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A series of novel conjugates of benzoselenazole or selenazole and CPI-1 were designed, synthesized, and evaluated for inhibitory activities against the botulinum neurotoxin A (BoNT/A) light chain (LC) and BoNT/A in vivo. The results show that these compounds exhibit potent inhibitory activities to the LC with IC50 of 0.5-4.1 µM. The reaction kinetics and the mass spectra of the reaction products of LC with benzoselenazole- or selenazole- coupled CPI-1 demonstrate that the benzoselenazole group of most inhibitors is coupled to the LC of BoNT/A. These data indicate that the CPI-1 conjugates can inhibit both the active center of BoNT/A LC as well as Cys165, therefore functioning as irreversible bifunctional inhibitors. The detoxification activities in vivo show that one of the benzoselenazole-CPI-1 compounds prolongs the survival time of mice challenged by 2 × LD50 of BoNT/A. This work provides a new strategy to design potent antidotes of BoNT/A.
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Toxinas Botulínicas Tipo A , Animais , Camundongos , Cinética , Ligação ProteicaRESUMO
Oxidative stress induces granulosa cell (GC) apoptosis and subsequent follicular atresia. Since our previous studies indicate that microRNA-181a (miR-181a) expression is increased in GCs undergoing apoptosis, the present study was designed to define the relationship between exposure to oxidative stressors in GCs and changes in miR-181a expression and function. To achieve this, we employed an H2O2-induced in vitro model and a 3-nitropropionic acid-induced in vivo model of ovarian oxidative stress. We demonstrated that in vitro miR-181a overexpression promoted GC apoptosis in a dose-dependent manner; sphingosine-1-phosphate (S1P) significantly reversed both H2O2-induced and miR-181a-induced apoptosis in GCs. Moreover, we identified sphingosine-1-phosphate receptor 1 (S1PR1), a critical receptor of S1P, as a novel target of miR-181a in GCs. MicroRNA-181a induced GC apoptosis by repressing S1PR1 expression in vitro. Importantly, increased miR-181a expression and decreased S1PR1 expression were detected in the in vivo ovarian oxidative stress model by Western blot analysis and immunohistochemistry. Furthermore, we found similar expression patterns of miR-181a and S1PR1 in GCs from patients with premature ovarian insufficiency. In conclusion, our results suggest that miR-181a directly suppresses expression of S1PR1, which has critical roles in mediating oxidative stress-induced GC apoptosis both in vitro and in vivo.
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Apoptose/fisiologia , Células da Granulosa/fisiologia , MicroRNAs/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Adenoviridae , Animais , Morte Celular , Regulação para Baixo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Peróxido de Hidrogênio/farmacologia , Camundongos Endogâmicos ICR , MicroRNAs/genética , Receptores de Esfingosina-1-Fosfato/genéticaRESUMO
It is well known that both of the separation efficiency of photogenerated carriers and the response capability to visible light remarkably affect the photocatalytic performance. In the present work, a 3D microsphere of Bi5O7I/BiOCl heterojunction catalyst was synthetised. The synergy of Bi5O7I and BiOCl not only significantly enhances the transfer rate and separation efficiency of carriers, but also heightens light absorption capacity. As-prepared Bi5O7I/BiOCl (40 wt% BiOCl) has a higher degradation efficiency on doxycycline hydrochloride (DC) (90 min, 83.0%) and super high inhibition rate (90 min, 99.92%) on Escherichia coli under visible light, compared to the two monomers. Pollutants DC is finally decomposed into CO2, H2O and small molecule intermediates by generated h+, â¢OH and â¢O2-. The effects of reactive radicals follow the order of â¢OH radicals > h+ radicals â« â¢O2- and e- radicals. The possible structures of intermediates and four possible degradation pathways involved were also discussed. In addition, As-synthetised Bi5O7I/BiOCl has preferable reusability and excellent chemical stability. Biological toxicity experiments also verify that Bi5O7I/BiOCl is a green and environmentally friendly composite material. This strategy provides a green, low-toxic way for the application of traditional type II heterojunction in the fields of environmental remediation and photocatalysis.
