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1.
Polymers (Basel) ; 13(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805432

RESUMO

Dielectric elastomer (DE) is a type of electric field type electroactive polymer material that can produce greater deformation under the action of an electric field and has a faster recovery speed. It has the advantages of high energy density, large strain, low quality, and commercialization, and has become the most widely concerned and researched electroactive polymer material. In this study, copper calcium titanate (CCTO) particles with a large dielectric constant were selected as the filling phase, and a silicone rubber (PDMS) with better biocompatibility and lower elastic modulus was used as the matrix to prepare CCTO/PDMS, which is a new type of dielectric elastomer material. The structure of the dielectric elastomer is analyzed, and its mechanical properties, dielectric properties, and driving deformation are tested. Then, KH550, KH560, and KH570 modified CCTO is used in order to improve the dispersibility of CCTO in PDMS, and modified particles with the best dispersion effect are selected to prepare dielectric elastomer materials. In addition, mechanical properties, dielectric properties, and driving deformation are tested and compared with the dielectric elastomer material before modification. The results show that as the content of CCTO increases, the dielectric constant and elastic modulus of the dielectric elastomer also increase, and the dielectric loss remains basically unchanged at a frequency of 100 Hz. When the filling amount reaches 20 wt%, the dielectric constant of the CCTO/PDMS dielectric elastomer reaches 5.8 (100 Hz), an increase of 120%, while the dielectric loss at this time is only 0.0038 and the elastic modulus is only 0.54 MPa. When the filling amount is 5 wt%, the dielectric elastomer has the largest driving deformation amount, reaching 33.8%. Three silane coupling agents have been successfully grafted onto the surface of CCTO particles, and the KH560 modified CCTO has the best dispersibility in the PDMS matrix. Based on this, a modified CCTO/PDMS dielectric elastomer was prepared. The results show that the improvement of dispersibility improves the dielectric constant. Compared with the unmodified PDMS, when the filling content is 20 wt%, the dielectric constant reaches 6.5 (100 Hz). Compared with PDMS, it has increased by 150%. However, the improvement of dispersion has a greater increase in the elastic modulus, resulting in a decrease in its strain parameters compared with CCTO/PDMS dielectric elastomers, and the electromechanical conversion efficiency has not been significantly improved. When the filling amount of modified CCTO particles is 5 wt%, the dielectric elastomer has the largest driving deformation, reaching 27.4%.

2.
Aging (Albany NY) ; 13(8): 11150-11169, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819182

RESUMO

Alzheimer's disease (AD) is characterized by cognitive decline due to the accumulation of extracellular ß-amyloid (Aß) plaques and neurofibrillary tangles in the brain, which impair glutamate (Glu) metabolism. Deproteinized Calf Blood Extractive Injection (DCBEI) is a biopharmaceutical that contains 17 types of amino acids and 5 types of nucleotides. In this study, we found that DCBEI pretreatment reduced L-Glu-dependent neuroexcitation toxicity by maintaining normal mitochondrial function in HT22 cells. DCBEI treatment also reduced the expression of pro-apoptosis proteins and increased the expression of anti-apoptosis proteins. Furthermore, DCBEI attenuated AD-like behaviors (detected via the Morris water maze test) in B6C3-Tg (APPswePSEN1dE9)/Nju double transgenic (APP/PS1) mice; this effect was associated with a reduction in the amount of Aß and neurofibrillary tangle deposition and the concomitant reduction of phospho-Tau in the hippocampus. Metabonomic profiling revealed that DCBEI regulated the level of neurotransmitters in the hippocampus of APP/PS1 mice. Label-free proteomics revealed that DCBEI regulated the expression of Nrf-2 and its downstream targets, as well as the levels of phospho-protein kinase B and mitogen-activated protein kinase. Together, these data show that DCBEI can ameliorate AD symptoms by upregulating Nrf2-mediated antioxidative pathways and thus preventing mitochondrial apoptosis.

