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1.
Phys Chem Chem Phys ; 22(3): 981-984, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31912822

RESUMO

Herein, we propose a new approach of molecule occupancy via a vapor treatment to facilitate the conversion of PbI2 to perovskite in sequential deposition. We have shown that the morphology of PbI2 and the subsequent crystallization of perovskite can be effectively tuned, thus leading to the elimination of residual PbI2 and promotion of perovskite growth.

3.
Nat Genet ; 51(11): 1607-1615, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31676864

RESUMO

Melon is an economically important fruit crop that has been cultivated for thousands of years; however, the genetic basis and history of its domestication still remain largely unknown. Here we report a comprehensive map of the genomic variation in melon derived from the resequencing of 1,175 accessions, which represent the global diversity of the species. Our results suggest that three independent domestication events occurred in melon, two in India and one in Africa. We detected two independent sets of domestication sweeps, resulting in diverse characteristics of the two subspecies melo and agrestis during melon breeding. Genome-wide association studies for 16 agronomic traits identified 208 loci significantly associated with fruit mass, quality and morphological characters. This study sheds light on the domestication history of melon and provides a valuable resource for genomics-assisted breeding of this important crop.


Assuntos
Mapeamento Cromossômico , Cucurbitaceae/genética , Domesticação , Genoma de Planta , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Cucurbitaceae/classificação , Cucurbitaceae/crescimento & desenvolvimento , Estudo de Associação Genômica Ampla , Genômica , Fenótipo , Melhoramento Vegetal
4.
Bioorg Med Chem Lett ; 29(23): 126683, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627991

RESUMO

Histone lysine-specific demethylase 1 (LSD1) was the first discovered histone demethylase. Inactivating LSD1 or downregulating its expression inhibits cancer-cell development, and thus, it is an attractive molecular target for the development of novel cancer therapeutics. In this study, we worked on the structural optimization of natural products and identified 30 novel LSD1 inhibitors. Utilizing a structure-based drug design strategy, we designed and synthesized a series of curcumin analogues that were shown to be potent LSD1 inhibitors in the enzyme assay. Compound WB07 displayed the most potent LSD1 inhibitory activity, with an IC50 value of 0.8 µM. Moreover, WA20 showed an anticlonogenic effect on A549 cells with an IC50 value of 4.4 µM. Molecular docking simulations were also carried out, and the results indicated that the inhibitors bound to the protein active site located around the key residues of Asp555 and Asp556. These findings suggested that compounds WA20 and WB07 are the first curcumin analogue-based LSD1 inhibitors with remarkable A549 suppressive activity, providing a novel scaffold for the development of LSD1 inhibitors.

5.
Cancer Biol Med ; 16(2): 220-233, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31516744

RESUMO

Objective: Heat shock factor 1 (HSF1), a transcriptional regulator of heat shock proteins (HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far. Methods: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies. Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth. Results: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression. Conclusions: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance. Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.

6.
Opt Express ; 27(18): 26050-26059, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31510465

RESUMO

Optical image encryption technique has become extremely important in these years. However, most of the proposed multiple-image encryption systems are illuminated with coherent light source. Here we present a multiple-image double-encryption method with spatially incoherent illumination. The first-encryption of multiple images is based on the speckle rotation decorrelation property, and the second-encryption of images' order is based on the speckle shift decorrelation out of the angular memory-effect range. The double-encryption via two-dimensional rotations of the random phase mask enhances the security and keeps the simplicity of the cryptosystem. The capacity of the ciphertext is greatly increased by multiplexing, and further increased after crosstalk noise removal. The use of incoherent light source reduces the requirements for experimental conditions, and makes the cryptosystem easy to implement in various application scenarios.

