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1.
Nanotechnology ; 30(47): 475201, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31434061

RESUMO

Some enhanced performances can be obtained by doping multi-walled carbon-nanotube (MWCNT) into self-organized nematic liquid crystal (NLC). However, the dispersion of MWCNT in NLC is very few, thus the enhancement is restricted. In this work, a nickel plated MWCNT (MWCNT@Ni) is synthesized to obtain a relatively high dispersion. The morphology, element and chemical bond differences between MWCNT and MWCNT@Ni are characterized. For MWCNT@Ni, there is a layer of coaxial nickel coated on the surface of MWCNT, which weakens the interaction energy between the adjacent MWCNTs and further results in a relatively high dispersion. Moreover, MWCNT@Ni has a more orderly arrangement in NLC compared with MWCNT. The results suggest that the dielectric anisotropy of MWCNT@Ni/NLC with mass fraction of 0.01 wt% is increased by ∼3.6%, and the saturation voltage is reduced by ∼7.3%. Besides, the rise time is decreased by ∼9.5% at 5 V and 1 kHz. These performances have been improved compared with MWCNT/NLC under the same mass fraction. The effect of mass fraction of MWCNT@Ni on rise time is further investigated. As a result, the rise time is decreased by ∼16.7% as MWCNT@Ni with mass fraction of 0.10 wt% is added into NLC. In general, the method to increase dispersion of dopant in NLC is proposed, which can serve as a reference to improve the performances of NLC composites.

2.
Cell Death Dis ; 10(9): 623, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31423012

RESUMO

Eukaryotic translation initiation factor 3 (eIF3) plays an important role in the regulation of mRNA translation, cell growth and cancer development. eIF3b is the main scaffolding subunit in the eIF3 complex and has been demonstrated to contribute to the development of several cancers. First, our study found that the downregulation of eIF3b could inhibit the proliferation and metastasis of gastric cancer cells by regulating the expression of cancer-related genes. In addition, the expression of eIF3b correlated with the stage and progression of gastric cancer and was shown to be upregulated in human chronic gastritis and in gastric cancer tissues compared with the expression of eIF3b in normal gastric tissues. Moreover, Helicobacter pylori (H. pylori) infection could upregulate the expression of eIF3b in gastric cancer cells, suggesting that eIF3b might be involved in the carcinogenic process of H. pylori. The above findings identified the oncogenic role of eIF3b in gastric cancer development, and this may contribute to the exploration and discovery of novel therapeutic targets for gastric cancer treatment.

3.
Colloids Surf B Biointerfaces ; 183: 110441, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31445357

RESUMO

With increasing attention paid to smart materials, self-healing hydrogels with thermo-responses have been greatly developed in the past several years. At the same time, fluorescent or light emitting polymers have been studied for use as bioimaging tools and drug delivery vehicles. In this research, thermo-responsive self-healing hydrogels with aggregation-induced emission (AIE) property were prepared from tetraphenylethylene (TPE) containing TPE-poly(N,N-dimethylacrylamide-stat-Diacetone acrylamide) [TPE-P(DMA-stat-DAA)] cross-linked by diacylhydrazide. In addition to self-healing based on reversible acylhydrazone bond, the copolymer and hydrogels showed thermo-responses. The lower critical solution temperature (LCST) of the hydrogels was regulated to body temperature. Based on the AIE property of the TPE unit, the hydrogels showed an enhanced light emitting property above the LCST, which was regulated by temperature change. The in vitro cytotoxicity experiment showed that the hydrogels are not toxic, and the DOX release rate can be enhanced by low pH values, which endowed this kind of thermo-responsive light emitting hydrogel with great potential for applications in bio-diagnosis, drug delivery, artificial organs with light sensitive detection, etc.