3.
Anal Chim Acta ; 1154: 338295, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33736817

RESUMO

A unique electrochemical sensor was constructed based on designed peptide hydrogels loaded with ciprofloxacin and gold nanoparticles, which exhibited excellent biocompatibility, antibacterial capability and electrochemical catalytic property. The peptide hydrogel was prepared base on the self-assembly of a designed short peptide sequence of Phe-Glu-Lys-Phe (FEKF) with the N-terminal modified with a fluorene methoxycarbonyl (Fmoc) group. The peptide hydrogel possessed nanofibrous network structure and exhibited good shear-thinning behavior and excellent biocompatibility, and it can be easily doped with gold nanoparticles and the antibiotic drug ciprofloxacin. The loaded antibacterial drug offered remarkable antibacterial activity of the hydrogel, while the loaded gold nanoparticles rendered the hydrogel excellent electrochemical catalytic capability towards the detection of a typical neurotransmitter dopamine. The combination of the antibacterial property and the electrochemical catalytic ability within a peptide hydrogel ensured the development of sensitive and antibacterial electrochemical sensors, and this strategy was expected to promote the construction of implantable sensors without infection.

4.
Sci Total Environ ; 772: 145522, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33571779

RESUMO

With the continuous development of industrialization, a growing number of refractory organic pollutants are released into the environment. These contaminants could cause serious risks to the human health and wildlife, therefore their degradation and mineralization is very critical and urgent. Recently sulfate radical-based advanced oxidation technology has been widely applied to organic pollutants treatment due to its high efficiency and eco-friendly nature. This review comprehensively summarizes different methods for persulfate (PS) and peroxymonosulfate (PMS) activation including ultraviolet light, ultrasonic, electrochemical, heat, radiation and alkali. The reactive oxygen species identification and mechanisms of PS/PMS activation by different approaches are discussed. In addition, this paper summarized the toxicity of degradation intermediates through bioassays and Ecological Structure Activity Relationships (ECOSAR) program prediction and the formation of toxic bromated disinfection byproducts (Br-DBPs) and carcinogenic bromate (BrO3-) in the presence of Br-. The detoxification and mineralization of target pollutants induced by different reactive oxygen species are also analyzed. Finally, perspectives of potential future research and applications on sulfate radical-based advanced oxidation technology in the treatment of organic pollutants are proposed.


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , Humanos , Oxirredução , Sulfatos/toxicidade , Poluentes Químicos da Água/análise
5.
Vet Res ; 52(1): 28, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597018

RESUMO

CD9 is a glycoprotein of the transmembrane 4 superfamily that is involved in various cellular processes. Studies related to the immune functions and activities of CD9 in teleost fish are limited. In this study, we characterized two CD9 homologs, PoCD9.1 and PoCD9.3, from Japanese flounder (Paralichthys olivaceus). Sequence analysis showed that PoCD9.1 and PoCD9.3 possess characteristic transmembrane 4 superfamily (TM4SF) structures. PoCD9.1 shares 70.61% sequence identity with PoCD9.3. The expression of PoCD9.1 and PoCD9.3 in the three main immune tissues was significantly induced in a time-dependent manner by extracellular and intracellular pathogen infection, which indicates that the two CD9 homologs play an important role in the response to pathogenic infection. Following infection with the extracellular pathogen Vibrio anguillarum, the expression profiles of both PoCD9.1 and PoCD9.3 were similar. After infection with the intracellular pathogen Edwardsiella piscicida, the expression levels of PoCD9.1 and PoCD9.3 were different at different stages of infection, especially in the spleen. The spleen was the most important tissue for the PoCD9.1 and PoCD9.3 responses to pathogen infection among the three examined immune tissues. Knockdown of PoCD9.1 and PoCD9.3 attenuated the ability of host cells to eliminate pathogenic bacteria, and PoCD9.1 knockdown was more lethal than PoCD9.3 knockdown for host cells with E. piscicida infection. Overexpression of PoCD9.1 and PoCD9.3 promoted host or host cell defence against E. piscicida infection. These findings suggest that PoCD9.1 and PoCD9.3 serve as immune-related factors, play an important role in the immune defence system of Japanese flounder, and display different functions in response to different pathogens at different stages of infection.


