causing genomic alterations with the goal of creating a comprehensive 'atlas' of cancer genomic profiles. The availability of this genome-wide information provides an unprecedented opportunity to expand our knowledge of tumourigenesis. Computational analytics and mining are frequently used as effective tools for exploring this byzantine series of biological and biomedical data. However, some of the more advanced computational tools are often difficult to understand or use, thereby limiting their application by scientists who do not have a strong computational background. Hence, it is of great importance to build user-friendly interfaces that allow both computational scientists and life scientists without a computational background to gain greater biological and medical insights. To that end, this survey was designed to systematically present available Web-based tools and facilitate the use TCGA data for cancer research.

11.
Se Pu ; 36(2): 173-178, 2018 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-29582604

RESUMO

In order to develop a fast investigation method for phthalate esters (PAEs) from vegetable oils, a gas-liquid micro-extraction (GLME) technique that combined with GC-MS was established. A vegetable oil sample (0.1 g) was directly added into the GLME device. The integrated process of extraction, clean-up, and concentration of PAEs was completed within 5 min. Internal standard method was applied to ensure the accuracy of the results. Soybean oil, blend oil, olive oil, and sesame oil were spiked with 200 µg/kg of a mixed 15 PAEs standard, and the ranges of the recoveries and RSDs were between 60.0% to 112.3% and 0.9% to 28.4%, respectively. Compared with some traditional sample pretreatment methods such as liquid-liquid extraction, liquid-liquid micro-extraction, gel permeation chromatography, this method is simple and fast, with high accuracy, good repeatability and low matrix effect. This study verified the suitability of the GLME method for field detection of food products in food safety sector and exhibits great significance for the completion of food safety system in China.


Assuntos
Ésteres/isolamento & purificação , Ácidos Ftálicos/isolamento & purificação , Óleos Vegetais/análise , Cromatografia em Gel , Cromatografia Gasosa-Espectrometria de Massas , Extração Líquido-Líquido
12.
Int J Mol Sci ; 19(3)2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29534529

RESUMO

ZmbZIP25 (Zea mays bZIP (basic leucine zipper) transcription factor 25) is a function-unknown protein that belongs to the D group of the bZIP transcription factor family. RNA-seq data showed that the expression of ZmbZIP25 was tissue-specific in maize silks, and this specificity was confirmed by RT-PCR (reverse transcription-polymerase chain reaction). In situ RNA hybridization showed that ZmbZIP25 was expressed exclusively in the xylem of maize silks. A 5' RACE (rapid amplification of cDNA ends) assay identified an adenine residue as the transcription start site of the ZmbZIP25 gene. To characterize this silk-specific promoter, we isolated and analyzed a 2450 bp (from -2083 to +367) and a 2600 bp sequence of ZmbZIP25 (from -2083 to +517, the transcription start site was denoted +1). Stable expression assays in Arabidopsis showed that the expression of the reporter gene GUS driven by the 2450 bp ZmbZIP25 5'-flanking fragment occurred exclusively in the papillae of Arabidopsis stigmas. Furthermore, transient expression assays in maize indicated that GUS and GFP expression driven by the 2450 bp ZmbZIP25 5'-flanking sequences occurred only in maize silks and not in other tissues. However, no GUS or GFP expression was driven by the 2600 bp ZmbZIP25 5'-flanking sequences in either stable or transient expression assays. A series of deletion analyses of the 2450 bp ZmbZIP25 5'-flanking sequence was performed in transgenic Arabidopsis plants, and probable elements prediction analysis revealed the possible presence of negative regulatory elements within the 161 bp region from -1117 to -957 that were responsible for the specificity of the ZmbZIP25 5'-flanking sequence.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas de Plantas/genética , Regiões Promotoras Genéticas , Zea mays/genética , Arabidopsis/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas de Plantas/metabolismo , Xilema/metabolismo
13.
Anal Chem ; 90(4): 2816-2825, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29376642