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Bismuto , Poluentes Ambientais , Bismuto/química , Catálise , Escherichia coli , Luz , MicroesferasRESUMO
In order to study the synergistic effects of organic and inorganic thickening agents on the rheological properties of cement paste, the rheological parameters, thixotropy cement-paste containing limestone powder (LP), re-dispersible polymer powder (RPP), and hydroxypropyl methylcellulose ether (HPMC) were investigated using the Anton Paar MCR 102 rheometer at different resting times. The early-age hydration process, hydration products, and microstructure were also analyzed with scanning electron microscopy (SEM) and thermogravimetry analyses (TGA). The results showed that the addition of LP, RPP, and HPMC affected the rheological properties of cement paste, but the thickening mechanism between organic and inorganic thickening agents was different. The small amount of LP increased the plastic viscosity but decreased the yield stress of cement paste due to its dense filling effect. Adding 1% of RPP improved the thixotropic property of cement paste by 50%; prolonging the standing time could improve the thixotropic performance by as much as two times. Only 0.035% HPMC added to the cement paste increased the plastic viscosity by 20%, while the yield stress increased nearly twice. The more HPMC added, the more significant effect it showed. Cement paste compounds with LP, RPP, and HPMC balanced the yield stress and plastic viscosity and improved the thixotropy. The C-L6-R1.0-H0.035 paste presented as a pseudoplastic, its rheological indexes were close to one, and it was hardly affected by the resting time. The composite superposition effect of organic and inorganic thickening agents reduced the impact of resting time for all pastes. As the organic thickening component inhibited the hydration more than the LP promoted the hydration of the cement paste, indicating that the C-L6-R1.0-H0.035 paste remained in the particle fusion stage after curing for three days, as shown by the SEM images.
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A novel magnetic short-channel mesoporous silica SBA-15 composite adsorbent was prepared by the copolymerization of pyrrole and aniline. The prepared novel nanoadsorbent polypyrrole-polyaniline/CoFe2O4-SBA-15 (PPy-PANI/M-SBA-15) has a significant adsorption effect on heavy metal mercury ions. The batch adsorption experiment was carried out to study the effects of various parameters including solution pH, initial concentration (C 0), adsorbent dose (dosage), temperature (T), and contact time on the adsorption effect. The analysis results of the response surface method (RSM) and central composite design (CCD) show that the importance for adsorption factors is pH > C 0 > T > dosage, and the maximum capacity of PPy-PANI/M-SBA-15 is 346.2 mg/g under the optimal conditions of pH = 6.7, T = 310 K, C 0 = 29.5 mg/L, and a dosage of 0.044 g/L. The pseudo-second-order kinetic model and the Langmuir isotherm model simulate the adsorption behavior of mercury ions. In addition, thermodynamic parameters indicate self-heating and reversible adsorption processes. A covalent bond is formed between the nitrogen-containing functional group and the mercury ions. Excellent magnetic properties and high reproducibility indicate that PPy-PANI/M-SBA-15 has excellent recyclability and environmentally friendly properties and can become a potential heavy metal ion adsorbent in practical applications.
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INTRODUCTION: Due to individual deviations in tumor tissue uptake, the role of [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in hepatocellular carcinoma (HCC) diagnosis is limited. ß-Hydroxy ß-methylglutaryl-CoA reductase degradation 1 (HRD1) plays a key role in clearing misfolded proteins. This study is aimed to investigate the role and mechanism of HRD1 in [18F]FDG uptake for the diagnosis of HCC. METHODS: HRD1 expression level was detected using immunohistochemical (IHC) staining in 9 HCC patients. [18F]FDG PET/CT scans were conducted before treatment. [18F]FDG uptakes in HRD1 overexpressed and knockdown transgenic models were measured by γ-counter and microPET imaging. The GLUT1-HRD1 complex was examined by co-immunoprecipitation and IHC assays. GLUT1 expression in different cell lines, xenograft models and HCC patients was evaluated by Western blot and IHC assays. RESULTS: HRD1 was highly expressed in the HCC tumors of patients with low [18F]FDG uptake, while the HRD1 expression was obviously low in the higher [18F]FDG uptake group. Both in vitro and in vivo studies found that HRD1 significantly inhibited [18F]FDG uptake in HCC Huh7 cell lines and animal models. Furthermore, the co-location and interaction of HRD1 with GLUT1 were detected, and the results also indicate that HRD1 could induce the degradation of GLUT1 in vitro and in vivo. CONCLUSION: HRD1 inhibits the high uptake of [18F]FDG in HCC tumor cells by inducing degradation of GLUT1, which leads to decreased diagnostic efficiency of [18F]FDG PET imaging for HCC. ADVANCES IN KNOWLEDGE: This study suggests that HRD1 inhibits the high uptake of [18F]FDG in HCC tumor by inducing degradation of GLUT1. IMPLICATIONS FOR PATIENT CARE: HCC diagnosis with [18F]FDG PET should be accompanied by determination of HRD1 expression, and patients with high tumor HRD1 expression might be unsuitable for [18F]FDG PET.