Assuntos
Linguado/genética , Linguado/imunologia , Regulação da Expressão Gênica/imunologia , Tetraspanina 29/genética , Sequência de Aminoácidos , Animais , Linhagem Celular , Edwardsiella , Escherichia coli , Brânquias/citologia , Rim Cefálico/metabolismo , Iridoviridae , Fígado/metabolismo , Modelos Moleculares , Conformação Proteica , Baço/metabolismo , Tetraspanina 29/metabolismo , Transcriptoma , Vibrio
6.
Mol Cell ; 81(8): 1698-1714.e6, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33626321

RESUMO

The DREAM complex orchestrates cell quiescence and the cell cycle. However, how the DREAM complex is deregulated in cancer remains elusive. Here, we report that PAF (PCLAF/KIAA0101) drives cell quiescence exit to promote lung tumorigenesis by remodeling the DREAM complex. PAF is highly expressed in lung adenocarcinoma (LUAD) and is associated with poor prognosis. Importantly, Paf knockout markedly suppressed LUAD development in mouse models. PAF depletion induced LUAD cell quiescence and growth arrest. PAF is required for the global expression of cell-cycle genes controlled by the repressive DREAM complex. Mechanistically, PAF inhibits DREAM complex formation by binding to RBBP4, a core DREAM subunit, leading to transactivation of DREAM target genes. Furthermore, pharmacological mimicking of PAF-depleted transcriptomes inhibited LUAD tumor growth. Our results unveil how the PAF-remodeled DREAM complex bypasses cell quiescence to promote lung tumorigenesis and suggest that the PAF-DREAM axis may be a therapeutic vulnerability in lung cancer.


Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Proteínas Interatuantes com Canais de Kv/genética , Neoplasias Pulmonares/genética , Pulmão/patologia , Proteínas Repressoras/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Carcinogênese/patologia , Divisão Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Nus , Células NIH 3T3 , Ativação Transcricional/genética , Transcriptoma/genética
7.
Nat Metab ; 3(1): 90-106, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398195

RESUMO

Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.


Assuntos
Ciclo do Ácido Cítrico/fisiologia , Mitocôndrias/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Feminino , Homeostase , Humanos , Lisossomos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nutrientes , Organelas/metabolismo , RNA Neoplásico/genética
8.
Virol Sin ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33400094

RESUMO

Dengue virus is an arthropod-borne pathogen that is transmitted to humans primarily by Aedes spp. mosquitos, causing the acute infectious disease, dengue fever (DF). Until 2019, no dengue outbreak had been reported in Hainan Province for over 20 years. However, in early September of 2019, an increasing number of infected cases appeared and the DF outbreak lasted for over one month in Haikou City, Hainan Province. In our study, we collected 97 plasma samples from DF patients at three hospitals, as well as 1585 mosquito larvae samples from puddles in different areas of Haikou. There were 49 (50.5%) plasma samples found to be strongly positive and 9 (9.3%) plasma samples were weakly positive against the NS1 antigen. We discovered DENV both in the patient's plasma samples and mosquito larvae samples, and isolated the virus from C6/36 cells inoculated with the acute phase serum of patients. Phylogenetic analysis revealed that the new strains were the most closely related to the epidemic strain in the southern regions of China, belonging to lineage IV, genotype I, DENV-1. Compared to the seven closest strains from neighboring countries and provinces, a total of 18 amino acid mutations occurred in the coding sequences (CDS) of the new isolated strain, DENV1 HMU-HKU-2. Our data shows that dengue virus is re-emerged in Hainan, and pose new threats for public health. Thus regular molecular epidemiological surveillance is necessary for control and prevention of DENV transmission.