4.
J Biol Chem ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346035

RESUMO

Seminal amyloid fibrils are made up of naturally occurring peptide fragments and are key targets for the development of combination microbicides or antiviral drugs. Previously, we reported that the poly-sulfonic compound ADS-J1 is a potential candidate microbicide that not only inhibits HIV-1 entry, but also seminal fibrils. However, the carcinogenic azo moieties in ADS-J1 preclude its clinical application. Here, we screened several ADS-J1-like analogs and found that the antiparasitic drug suramin most potently inhibited seminal amyloid fibrils. Using various biochemical methods, including Congo red staining, CD analysis, TEM, viral infection assays, surface plasmon resonance imaging, and molecular dynamics simulations, we investigated suramin's inhibitory effects and its putative mechanism of action. We found that by forming a multivalent interaction, suramin binds to proteolytic peptides and mature fibrils, thereby inhibiting seminal fibril formation and blocking fibril-mediated enhancement of viral infection. Of note, suramin exhibited potent anti-HIV activities, and combining suramin with several antiretroviral drugs produced synergistic effects against HIV-1 in semen. Suramin also displayed a good safety profile for vaginal application. Moreover, suramin inhibited the semen-derived enhancer of viral infection (SEVI)/semen-mediated enhancement of HIV-1 transcytosis through genital epithelial cells and the subsequent infection of target cells. Collectively, suramin has great potential for further development as a combination microbicide to reduce the spread of the AIDS pandemic by targeting both viral and host factors involved in HIV-1 sexual transmission.

5.
Gynecol Obstet Invest ; : 1-7, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31336374

RESUMO

AIMS: Early evaluation of pelvic floor muscle (PFM) in postpartum women is important for the treatment of stress urinary incontinence (SUI). Digital vaginal palpation and electromyography (EMG) evaluation based on Glazer protocol are widely used for the assessment of PFM. However, the correlation among digital palpation, EMG, and morbidity of postpartum SUI is still unclear. This study aims to investigate the relationship between postpartum SUI and PFM examinations. METHODS: This hospital-based cross-sectional study included 1,380 parturients during September 2016 to January 2018. We collected the clinical characteristics, PFM strength, and EMG variables of parturients 6-8 weeks after birth. Then the correlation among the results of EMG, digital palpation, and the occurrence of SUI was analyzed. RESULTS: There is no significant difference in digital palpation scores of PFM strength between SUI and non-SUI parturients. The EMG values were closely related to SUI: the multivariate logistic regression revealed that the most reliable evaluation indicators of postpartum SUI were pelvic floor contractile amplitude of endurance contraction (B = 0.021, p = 0.019) and pretest resting baseline (B = 0.056, p = 0.019). Correlation analysis demonstrated that the contraction variables of EMG had a significant correlation with the digital palpation PFM strength in postpartum women (r = 0.467-0.545, p < 0.001). CONCLUSION: The EMG proved to be reliable in assessing the PFM function in postpartum women. The decreased PFM activity, according to EMG, was correlated with postpartum SUI. Although digital palpation scores were positively correlated with EMG results, no correlation was observed with SUI incidence.

6.
Environ Sci Technol ; 53(16): 9866-9875, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31355638

RESUMO

Animal studies have indicated that persistent organic pollutants (POPs) affect thyroid hormone homeostasis, while epidemiological studies involving human have not shown consistent results. In this study, we investigated the associations between POP exposure and thyroid function among adult population of East China. One hundred eighty-six participants diagnosed with thyroid disease and 186 participants without thyroid disease from Shandong, China were enrolled in the case-control study during 2016 to 2017. We found that POP exposure was significantly and positively associated with the risk of thyroid disease. The association of thyroid disease with a sum of 17 POPs followed a nonmonotonic dose response, with an adjusted odds ratio of 2.09 (95% confidence intervals: 1.13-3.87, p = 0.019) for the second quartile. Among 186 participants in the control group, concentrations of POPs showed negative associations with triiodothyronine (T3), free T3 (FT3), thyroxine (T4), and free T4 (FT4) in males and positive associations with T4 and FT4 in females. Taken together, these findings suggest that POP exposure can disrupt thyroid hormone homeostasis and increase the risk of thyroid disease.

7.
FEBS J ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361392

RESUMO

Metabolic reprogramming, hallmarked by enhanced glycolysis and reduced mitochondrial activity, is a key event in the early phase of somatic cell reprogramming. Although extensive work has been conducted to identify the mechanisms of mitochondrial remodeling in reprogramming, many questions remain. In this regard, different laboratories have proposed a role in this process for either canonical (ATG5-dependent) autophagy-mediated mitochondrial degradation (mitophagy), noncanonical (ULK1-dependent, ATG5-independent) mitophagy, mitochondrial fission or reduced biogenesis due to mTORC1 suppression. Clarifying these discrepancies is important for providing a comprehensive picture of metabolic changes in reprogramming. Yet, the comparison among these studies is difficult because they use different reprogramming conditions and mitophagy detection/quantification methods. Here, we have systematically explored mitochondrial remodeling in reprogramming using different culture media and reprogramming factor cocktails, together with appropriate quantification methods and thorough statistical analysis. Our experiments show lack of evidence for mitophagy in mitochondrial remodeling in reprogramming, and further confirm that the suppression of the mTORC1-PGC1 pathway drives this process. Our work helps to clarify the complex interplay between metabolic changes and nutrient sensing pathways in reprogramming, which may also shed light on other contexts such as development, aging and cancer.