RESUMO

Iron ions, as a main component of intracellular labile iron, not only play an important function in oxygen transport, enzymatic reactions, and electron transport but also are vitally important in oxidative stress. In this work, we developed a ratiometric fluorescent biosensor for ferrous ion (Fe2+), in which gold nanoclusters (AuNCs) were synthesized as a stable fluorescent probe and a ligand (FeL) was designed for specific recognition of Fe2+ and conjugated onto AuNCs (AuNC@FeL). Meanwhile, water-soluble sulfocyanine 7 N-hydroxysuccinimide ester (Cy7 NHS ester) was immobilized onto AuNC@FeL as a reference element. The developed ratiometric fluorescent nansosensor displayed good linearity with the concentration of Fe2+ in the range of 1-105 µM, and detection limit was achieved down to 210 nM. In addition, this nanosensor responded to Fe2+ in less than 1.23 s and showed high selectivity against other metal ions, amino acids, and reactive oxygen species. With the advantages of high selectivity and accuracy, as well as quick response and long-term stability, this organic-inorganic ratiometric fluorescent probe was successfully applied in real-time biosensing and bioimaging of Fe2+ in neurons and HepG2 cells. By use of this tool, it was found that the increasing concentration of Fe2+ in live cells was closely related to oxidative stress.

14.
Front Plant Sci ; 8: 869, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28611798

RESUMO

We analyzed tissue-specific transcriptomes of Arabidopsis thaliana and identified 66 gene families with a high frequency of "gradient genes" - genes showing a significant expression gradient between tissues. Gradient gene families include many with roles in hormone and peptide signaling, cell wall synthesis and remodeling, secondary metabolism, transcriptional regulation, and transport between cells. We compared the size of the gradient gene families among the genomes of four plant species with radically different body plans - a single-celled algae, a moss, a eudicot, and a monocot - and found that most of the gradient gene families (58/66) expanded in parallel with the evolution of morphological complexity. A novel measure of tissue diversity was used to show that members of any one gradient gene family tend not to be clustered in a single tissue, but are rather apportioned evenly across the tissues studied. Considered together, our results suggest that the diversification of these gene families supported the diversification of tissue types and the evolution of body plan complexity in plants.

15.
J Gastrointest Surg ; 21(6): 936-946, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28374183

RESUMO

OBJECTIVES: Transversus abdominis plane (TAP) block is an analgesic technique. Adding dexmedetomidine can enhance regional anesthesia. This study's aim was to evaluate whether dexmedetomidine prolonged analgesic time of TAP block after gastrectomy. METHODS: Patients scheduled for gastrectomy were randomly assigned to receive a TAP block with saline (group S), ropivacaine (group R), or ropivacaine and dexmedetomidine (group RD). Visual analogue scale (VAS) scores, postoperative nausea and vomiting (PONV) scores, sedation scores, tramadol consumption, ropivacaine concentration, and Quality of Recovery Questionnaire 40 (QoR-40) were recorded. RESULTS: Patients in group R and group RD had lower VAS scores 2, 4, 12, and 24 h after surgery compared with group S (P < 0.05). PONV scores were lower in group R and group RD compared with group S after 2, 12, 24, and 36 h (P < 0.05). Patients in group R and group RD required less tramadol and had better QoR-40 scores than those in group S (P < 0.05). The aforementioned variables and ropivacaine concentrations did not differ between group R and group RD (P > 0.05). Sedation scores were similar between three groups (P > 0.05). CONCLUSIONS: TAP block can provide analgesia and improve the quality of recovery. Adding dexmedetomidine does not significantly improve the quality or duration of TAP block.