9.
Sci Adv ; 6(49)2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33277245

RESUMO

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33188385

RESUMO

OBJECTIVES: Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). METHODS: This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval ('70% fT>MIC')] and to investigate the tolerance and safety in neonates. RESULTS: A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7-41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3-41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. CONCLUSIONS: Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

11.
Arch Med Sci ; 16(5): 1176-1188, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864007

RESUMO

Introduction: Uveal melanoma is known as a frequent intraocular tumor, with high metastasis and poor prognosis. Mitogen- and stress-activated protein kinase 1 (MSK1) is a serine/threonine kinase that has been reported to be associated with tumor progression in several types of human cancer. However, the role of MSK1 has rarely been studied in uveal melanoma and the underlying mechanism remained unclear. Material and methods: The expression level of MSK1 in human uveal melanoma tissues and normal uveal tissues was determined by qRT-PCR analysis, western blotting and immunohistochemistry (IHC). Subsequently, MTT assay, colony formation assay and flow cytometry assay were performed to assess the effects of MSK1 on cell proliferation. Wound-healing and transwell chamber assays were adopted to clarify the role of MSK1 in cell metastasis. Finally, the function of MSK1 was confirmed in vivo in a tumor-bearing mouse model. Results: The expression levels of MSK1 and p-cyclic AMP-responsive element binding protein (CREB) were strongly up-regulated in human uveal melanoma tissues. MSK1 overexpression facilitated cell viability and clone formation, and promoted migration and invasion of uveal melanoma cells. However, mutation of cyclic AMP-responsive element binding protein (CREB) at Ser133 residues reversed the effect of MSK1 on uveal melanoma cell proliferation and metastasis. The in vivo experiment suggested that the tumor weight was lower and the tumor mass grew more slowly in the shMSK1 group as compared to the shNC group. Conclusions: MSK1 promotes proliferation and metastasis of uveal melanoma cells by phosphorylated CREB at Ser133 residues. Therefore, MSK1 could be a promising candidate for uveal melanoma therapy and especially has tremendous potential in the treatment of cancers in which the MSK1-CREB pathway is abnormally active.

12.
Appl Opt ; 59(22): 6573-6583, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32749357

RESUMO

3D measurement plays an important role in the processing and assembling of large components in the aviation and aerospace industry. However, precision control is a challenging problem due to the complex on-site illumination environment and serious background interference. For the binocular stereovision measurement system based on auxiliary laser scanning, this paper proposes an extraction method of laser stripe for 3D reconstruction. First, an evaluation method for the laser stripe is proposed by analyzing the features of the stripe image. Then, a laser stripe extraction method based on self-adaptive threshold is proposed. To further improve the efficiency of image processing, an improved Kalman filter algorithm is adopted to fast-track and locate the region of interest of laser stripes in the sequence images. Finally, measurement experiments for a large-scale aircraft panel are carried out on-site. The results show that the center extraction error is less than 0.1 pixel and 3D reconstruction error is less than 0.06 mm. The proposed methods improve the efficiency and accuracy of 3D reconstruction of large components, and the feasibility of on-site application is also verified.

13.
Cell Rep ; 32(1): 107860, 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32640226

RESUMO

Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) constitute a mammalian STE20-like serine/threonine kinase subfamily. Recent studies provide substantial evidence for MAP4K family kinases in the Hippo pathway regulation, suggesting a broad role of MAP4Ks in human physiology and diseases. However, a comprehensive analysis of the regulators and effectors for this key kinase family has not been fully achieved. Using a proteomic approach, we define the protein-protein interaction network for human MAP4K family kinases and reveal diverse cellular signaling events involving this important kinase family. Through it, we identify a STRIPAK complex component, STRN4, as a generic binding partner for MAP4Ks and a key regulator of the Hippo pathway in endometrial cancer development. Taken together, the results of our study not only generate a rich resource for further characterizing human MAP4K family kinases in numerous biological processes but also dissect the STRIPAK-mediated regulation of MAP4Ks in the Hippo pathway.