7.
Microb Cell Fact ; 18(1): 149, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481079

RESUMO

BACKGROUND: Polyol esters of fatty acids (PEFA) are a kind of promising biosurfactants and mainly secreted by Rhodotorula strains. In addition, some strains of Rhodotorula are reliable producers of microbial lipid. Therefore, it is feasible to establish a one step fermentation process for efficient simultaneous production of PEFA and microbial lipids by a suitable Rhodotorula strain. RESULTS: A newly isolated deep-sea yeast, Rhodotorula paludigena P4R5, was shown to simultaneously produce high level of intracellular lipid and extracellular PEFA. Under the optimized conditions, it could yield 48.5 g/L of PEFA and 16.9 g/L of intracellular lipid within 156 h from inulin during 10-L batch fermentation. The PEFA consisting of a mixture of mannitol esters of 3-hydroxy C14, C16 and C18 fatty acids with variable acetylation showed outstanding surface activity and emulsifying activity, while the fatty acids of the intracellular lipid were mainly C16 and C18 and could be high-quality feedstock for biodiesel production. CONCLUSION: The deep-sea yeast strain R. paludigena P4R5 was an excellent candidate for efficient simultaneous of biosurfactants and biodiesel from inulin. Our results also suggested that the establishment of fermentation systems with multiple metabolites production was an effective approach to improve the profitability.


Assuntos
Biocombustíveis , Ésteres/metabolismo , Ácidos Graxos/metabolismo , Inulina/metabolismo , Polímeros/metabolismo , Rhodotorula/metabolismo , Técnicas de Cultura Celular por Lotes , Reatores Biológicos , Fermentação
8.
Int J Biol Macromol ; 141: 298-306, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465808

RESUMO

Extraction polysaccharide from microorganism is a research hotspot. In this work, a new type of water-soluble exopolysaccharides (EPS) was isolated from Bacillus licheniformis. Firstly, response surface methodology (RSM), based on a three-level, three-factor, was used to determine optimum conditions for EPS extraction. And RSM analysis indicated optimum condition was at the temperature of 8 °C for 10.44 h with ethanol at a concentration of 79.22% (v/v), the maximum yield of EPS was 3.07 g/mL. Secondly, EPS were seperated using DEAE-Sepharose Fast Flow column chromatography and acquired two polysaccharide fractions, BL-P1 and BL-P2. BL-P1 had larger molecular weight than BL-P2 from structural analyses, because of higher content of mannose, ribose, glucuronic acid, galactose, arabinose and fructose in BL-P2. Moreover, the characterization of BL-P1 and BL-P2 was investigated with Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy, the results indicated that EPS was mainly composed of→3)-α-d-Galp-(1→, →3,5)-α-l-Araf-(1→, →3)-ß-d-Glcp-(1→, ß-d-Glcp-(1 → and→4)-ß-l-Fucp-(1 → 4)-ß-d-Xylp-(1 → 4)-α-l-Rhap (1 → 3) -ß-d-Manp-(4 → residues. In vitro antioxidant activity assay, EPS exhibited potent quenching capacities on hydroxyl and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals in a dose-dependent manner. Furthermore, BL-P2 had higher activity than BL-P1 in inhibiting α-amylase and α-glucosidase, which would have potential to be applied in nutraceutical and pharmaceutical industries.

9.
Opt Express ; 27(10): 14567-14576, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31163902

RESUMO

Optical imaging and tracking moving objects through scattering media is a challenge with important applications. However, previous works suffer from time-consuming recovery process, object complexity limit, or object information lost. Here we present a method based on the speckle rotation decorrelation property. The rotational speckles detected at short intervals are uncorrelated and multiplexed in a single-shot camera image. Object frames of the video are recovered by cross-correlation deconvolution of the camera image with a computationally rotated point spread function. The near real-time recovery provides sharp object image frames with accurate object relative positions, exact movement velocity, and continuous motion trails. This multiplexing technique has important implications for a wide range of real-world imaging scenarios.