8.
J Proteomics ; 204: 103414, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31195151

RESUMO

Thyroid papillary microcarcinoma is now a common clinical problem. Cervical lymph node metastasis is the main metastasis mode of PTMC. However, before operation, it is still difficult to determine exactly whether PTMC patient is suffering with cervical lymph node metastasis. To resolve this dilemma, for better selection of optimum treatment plans, it is necessary to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. In total, 3391 proteins of the 3793 protein groups identified were quantified. Bioinformatics analysis indicated that differentially expressed proteins were involved in multiple biological functions, metastasis-related pathways. Moreover, IFN-stimulated gene 15 proteins were found to be well distinguished between patients with lymph node metastatic and patients with nonmetastatic PTMC. Knocking down ISG15 with shRNA inhibited the xenografted tumor growth. This study provided a reference proteome map for lymph node metastatic PTMC. ISG15 probably is a prognosis marker of thyroid papillary microcarcinoma patients with lymph node metastasis. SIGNIFICANCE: Nowadays, thyroid cancer has become a widespread epidemic. The rate of thyroid cancer incidence has been faster than any other cancers, reported by the American Cancer Society. Papillary thyroid microcarcinoma (PTMC) is a subset of PTC defined as PTC measuring≤1 cm in size, which comprises nearly one-half of all the cases of PTCs. Actually, the rapidly increasing global incidence of PTC is mainly attributed to the corresponding increase in the diagnosis of PTMC. Scholars have figuratively compared the increase of PTMC to the "tsunami". The treatment scheme for PTMC is still not uniform, and the controversy is mainly focused on the necessity of surgery treatment. PTMCs often have an indolent course in the absence of evidence of metastatic cervical lymph nodes, distant metastases and extrathyroidal extension. Therefore, it is important for us to reliably differentiate the small number of PTMC patients developing significant metastases progression from the larger population of patients that harbor indolent PTMCs. The present study aimed to investigate the overall changes in proteomes of PTMC, and evaluate the potential of biomarkers to predict lymph node metastasis. Tandem mass tags (TMT) combined with multidimensional liquid chromatography and mass spectrometry analyses were used aiming to screen the proteomic profiles of fine-needle aspiration biopsy (FNAB) samples. Quantitative proteomic analysis, significant pathway and functional categories were investigated. Our results showed that some differential expression proteins were likely to be important resources for finding new diagnostic biomarkers.

10.
Protein Expr Purif ; 160: 19-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30904445

RESUMO

Hispidalin is a novel antimicrobial peptide isolated from the seeds of Benincasa hispida and is reported to have broad antimicrobial activity against various bacterial and fungal pathogens. To produce significant amounts of Hispidalin, a recombinant Hispidalin with an N-terminal 6 × His tag and an enterokinase sequence, for the first time, was successfully expressed in Escherichia coli or Pichia pastoris cell factory. Results showed that the E. coli-derived recombinant Hispidalin did not show any antimicrobial activity against all the tested strains, whereas the P. pastoris-derived recombinant Hispidalin (rHispidalin) showed a broad antibacterial spectrum against five pathogenic bacteria of both Gram-negative and Gram-positive. rHispidalin also has bactericidal activity and completely killed all of the Staphylococcus aureus within 40 min. Additionally, rHispidalin showed a broad range of thermostability and pH stability, and a hemolytic activity of less than 2% even at a concentration of 300 µg/ml; it was resistant to trypsin and proteinase K, but was moderately sensitive to pepsin and papain. Moreover, rHispidalin effectively permeabilized the cytoplasmic membrane and disrupted the morphology of targeted bacterial cells. After an initial optimization was performed, the amount of rHispidalin accumulation could reach as high as 98.6 µg/ml. These results indicate that Hispidalin could be produced on a large scale by P. pastoris and has a great potential to be utilized as a new antibacterial agent for further development.