14.
Huan Jing Ke Xue ; 41(2): 867-875, 2020 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608748

RESUMO

This paper investigated domestic sewage with a low C/N ratio. Mature phosphorus removal granules were inoculated to cultivate granules with a simultaneous short-cut nitrification and denitrification function. The characteristics of nitrogen and phosphorus removal of this process were analyzed. Results show that AOB can be enriched by prolonging the sludge age for 30 days with an aeration intensity of 5 L·(h·L)-1 and shorter aeration time (140 min), whereas the simultaneous nitrification and denitrification ability could not be improved. The nitrogen loss increased at the aerobic time when aeration intensity was reduced by 3.5 L·(h·L)-1 and aeration time was prolonged by 200 min. The aeration time was further optimized to restrain the transformation of NO2- to NO3-, and finally the effluent of TP < 0.5 mg·L-1 and TN < 15 mg·L-1. During the process of the system function transformation from phosphorus removal to nitrogen and phosphorus removal, the phosphorus release decreased, however PAOs still played a dominant role (60%) in the process of internal carbon storage. Batch experiments showed that DPAOs that can utilize nitrite as an electron acceptor accounts for 52.43% in the total PAOS, which alleviated the pressure of the carbon source and improved the simultaneous nitrogen and phosphorus removal.

15.
Onco Targets Ther ; 13: 4691-4704, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547098

RESUMO

Background: Sodium butyrate (NaB) is a short-chain fatty acid which is produced by bacterial fermentation of nondigestible dietary fiber and has been reported to exert anti-tumor effects in many tumors including colorectal cancer (CRC). However, the role of thioredoxin-1 (Trx-1) in NaB-induced anti-tumor effect has not been completely clarified. Materials and Methods: Effects of NaB on the growth of CRC cell lines HT29 and SW480 were detected by the Cell Counting Kit-8 (CCK-8) and colony formation assays. The apoptotic cells were determined by flow cytometry, and cell migration was assessed by a Transwell assay. Western blot analysis was used to test the Trx-1 and epithelial-to-mesenchymal transition (EMT)-related proteins level. Reactive oxygen species (ROS) level was determined and N-acetylcysteine (NAC) recovery experiment was performed in CRC cells. In addition, mice xenograft model was established to test the effect of NaB on CRC growth in vivo. Further, the effects of NaB on CRC cells with overexpression or knockdown were tested by the CCK-8 and Transwell assays. Results: NaB treatment significantly inhibited cell growth and decreased Trx-1 protein expression in CRC cells but not in normal colon epithelial cells. NaB also induced apoptosis, inhibited colony formation, migration and EMT in CRC cells. Besides, NaB increased ROS level in CRC cells and NAC reversed NaB-induced inhibition of cell proliferation. Moreover, downregulation of Trx-1 significantly enhanced NaB-induced inhibitory effects on cell growth and migration, whereas overexpression of Trx-1 attenuated NaB-induced inhibitory effects on growth and migration in CRC cells. Conclusion: These findings indicate that the NaB-mediated anti-tumor effects on CRC cells are related to downregulation of Trx-1.

16.
Arch Med Sci ; 16(4): 941-956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542098

RESUMO

Introduction: Retinoblastoma (RB) is a malignant tumor that is derived from photoreceptors. It is common in children under 3 years old with a family genetic predisposition. MicroRNA-133a-3p (miR-133a-3p) is one of the tumor-related miRNAs that interprets a critical function in the genesis and development of various tumors. This study investigated the effects and underlying mechanisms of miR-133a-3p in RB. Material and methods: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was used to assess the miR-133a-3p expression in RB tissues and a cell model. MTT assay, western blot, flow cytometry and luciferase reporter assay were performed to evaluate the effect of miR-133a-3p on cell viability, apoptosis and the cell cycle. An RB xenograft model was established to assess the in vivo influence of miR-133a-3p on RB growth. Results: MiR-133a-3p level was reduced in RB tissues and the cell model (p < 0.01 or p < 0.001). Addition of miR-133a-3p reduced cell viability, and increased apoptosis and cell cycle arrest (p < 0.001). Additionally, CREB1 was identified to be the target of miR-133a-3p in RB cell lines (p < 0.001). Cell viability reduction, apoptosis and cell cycle arrest increases mediated by miR-133a-3p were attenuated by CREB1 overexpression (p < 0.001). MiR-133a-3p inhibited tumor growth of RB in vivo (p < 0.001). Conclusions: Our results reveal that miR-133a-3p exhibits anti-cancer effects by targeting CREB1 in RB. This study provides a new direction for effective targeted treatment of this disease.