Assuntos
Músculos Abdominais/inervação , Amidas/administração & dosagem , Anestésicos Locais/administração & dosagem , Dexmedetomidina/administração & dosagem , Gastrectomia , Bloqueio Nervoso/métodos , Ultrassonografia de Intervenção , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados (Cuidados de Saúde) , Estudos Prospectivos , Ropivacaina
16.
Anal Chem ; 89(4): 2553-2560, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28192925

RESUMO

Zinc ion (Zn2+) not only plays an important function in the structural, catalytic, transcription, and regulatory of proteins, but is also an essential ionic signal to regulate brain neurotransmitters pass process. In this work, we designed and synthesized an intramolecular charge transfer-based ratiometric two-photon fluorescence probe, P-Zn, for imaging and biosensing of Zn2+ in live cell, hippocampal tissue, and zebrafish. The developed probe demonstrated high two-photon absorption cross section (δ) of 516 ± 77 GM, which increased to 958 ± 144 GM after the probe was coordinated with Zn2+. Furthermore, this P-Zn probe quickly recognized Zn2+ with high selectivity, over other metal ions, amino acids, and reactive oxygen species. More interestingly, the initial emission peak of the present probe at 465 nm decreased with a new peak increased at 550 nm, leading to the ratiometric determination of Zn2+ with high accuracy. Finally, this two-photon fluorescence probe with high temporal resolution and remarkable analytical performance, as well as low-cytotoxicity, was successfully applied in imaging of live cells, hippocampal tissues, and zebrafishes. The present P-Zn probe combined with FLIM provided accurate mapping of Zn2+ distribution at single-cell level. More interestingly, the two-photon spectroscopic results demonstrated that the level of Zn2+ in hippocampal tissue of mouse with AD was higher than that in normal mouse brain.

17.
Food Chem Toxicol ; 109(Pt 2): 923-929, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28223120

RESUMO

Nitidine chloride (NC) has demonstrated promising anticancer activity. However, NC has also shown non-specific toxicity in various healthy organs such as the liver. In this study, we aimed to develop a supramolecular formulation of NC and investigate the associated benefits of such a supramolecular formulation on modulating its inherent hepatotoxicity and anticancer activity. The formation of NC-cucurbit[7]uil (NC@CB[7]) complexes was characterized by 1H nuclear magnetic resonance and Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction analysis. As a consequence of the supramolecular complexation, NC@CB[7] showed significantly lower toxicity (IC50: 6.87 ± 0.80 µM) on a liver cell line (LO2), and higher cytotoxicity (IC50: 2.94 ± 0.15 µM) on a breast cancer cell line (MCF-7), when compared with the free drug (IC50 of 3.48 ± 0.49 µM and 7.28 ± 0.36 µM, on these two cell lines, respectively). Investigation of cellular uptakes revealed that CB[7]'s capability in modulating the toxicity/activity of NC was mainly attributed to the drug's different cellular uptake behaviors that were influenced by CB[7]'s complexation. Taken together, we have demonstrated that supramolecular formulation of NC by CB[7] significantly alleviated its hepatotoxicity and improved its anticancer activity in vitro.


Assuntos
Antineoplásicos/toxicidade , Benzofenantridinas/química , Benzofenantridinas/toxicidade , Hidrocarbonetos Aromáticos com Pontes/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Imidazóis/química , Fígado/efeitos dos fármacos , Zanthoxylum/química , Antineoplásicos/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Composição de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier
18.
Int J Mol Sci ; 17(12)2016 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-27999284

RESUMO

Aspirin down regulates transferrin receptor 1 (TfR1) and up regulates ferroportin 1 (Fpn1) and ferritin expression in BV-2 microglial cells treated without lipopolysaccharides (LPS), as well as down regulates hepcidin and interleukin 6 (IL-6) in cells treated with LPS. However, the relevant mechanisms are unknown. Here, we investigate the effects of aspirin on expression of hepcidin and iron regulatory protein 1 (IRP1), phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3) and P65 (nuclear factor-κB), and the production of nitric oxide (NO) in BV-2 microglial cells treated with and without LPS. We demonstrated that aspirin inhibited hepcidin mRNA as well as NO production in cells treated with LPS, but not in cells without LPS, suppresses IL-6, JAK2, STAT3, and P65 (nuclear factor-κB) phosphorylation and has no effect on IRP1 in cells treated with or without LPS. These findings provide evidence that aspirin down regulates hepcidin by inhibiting IL6/JAK2/STAT3 and P65 (nuclear factor-κB) pathways in the cells under inflammatory conditions, and imply that an aspirin-induced reduction in TfR1 and an increase in ferritin are not associated with IRP1 and NO.