11.
Biochem J ; 476(6): 1021-1035, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30877194

RESUMO

Semen-derived amyloid fibrils, comprising SEVI (semen-derived enhancer of viral infection) fibrils and SEM1 fibrils, could remarkably enhance HIV-1 sexual transmission and thus are potential targets for the development of an effective microbicide. Previously, we found that ADS-J1, apart from being an HIV-1 entry inhibitor, could also potently inhibit seminal amyloid fibrillization and block fibril-mediated enhancement of viral infection. However, the remodeling effects of ADS-J1 on mature seminal fibrils were unexplored. Herein, we investigated the capacity of ADS-J1 to disassemble seminal fibrils and the potential mode of action by applying several biophysical and biochemical measurements, combined with molecular dynamic (MD) simulations. We found that ADS-J1 effectively remodeled SEVI, SEM186-107 fibrils and endogenous seminal fibrils. Unlike epigallocatechin gallate (EGCG), a universal amyloid fibril breaker, ADS-J1 disaggregated SEVI fibrils into monomeric peptides, which was independent of oxidation reaction. MD simulations revealed that ADS-J1 displayed strong binding potency to the full-length PAP248-286 via electrostatic interactions, hydrophobic interactions and hydrogen bonds. ADS-J1 might initially bind to the fibrillar surface and then occupy the amyloid core, which eventually lead to fibril disassembly. Furthermore, the binding of ADS-J1 with PAP248-286 might induce conformational changes of PAP248-286 Disassembled PAP248-286 might not be favorable to re-aggregate into fibrils. ADS-J1 also exerts abilities to remodel a panel of amyloid fibrils, including Aß1-42, hIAPP1-37 and EP2 fibrils. ADS-J1 displays promising potential to be a combination microbicide and an effective lead-product to treat amyloidogenic diseases.

12.
Environ Pollut ; 249: 381-389, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30913437

RESUMO

Annual air samples were collected at various sites in the Fildes Peninsula, West Antarctica from December 2010 to January 2018 using XAD-2 resin passive air samplers to investigate concentrations, temporal trends and potential sources of persistent organic pollutants (POPs) in Antarctic air. Relatively low concentrations of polychlorinated biphenyls (PCBs) (Σ19PCBs: 1.5-29.7 pg/m3), polybrominated diphenyl ethers (PBDEs) (Σ12PBDEs: 0.2-2.9 pg/m3) and organochlorine pesticides (OCPs) (Σ13OCPs: 101-278 pg/m3) were found in the atmosphere of West Antarctica. PCB-11, BDE-47 and hexachlorobenzene (HCB) were the predominant compounds in the atmosphere. The concentrations of PCBs, HCHs, DDTs and endosulfans were found to show decreasing temporal trends, whereas uniform temporal trends were observed for HCB. The atmospheric half-life values for PCBs, HCHs, DDTs and endosulfans in Antarctic air were estimated for the first time, using regressions of the natural logarithm of the concentrations versus the number of years, obtaining the values of 2.0, 2.0, 2.4 and 1.2 year, respectively. An increasing ratio of α-HCH/γ-HCH indicated long residence time for α-HCH and possible transformation of γ-HCH to α-HCH in the atmosphere. The ratios of p,p'-DDT/p,p'-DDE were mostly lower than unity in this study, which could be attributed to aged sources. It was found that long-range atmospheric transport was still considered to be the main contributing factor to the atmospheric levels of the POPs in West Antarctica whereas the contribution of human activities at the Chinese Great Wall Station was minor. The results of this study give a view on the most recent temporal trends and provide new insights regarding the occurrence of various POPs in the Antarctic atmosphere.


Assuntos
Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Éteres Difenil Halogenados/análise , Hidrocarbonetos Clorados/análise , Praguicidas/análise , Bifenilos Policlorados/análise , Regiões Antárticas , Atmosfera , Endossulfano/análise , Hexaclorobenzeno/análise , Hexaclorocicloexano/análise , Humanos
13.
Int J Biol Macromol ; 129: 601-607, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738168