18.
Xenobiotica ; 50(11): 1275-1284, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32400275

RESUMO

First dose prediction is challenging in neonates. Our objective in this proof-of-concept study was to perform a pharmacokinetic (PK) bridging study from juvenile mice to neonates for drugs metabolized by CYP3A. We selected midazolam and clindamycin as model drugs. We developed juvenile mice population PK models using NONMEM. The PK parameters of these two drugs in juvenile mice were used to bridge PK parameters in neonates using different correction methods. The bridging results were evaluated by the fold-error of 0.5- to 1.5-fold. Simple allometry with and without a correction factor for maximum lifespan potential could be used for a bridging of clearance (CL) and volume of distribution (Vd), respectively, from juvenile mice to neonates. Simulation results demonstrated that for midazolam, 100% of clinical studies for which both the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. For clindamycin, 75% and 100% of clinical studies for which the predictive CL and Vd were within 0.5- to 1.5-fold of the observed. A PK bridging of drugs metabolized by CYP3A is feasible from juvenile mice to neonates. It could be a complement to the ADE and PBPK models to support the first dose in neonates.


Assuntos
Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Animais , Clindamicina/farmacocinética , Camundongos , Midazolam/farmacocinética , Modelos Biológicos
19.
ACS Appl Mater Interfaces ; 12(22): 25353-25362, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32347700

RESUMO

Flexible ionic conductive hydrogel is attracting significant interest as it could be one of the crucial components for multifunctional ionotronic devices. However, their features of inevitably drying out without package and freezing at subzero temperatures may greatly limit the applications of conventional hydrogels in specific situations. Here, we present an ionic conductive hydrogel with water retention and freezing tolerance that consists of silk fibroin, ionic liquid, water, and inorganic salt. It is discovered that the ionic liquid serves multiple purposes to prevent water evaporation, decrease the freezing point, provide the essential conductivity of the hydrogel, etc. As a binary mixed solvent, the ionic liquid/water mixture enhances both water retention and freezing tolerance of the hydrogel electrolyte. Based on the silk fibroin (SF)/1-ethyl-3-methylimidazolium acetate (EMImAc)/H2O/KCl hydrogel electrolyte, the flexible fiberlike supercapacitor could still function well at a temperature as low as -50 °C and after being stored in the open air for a long time. It is anticipated that this hydrogel will prove useful in developing new applications operating under harsh environments.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32247185

RESUMO

Antimicrobial activity of cefoperazone, a high protein bound cephalosporin, depends on its unbound concentration. However, the protein binding data of cefoperazone in children is limited, making it challenging to optimize antimicrobial therapy in pediatric clinical practice. Furthermore, a validated method to measure the free part in children is unavailable with the small volume of samples that can be obtained. Therefore, in the present study, we developed and validated an LC-MS/MS method for the determination of free cefoperazone in children. In this study, 70 µL of plasma was used to prepare the ultrafiltrate (only containing the free drug). Chromatographic separation of the analyte was achieved on a C18 column using gradient elution with a mobile phase of acetonitrile and water (0.1% formic acid). Negative electrospray ionisation in the multiple reaction monitoring mode was applied for the detection of cefoperazone and ceftiofur (internal standard). The calibration curve was prepared in the range of 5-5000 ng/mL with excellent linearity. For each level of quality control samples, the intra- and inter-day precision (CV) was below 9.0%, and the accuracy ranged from 91.5% to 105.0%. The matrix effect was less than 11.7%, and the recovery was between 92.9% and 95.9% of cefoperazone. The validated method has been successfully applied to the determination of free plasma concentration of cefoperazone in pediatric patients. The results of the unbound fraction showed considerable individual variability (range: 8.1-48.0%). The correlation analysis showed that age and albumin had significant effects on the protein binding of cefoperazone.


Assuntos
Cefoperazona/sangue , Fatores Etários , Técnicas Biossensoriais/métodos , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactente , Recém-Nascido , Limite de Detecção , Masculino , Ligação Proteica , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
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