10.
Eur Radiol ; 29(12): 6519-6528, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31250172

RESUMO

AIM: The purpose of this study was to determine the relative diagnostic benefit of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) over contrast-enhanced multi-detector computed tomography (CEMDCT) for the detection of hepatocellular carcinoma (HCC). METHODS: Two investigators searched multiple databases from inception to January 8, 2019, for studies comparing Gd-EOB-DTPA-enhanced MRI with CEMDCT in adults suspected of HCC. Two reviewers independently selected studies and extracted data. RESULTS: Eight studies were included enrolling 498 patients. MRI showed significantly higher sensitivity than CT (0.85 vs. 0.68). There was no significant difference in the specificity of MRI and CT (0.94 vs. 0.93). The negative likelihood ratio and positive likelihood ratio of MRI and CT were not significantly different (0.16 vs. 0.15 and 14.7 vs. 11.2, respectively). The summary receiver operating characteristics (SROC) of MRI was higher than that of CT at 0.96 vs. 0.91. In the subgroup analysis with a lesion diameter below 2 cm, the sensitivity of MRI was significantly higher than that of CT (0.79 vs. 0.46). CONCLUSION: Gd-EOB-DTPA-enhanced MRI showed higher sensitivity and overall diagnostic accuracy than CEMDCT especially for hepatocellular carcinoma lesions smaller than 2 cm. KEY POINTS: • Gd-EOB-DTPA-enhanced MRI can detect small lesions of hepatocellular carcinoma. • Gd-EOB-DTPA-enhanced MRI showed higher sensitivity and overall diagnostic accuracy than CEMDCT in patients with hepatocellular carcinoma. • Eight prospective studies showed that Gd-EOB-DTPA-enhanced MRI provides greater diagnostic confidence.

11.
Sci Rep ; 8(1): 17843, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30552379

RESUMO

Fine mapping and discovery of candidate genes underlying seed size are important for modern watermelon breeding. Here, by using a high-resolution genetic map and whole-genome genetic variation detection aided by genome survey sequencing, we fine mapped and discovered candidate genes for seed size in watermelon. QTL (quantitative trait locus) mapping identified two pleiotropic QTLs for seed size, namely, qSS4 and qSS6, using a high-density genetic map constructed by specific length amplified fragment sequencing. qSS6 explained 93.00%, 94.11% and 95.26% of the phenotypic variation in thousand-seed weight, seed length and seed width, respectively, and was defined as a major QTL. Then, high-coverage re-sequencing of two parental lines detected a total of 193,395 SNPs (single nucleotide polymorphisms) and 45,065 indels (insertions/deletions), which corresponded to a frequency of 534 SNPs/Mb and 124 indels/Mb. Based on the genetic variation in the two parental lines, newly developed PCR-based markers allowed the region of qSS6 to be narrowed to 55.5 kb. Three potential candidates were identified, including a known seed size regulator in rice, SRS3. Taken together, our results reveal successful rapid fine mapping and discovery of candidate genes for seed size in watermelon, which could be applied to many traits of interest in plants.


Assuntos
Mapeamento Cromossômico , Citrullus/anatomia & histologia , Citrullus/genética , Estudos de Associação Genética , Sementes/anatomia & histologia , Sementes/genética , Variação Genética , Genoma de Planta , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Análise de Sequência de DNA
12.
Front Plant Sci ; 9: 1577, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30429864