RESUMO

After spinal cord injury, microglial cells are activated and converted to an M1 phenotype. Emerging evidence supports the hypothesis that glucose reprogramming accompanies microglial activation. What contributes to the activation of microglia and glucose reprogramming, however, remains unclear. In the current study, we investigated the role and underlying mechanism of a-synuclein in regulating the aerobic glycolysis in microglia. We found that a-synuclein contributed to the reprogramming of glucose metabolism in microglia by promoting glycolysis and inhibiting mitochondrial biogenesis and oxidative phosphorylation. Further studies demonstrated that pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, mediated glucose reprogramming regulated by a-synuclein. A co-immunoprecipitation assay and Western blot assay demonstrated that a-synuclein interacted with PKM2. Further studies demonstrated that knockdown of PKM2 in a-synuclein-exposed microglia markedly reduced glycolysis and lactate production. Additionally, a-synuclein exposure promoted migration abilities in glucose-cultured microglia, whereas migration ability was suppressed in PKM2 knockdown microglia. Additionally, the PKM2 activator TEPP-46 promoted migration ability in a-synuclein-treated microglia, compared to treatment with a-synuclein alone. In conclusion, we demonstrate a PKM2-dependent glycolysis of a-synuclein in microglial.


Assuntos
Movimento Celular/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Microglia/citologia , Microglia/efeitos dos fármacos , Piruvato Quinase/metabolismo , alfa-Sinucleína/farmacologia , Animais , Glucose/metabolismo , Transportador de Glucose Tipo 1/genética , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Humanos , Microglia/metabolismo , Piruvato Quinase/deficiência , Piruvato Quinase/genética , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
14.
Environ Sci Technol ; 53(5): 2862-2872, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30739451

RESUMO

Exposure to environmental chemicals could disturb lipidome homeostasis in biotas. Comprehensive identification and interpretation of lipid molecules in biological samples are of great importance to elucidate the potential changes in lipid homeostasis upon exposure to various environmental stimuli. In this study, a total of 156 human blood samples were collected including 108 general citizens (control group) and 48 employees in a municipal solid waste incineration (MSWI) plant (occupational exposure group). More than 1500 lipid molecules, belonging to five lipid classes, were screened in the blood samples by UPLC-QTOF-MS in the MSE acquisition mode. All of the coupled compounds with correlation coefficients ( R) of 0.7 or higher were selected for automated network correlation analysis. A global visual network was automatically produced from thousands of coregulated lipid species in the blood samples. In the automatically produced molecular network, the distributions of the major correlated lipids were in accordance with their metabolic pathways in the KEGG map. Different lipidomic profiles in the blood samples from the two groups of people were easily observed by this visualization technique. Among the intrinsic lipid classes, glycererides and sterol lipids might represent the most sensitively affected lipids upon exposure to various pollutants emitted from the MSWI plant. The visualized network of coregulated lipids identified in human blood presents a new approach for interpreting the metabolic relationships among the thousands of metabolites identified in toxicological and epidemiological studies.

15.
J Biosci Bioeng ; 128(2): 135-141, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30782423

RESUMO

N-Acetyl-d-glucosamine (GlcNAc) is a valuable monosaccharide widely used in the medical, agricultural, biofuel, and food industries. Its efficient and environment-friendly production depends on the binary system of ß-N-acetylhexosaminidase (HEX) and chitinase. In the present study, a HEX of glycoside hydrolasefamily 20 was identified in Streptomyces alfalfae ACCC40021, and was overexpressed in Escherichia coli. The purified recombinant SaHEX showed maximal activities at 60°C and pH 5.5, and retained stable up to 45°C. The enzyme not only exhibited broad substrate specificity including p-nitrophenyl ß-N-acetylglucosaminide, p-nitrophenyl ß-N-acetylgalactosaminide, chitooligosaccharides and colloidal chitin, but also had higher specific activities (up to 1149.7 ± 72.6 U/mg) towards natural and synthetic substrates. When combined with a commercial chitinase, it achieved a conversion rate of 93.7% from 1% of colloidal chitin to GlcNAc in 6 h, with the product purity of >98%. These excellent properties make SaHEX a potential enzyme candidate for the chitin conversion for various industrial purposes.

16.
Nat Commun ; 10(1): 34, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604769

RESUMO

The majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs.