Assuntos
Aspirina/farmacologia , Hepcidinas/biossíntese , Interleucina-6/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Linhagem Celular , Hepcidinas/genética , Inflamação/patologia , Proteína 1 Reguladora do Ferro/biossíntese , Janus Quinase 2/metabolismo , Camundongos , Óxido Nítrico/biossíntese , Fosforilação/efeitos dos fármacos , RNA Mensageiro/biossíntese , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
19.
Int J Pharm ; 509(1-2): 391-399, 2016 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-27282539

RESUMO

Two new 1:1 cocrystals of resveratrol (RES) with 4-aminobenzamide (RES-4ABZ) and isoniazid (RES-ISN) were synthesized by liquid assisted grinding (LAG) and rapid solvent removal (RSR) methods using ethanol as solvent. Their physiochemical properties were characterized using PXRD, DSC, solid state and solution NMR, FT-IR, and HPLC. Pharmaceutically relevant properties, including tabletability, solubility, intrinsic dissolution rate, and hygroscopicity, were evaluated. Temperature-composition phase diagram for RES-ISN cocrystal system was constructed from DSC data. Both cocrystals show higher solubility than resveratrol over a broad range of pH. They are phase stable and non-hygroscopic even under high humidity conditions. Importantly, both cocrystals exhibit improved solubility and tabletability compared with RES, which make them more suitable candidates for tablet formulation development.


Assuntos
Estilbenos/química , Comprimidos/química , Benzamidas/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Cristalização/métodos , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Difração de Pó/métodos , Resveratrol , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Temperatura Ambiente , Difração de Raios X/métodos , para-Aminobenzoatos/química
20.
Mod Rheumatol ; 26(6): 850-856, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26873570

RESUMO

OBJECTIVE: Evaluate the association between the multi-biomarker disease activity (MBDA) score and radiographic progression in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF)-α inhibitors. METHODS: Change (Δ) in modified total Sharp score (mTSS) over 52 weeks and disease activity scores were examined retrospectively by Spearman's rank correlation coefficient in patients (N = 83) with RA initiating TNF-inhibitor treatment. Relative risk (RR) of ΔmTSS >0.5 for low MBDA score and 28-joint count disease activity score (DAS28) categories and associations between ΔmTSS and MBDA score categories conditional on DAS28 categories were assessed. RESULTS: At 52 weeks, 34% of patients had ΔmTSS >0.5 and 12% had ΔmTSS >3. Strongest correlations were observed between ΔmTSS and MBDA score (r = 0.47) or DAS28 (r = 0.42) at Week 24 and for area under the curve at Week 52 (MBDA score: r = 0.44, DAS28: r = 0.41), all p < 0.001. At Week 24, RR of ΔmTSS >0.5 for moderate/high MBDA score (≥30) or DAS28 (>3.2) were 6.6 (p < 0.001) and 2.7 (p = 0.005), respectively. Low DAS28 had greater risk of ΔmTSS >0.5 at 52 weeks when MBDA score was ≥30 (p < 0.05). CONCLUSION: Higher MBDA score or DAS28 at Week 24 was associated with greater radiographic progression over 52 weeks of TNF-inhibitor treatment. MBDA score improved risk discrimination for radiographic progression within DAS28 categories.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores , Progressão da Doença , Etanercepte/uso terapêutico , Feminino , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Humanos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
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