RESUMO

Low temperature is an important abiotic stress that negatively affects morphological growth and fruit development in melon (Cucumis melo L.). Chilling stress at the seedling stage causes seedling injury and poor stand establishment, prolonging vegetative growth and delaying fruit harvest. In this study, association mapping was performed for chilling tolerance at the seedling stage on an expanded melon core collection containing 212 diverse accessions by 272 SSRs and 27 CAPSs. Chilling tolerance of the melon seedlings was evaluated by calculating the chilling injury index (CII) in 2016 and 2017. Genetic diversity analysis of the whole accession panel presented two main groups, which corresponded to the two subspecies of C. melo, melo, and agrestis. Both the subspecies were sensitive to chilling but with agrestis being more tolerant. Genome-wide association study (GWAS) was conducted, respectively, on the whole panel and the two subspecies, totally detecting 51 loci that contributed to 74 marker-trait associations. Of these associations, 35 were detected in the whole panel, 21 in melo, and 18 in agrestis. About half of the associations identified in the two subspecies were also observed in the whole panel, and seven associations were shared by both the subspecies. CMCT505_Chr.1 was repeatedly detected in different populations with high phenotypic contribution and could be a key locus controlling chilling tolerance in C. melo. Nine loci were selected for evaluation of the phenotypic effects related to their alleles, which identified 11 elite alleles contributing to seedling chilling tolerance. Four such alleles existed in both the subspecies and six in either of the two subspecies. Analysis of 20 parental combinations for their allelic status and phenotypic values showed that the elite alleles collectively contributed to enhancement of the chilling tolerance. Tagging the loci responsible for chilling tolerance may simultaneously favor dissecting the complex adaptability traits and elevate the efficiency to improve chilling tolerance using marker-assisted selection in melon.

13.
Pak J Med Sci ; 34(4): 923-928, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30190754

RESUMO

Objective: To compare glottis exposure of the same patients with potentially difficult tracheal intubation (PDTI) subjected to Airtraq laryngoscopy and Macintosh laryngoscopy under consciousness and topical anesthesia. Methods: A total of 147 PDTI patients with American Society of Anesthesiologists (ASA) I-III were subjected to Airtraq and Macintosh laryngoscopy performed by experienced anesthesiologists under consciousness and topical anesthesia. Results: All patients were successfully intubated. Among them, three patients were intubated with fiberoptic bronchoscopy, 13 with Macintosh laryngoscopy and 131 with Airtraq laryngoscopy. Of the patients with Cormack and Lehance (C&L) Grade-I glottic view, 88 were subjected to Airtraq laryngoscopy and five to Macintosh laryngoscopy; Of the patients with C&L Grade-II glottic view, 56 were subjected to Airtraq laryngoscopy and 21 to Macintosh bronchoscopy; Of the patients with C&L Grade-III glottic view, three were subjected to Airtraq laryngoscopy and 112 to Macintosh bronchoscopy; Of the patients with C&L Grade-IV glottic view, none was subjected to Airtraq laryngoscopy and 9 to Macintosh laryngoscopy. Conclusions: Airtraq laryngoscopy could significantly improve the glottis exposure and reduce the difficulty of intubation for patients with potentially tracheal intubation compared to the traditional Macintosh laryngoscopy.

14.
World Neurosurg ; 119: e598-e606, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30077021

RESUMO

OBJECTIVE: In this study, we aimed to evaluate the efficacy and safety of sufentanil-propofol (SF) versus remifentanil-propofol (RF) as maintenance therapy for anesthesia in patients undergoing craniotomy. METHODS: Randomized controlled studies on SF and RF as anesthesia for craniotomy were searched in electronic databases such as PubMed, Web of Science, Cochrane Library, Embase, CNKI, and Wanfang Data. All studies were published up to December 31, 2017. The primary outcomes were wake-up time, extubation time, and pain score. The secondary outcomes were heart rate, mean arterial pressure (MAP), and adverse reactions. RESULTS: In this meta-analysis, 14 studies involving 927 patients were investigated. Compared with the SF group, RF could significantly reduce the wake-up time and extubation time after craniotomy (P = 0.02, standardized mean difference [SMD], 1.19; 95% confidence interval [CI], 0.21-2.18; P = 0.0001; SMD, 1.87; 95% CI, 0.90-2.83, respectively). Meanwhile, SF had better efficacy to alleviate postoperative pain than RF (P = 0.001; SMD, 2.10; 95% CI, -3.37 to -0.82). However, there were no obvious differences in improving heart rate and MAP between the 2 groups (P = 0.46; SMD, 0.17; 95% CI, -0.28 to 0.62; P = 0.43; SMD, 0.16; 95% CI, -0.54 to 0.23, respectively). Moreover, there were no significant differences in the incidents of nausea and vomiting, shivering, fidgeting, and respiratory depression between the SF and RF groups. CONCLUSIONS: RF as anesthesia for craniotomy had better effects in reducing the time of postoperative wake-up and extubation and significantly alleviating pain. Moreover, there were no significant differences in the incidence of adverse reactions between the 2 groups. The findings will prove beneficial for the rational use of clinical anesthetic drugs in the future.