Assuntos
Cromatina/metabolismo , Elementos de DNA Transponíveis/genética , Epigênese Genética , Histonas/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Metilação de DNA/genética , Técnicas de Silenciamento de Genes , Código das Histonas , Histonas/genética , Camundongos , Células-Tronco Embrionárias Murinas
17.
Medicine (Baltimore) ; 98(1): e13986, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30608441

RESUMO

RATIONALE: Congenital internal carotid artery hypoplasia (CICAH) is rarely reported. This study aimed to discuss the epidemiological characteristics, clinical manifestation, imaging and treatment of CICAH. PATIENT CONCERNS: The case was male who showed barylalia and limited abilities of the left limbs as their main clinical manifestation. This patient was diagnosed CICAH by digital subtraction angiography (DSA) and computed tomography (CT). DIAGNOSIS: CICAH. INTERVENTIONS: The patient underwent anti platelet aggregation, lipid-lowering, improving cerebral circulation. OUTCOMES: The patient was in a stable condition after management of cerebrovascular risk. LESSONS: Given the asymptomatic and congenital nature of carotid agenesis, no treatment is necessary or possible to re-establish the internal carotid artery (ICA). However, with the high risk of aneurysm and cerebrovascular insufficiency, management of cerebrovascular risk is important. Urgent radiological assessment is necessary for patients with suspicious neurological symptoms.


Assuntos
Artéria Carótida Interna/anormalidades , Artéria Carótida Interna/patologia , Transtornos Cerebrovasculares/tratamento farmacológico , Angiografia Digital/métodos , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Artéria Carótida Interna/diagnóstico por imagem , Transtornos Cerebrovasculares/prevenção & controle , Clopidogrel/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/etiologia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
18.
Elife ; 82019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30648968

RESUMO

We have developed a method to introduce novel paratopes into the human antibody repertoire by modifying the immunoglobulin (Ig) genes of mature B cells directly using genome editing technologies. We used CRISPR-Cas9 in a homology directed repair strategy, to replace the heavy chain (HC) variable region in B cell lines with that from an HIV broadly neutralizing antibody (bnAb), PG9. Our strategy is designed to function in cells that have undergone VDJ recombination using any combination of variable (V), diversity (D) and joining (J) genes. The modified locus expresses PG9 HC which pairs with native light chains (LCs) resulting in the cell surface expression of HIV specific B cell receptors (BCRs). Endogenous activation-induced cytidine deaminase (AID) in engineered cells allowed for Ig class switching and generated BCR variants with improved HIV neutralizing activity. Thus, BCRs engineered in this way retain the genetic flexibility normally required for affinity maturation during adaptive immune responses. Peripheral blood derived primary B cells from three different donors were edited using this strategy. Engineered cells could bind the PG9 epitope and sequenced mRNA showed PG9 HC transcribed as several different isotypes after culture with CD40 ligand and IL-4.

19.
J Chem Inf Model ; 59(1): 522-534, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30607947

RESUMO

CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), belongs to the protein arginine methyltransferase (PRMT) family, which has emerged as a potential anticancer drug target. To discover new CARM1 inhibitors, we performed virtual screening against the substrate-binding site in CARM1. Structure-based pharmacophore models, which were generated according to three druggable subpockets embedding critical residues for ligand binding, were applied for virtual screening. The importance of the solvent-exposed substrate-binding cavity was highlighted due to significant hydrophobicity. Aided by molecular docking, 15 compounds structurally distinct from known CARM1 inhibitors were selected to evaluate their inhibitory effects on CARM1 methyltransferase activity, which resulted in seven compounds exhibiting micromolar inhibition, with selectivity over other members in the PRMT protein family. Moreover, three of them exhibited potent antiproliferation activities in breast cancer cells. Particularly, compound NO.2 exhibited potent activity both in vitro and in cultured cells, which will serve as a leading hit for developing CARM1 inhibitors with improved efficacy. The virtual screening strategy in this study will be applicable for the discovery of substrate-competitive inhibitors targeting other members in the PRMT protein family.

20.
Invest New Drugs ; 37(5): 1107-1116, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30612309

RESUMO

The human embryonic lethal abnormal visual protein, HuR, belongs to the Hu family of RNA-binding proteins. Over the past two decades, HuR has been extensively associated with multiple biological characteristics of tumors, including tumor development and progression, angiogenesis, invasion, migration and prognosis, since this protein regulates the stability of cancer-associated target mRNAs due to its posttranscriptional regulatory mechanisms. A recent investigation of the multiple functions of HuR has provided emerging evidence of its role in drug resistance in various tumors. Herein, we demonstrate the roles of HuR proteins in the development of drug resistance, examine their involvement in various mechanisms, including apoptosis, the ABC transporter family, the cell cycle and the DNA damage response, and provide insight into ongoing studies for developing therapeutic strategies aimed at targeting this molecule in tumor cells.

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