Assuntos
Analgésicos/administração & dosagem , Craniotomia , Propofol/administração & dosagem , Remifentanil/administração & dosagem , Sufentanil/administração & dosagem , Analgésicos/efeitos adversos , Anestesia/efeitos adversos , Anestesia/métodos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Humanos , Propofol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sufentanil/efeitos adversos
15.
Int J Oncol ; 52(6): 2079-2092, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29620156

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. Research investigating novel therapeutic strategies for the treatment of HCC is urgently required. Monoclonal antibodies (mAbs) that target the programmed cell death­1 (PD­1/PDCD1)/programmed death-ligand 1 (PD-L1) immune checkpoint have demonstrated substantial clinical benefit for a variety of solid tumors; however, these mAbs have not been well studied in HCC. In the present study, Sp2/0-Ag14 myeloma cells and spleen cells derived from BALB/c mice immunized with the recombinant human PD­1/PDCD1 protein were fused for the production of novel antibodies. The 9E11 mAb, which exhibited the highest specificity for PD­1 in HCC tissues in western blot and immunohistochemical staining analyses, was used to investigate the clinical significance of PD­1 expression in HCC tissues from 77 cases, which were collected and examined histologically. Overexpression of PD­1 was identified in peritumoral tissues, primarily in the liver portal region. Importantly, by analyzing the clinical data from 77 HCC patients, the expression of PD­1 was observed to be significantly correlated with larger tumor size (>5 cm) and poorly differentiated tumors. In addition, PD­1 expression was moderately correlated with venous thrombosis, but not correlated with patient sex or age, liver cirrhosis, hepatitis B, tumor, node and metastasis (TNM) stage or tumor location. The results of the present study suggest that high-level PD­1 expression may be an important factor associated with the immune checkpoint pathway in HCC. The results suggest that PD­1 serves an important role in tumor immune evasion and may be a valuable immunodiagnostic marker. In addition, PD­1 may serve as a therapeutic target for patients presenting with poorly differentiated HCC, thus indicating the potential application of a PD­1 inhibitor for the treatment of HCC patients.


Assuntos
Anticorpos Monoclonais/metabolismo , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Trombose Venosa/metabolismo , Adulto , Idoso , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunização , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Proteínas Recombinantes/metabolismo , Carga Tumoral , Regulação para Cima
16.
Chin Med J (Engl) ; 131(6): 631-637, 2018 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-29521283

RESUMO

Background:: Patients with potential difficult mask ventilation (DV) and difficult intubation (DI) are often managed with awake intubation, which can be stressful for patients and anesthesiologists. This prospective randomized study evaluated a new approach, fast difficult airway evaluation (FDAE). We hypothesized that the FDAE approach would reduce the need for awake intubation. Methods:: After obtaining informed consent, 302 patients with potential DV/DI undergoing elective surgeries were randomly assigned to the FDAE group (Group E) and the control group (Group C). In Group E, patients were gradually sedated, and adequacy of manual mask ventilation during spontaneous breathing was assessed at various sedation levels. Awake intubation was applied in those with inadequate mask ventilation. In Group C, DI was evaluated under local anesthesia. However, the care team could intubate under general anesthesia if the vocal cords were visible. The primary outcome was the rate of awake intubations in both groups and the induction efficiency assessed by the induction time. The secondary outcome was the incidence of serious complications. Results: The rate of awake intubation was significantly lower in Group E than that in Group C (5.81% vs. 36.05%, χ2 = 42.3, P < 0.001). The induction time was much shorter in Group E than in Group C (11.85 ± 4.82 min vs. 18.71 ± 7.85 min, t = 5.39, P < 0.001). There was no significant difference in the incidence of intubation related complications between the two groups. Patients in Group E had a much lower incidence of recall (9.68% vs. 44.90%, χ2 = 47.68, P < 0.001) of the induction process and higher satisfaction levels than patients in Group C (t = 15.36, P < 0.001). Conclusions: The FDAE significantly reduces the need for awake intubation and improves the efficiency of the intubation process without comprising safety in patients with potential difficult mask ventilation and DI. Trial Registration:: No. ChiCTR-TRC-11001418; http://www.gctr.org/cn/proj/show.aspx?proj=1562.


Assuntos
Intubação Intratraqueal/métodos , Máscaras Laríngeas , Adulto , Manuseio das Vias Aéreas , Feminino , Humanos , Masculino , Éteres Metílicos/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Sevoflurano , Vigília
17.
Cancer Res ; 78(11): 3041-3053, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29549164

RESUMO

Potassium ion channels are emerging as promalignant factors involved in cancer progression. In this study, we found that invading human gastric cancer cells express high levels of inwardly rectifying potassium channel 2.1 (Kir2.1). Silencing Kir2.1 markedly reduced the invasive and metastatic capabilities as well as the epithelial-mesenchymal transition (EMT) of gastric cancer cells. The promalignant nature of Kir2.1 in gastric cancer cells was independent of potassium permeation but relied on its interaction with serine/threonine-protein kinase 38 (Stk38) to inhibit ubiquitination and degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2). Degradation of MEKK2 was mediated by small mothers against decapentaplegic-specific E3 ubiquitin protein ligase 1 (Smurf1), which resulted in activation of the MEK1/2-ERK1/2-Snail pathway in gastric cancer cells. In human gastric cancer tissues, expression was high and positively correlated with invasion depth and metastatic status of the tumors as well as poor overall patient survival. Cox regression analysis identified Kir2.1 as an independent prognostic indicator for patients with gastric cancer. Our results suggest that Kir2.1 is an important regulator of gastric cancer malignancy and acts as a novel prognostic marker and a therapeutic target for gastric cancer.Significance: Kir2.1 contributes to invasion and metastasis by a noncanonical ion permeation-independent signaling pathway and may act as a novel prognostic marker and therapeutic target for gastric cancer. Cancer Res; 78(11); 3041-53. ©2018 AACR.


Assuntos
MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/genética , MAP Quinase Quinase Quinases/genética , Sistema de Sinalização das MAP Quinases/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas/genética , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética
18.
CNS Neurosci Ther ; 23(11): 855-865, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28941188

RESUMO

AIMS: Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (Aß) production and increases Aß degradation by neurons. Activated microglia are involved in AD by either clearing Aß deposits through uptake of Aß or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on Aß uptake and clearance and Aß-induced inflammatory response in microglia, on neuronal death induced by Aß-activated microglia, and explored underlying mechanisms. METHODS: Intracellular and extracellular Aß were examined by immunofluorescence staining and Western blot. Amyloid peptides (Aß) receptors, Aß degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-κB was examined by Western blot. RESULTS: We found that physiological concentrations of androgen enhanced Aß42 uptake and clearance, suppressed Aß42 -induced IL-1ß and TNFα expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by Aß42 -activated microglia. Androgen administration also reduced Aß42 -induced IL-1ß expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade Aß42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited Aß42 -induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-κB activation by Aß42 , in an androgen receptor independent manner. CONCLUSION: Our study demonstrates that androgen promotes microglia to phagocytose and clear Aß42 and inhibits Aß42 -induced inflammatory response, which may play an important role in reducing the neurotoxicity of Aß.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Androgênios/farmacologia , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Peptídeos beta-Amiloides/metabolismo , Androgênios/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Di-Hidrotestosterona/farmacologia , Enzimas Conversoras de Endotelina/metabolismo , Interleucina-1beta/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fragmentos de Peptídeos/metabolismo , Fagocitose/efeitos dos fármacos , Fagocitose/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Prep Biochem Biotechnol ; 47(10): 963-969, 2017 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-28718734

RESUMO

Pullulan with different molecular-weight could be applied in various fields. A UV-induced mutagenesis Aureobasidium pullulans UVMU6-1 was obtained from the strain A. pullulans CGMCC3.933 for the production of low-molecular-weight pullulan. First, the obtained polysaccharide from A. pullulans UVMU6-1 was purified and identified to be pullulan with thin-layer chromatography, Fourier transform infrared, and nuclear magnetic resonance. Then, culture medium and conditions for this strain were optimized by flask fermentation. Based on the optimized medium and culture conditions (pH 4, addition of 4 g/L Tween 80 for 96 hr of cultivation), continuously fermentation was performed. The highest pullulan production and dry biomass was 109 and 125 g/L after fermentation for 114 hr, respectively. The average productivity was about 1 g/L/hr, which was intensively higher than the previous reported. This study would lay foundations for the industrial production of pullulan.


Assuntos
Ascomicetos/metabolismo , Meios de Cultura/metabolismo , Glucanos/metabolismo , Microbiologia Industrial/métodos , Ascomicetos/química , Ascomicetos/genética , Cromatografia em Camada Delgada , Meios de Cultura/química , Fermentação , Glucanos/análise , Glucanos/genética , Espectroscopia de Ressonância Magnética , Mutagênese , Espectroscopia de Infravermelho com Transformada de Fourier
20.
PLoS One ; 12(6): e0180076, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28662102

RESUMO

Senile plaques consisting of Amyloid-beta (Aß) peptides, in particular Aß1-42, are the hallmark of Alzheimer's disease (AD) and have been the primary therapeutic targets. Passive immunotherapy with monoclonal antibodies (mAbs) has shown initial success in mouse models of AD. However, the existing Aß-directed mAbs mostly were tested on animal models or patients with advanced disease. The effects and mechanisms of mAbs on animals or human trial participants in the prodromal phase of AD are not fully clarified. In the current study, a novel mAb (3F5) directed against the 1-11 amino acids of Aß1-42 was generated by immunizing mice with an emulsion of full length human Aß1-42. The mAb (3F5) showed the ability to disrupt Aß1-42 aggregation and prevent Aß-mediated neurotoxicity in vitro. In a mouse model of AD, administration with 3F5 for 3 months in 6 months-old mice demonstrated that the mAb specifically bound with Aß1-42 to promote the depolymerization of Aß fibrils, facilitated endocytosis of Aß1-42 by microglia, and attenuated the death and apoptosis of neuronal cells, accompanied by neurite outgrowth. APP/PS1 double-transgenic mice treated with 3F5 mAb showed reduced memory loss, cognitive decline, and decreased levels of amyloid deposits in the brain. Aß1-42 levels in cerebral tissues were also significantly reduced, whereas serum Aß1-42 was markedly increased. Interestingly, the concentration of 3F5 in peripheral circulation is much higher than that in the brain. These results indicate that 3F5 is able to cross the blood-brain barrier (BBB) to bind Aß and initiates the phagocytosis of antibody/Aß complexes by microglia in the amyloid depositing mice. 3F5 also promotes Aß efflux from the brain. As a consequence, the antibody reduces plaques in the AD mouse brain, in association with reduction in the pathology of AD.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , Anticorpos Monoclonais/imunologia , Cognição , Modelos Animais de Doenças , Fragmentos de Peptídeos/imunologia , Placa Amiloide/prevenção & controle , Doença de Alzheimer/psicologia , Animais , Feminino , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos
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