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Carcinoma Hepatocelular , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Neoplasias Hepáticas , Pessoa de Meia-IdadeRESUMO
PPy-Fe3O4/Kaolin was prepared with polypyrrole functionalized magnetic Kaolin by a simple, green, and low cost method to improve the agglomeration and low adsorption capacity of Kaolin. PPy-Fe3O4/Kaolin was employed to remove Hg2+ and the results were characterized by various methods. Relevant factors, including solution pH, dosage of adsorbent, concentration (C0), and temperature (T), were optimized by Response Surface Methodology (RSM) and Central Composite Designs (CCD). The optimal results show that the importance for adsorption factors is pH > T > C0 > dosage, and the optimal adsorption conditions of PPy-Fe3O4/Kaolin are pH = 7.2, T = 315 K, C0 = 50 mg/L, dosage of 0.05 g/L, and the capacity is 317.1 mg/g. The adsorption process conforms to the pseudo-second-order and Langmuir models. Dubinin-Radushkevich model shows that adsorption process is spontaneous and endothermic. Moreover, the adsorption of mercury by PPy-Fe3O4/Kaolin was achieved mainly through electrostatic attraction, pore diffusion, and chelation between amino functional groups and Hg2+. PPy-Fe3O4/Kaolin has excellent reproducibility, dispersity, and chemical stability, and it is easy to be separated from solution through an external magnetic field. The experiments show that PPy-Fe3O4/Kaolin is an efficient and economical adsorbent towards mercury.
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HOXA10 is an important regulator of embryo adhesion. Reduced expression may contribute to embryo implantation failure. The expression of Nur77 and HOXA10 has been shown to be reduced in the endometrium of patients with recurrent implantation failure. In this study, we found that Nur77 was directly bound to the HOXA10 promoter and promoted HOXA10 protein expression in a dose-dependent manner in Ishikawa cells. Furthermore, the promoting effect of Nur77 on embryo adhesion was significantly blocked when endogenous HOXA10 expression was knocked down in Ishikawa cells. Moreover, the Nur77 agonist 6-MP was also confirmed to promote embryo adhesion. This study is the first to show that Nur77 promotes embryo adhesion by transcriptionally regulating HOXA10 expression. Nur77 and 6-MP may provide a basis to develop a new treatment for patients who suffer from embryo adhesion dysfunction.Abbreviations: HB-EGF: heparin-binding epidermal growth factor-like growth factor; HOXA10: homeobox A10; NGFI-B: nerve growth factor-induced gene B; RIF: recurrent implantation failure; RPL: recurrent pregnancy loss; 6-MP: 6-mercaptopurine; IGFBP-1: insulin-like growth factor binding protein-1; LIF: leukemia inhibitory factor; IL-1ß: Interleukin - 1ß; CRISPR/Cas9: Clustered Regularly Interspaced Short Palindromic Repeats; AF-1: activation function-1 domain; HIF-1α: hypoxia-inducible factor 1α; CREB: cAMP response element binding.
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Implantação do Embrião , Endométrio/metabolismo , Proteínas Homeobox A10/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , HumanosRESUMO
BACKGROUND: To evaluate the image quality and radiation dose of low-dose (LD) computed tomography (LD-CT) combining with iterative model reconstruction (IMR) algorithm for response assessment in patients after treatment of malignant tumor compared with routine-dose CT (RD-CT). METHODS: Forty-seven patients [mean age 57.8±10.9 years, 30 males, body mass index (BMI) 22.09±2.35 kg/m2] after treatment of malignant tumor underwent contrast-enhanced chest and abdomen CT twice for response assessment with an interval of 6 months according to clinical routine. The first CT scans were performed with RD protocol at 120 kVp and images were reconstructed with filtered back projection (FBP) algorithm; while the second scans were performed with LD protocol at 100 kVp and images were reconstructed with FBP and IMR algorithm respectively. All scans were performed using an automatic tube current modulation technique with 150 mAs as reference. Objective image quality including CT attenuation, image noise, and contrast to noise ratio (CNR), and subjective image quality including artifacts, noise, visualization of small structures and confidence of targeted lesions, as well as lesion detection were assessed and compared. RESULTS: Effective radiation dose of LD-CT scans was reduced 54.8% compared to RD-CT scans (26.89±3.35 vs. 12.14±2.09 mSv). Higher CT attenuation was found in both LD-IMR and LD-FBP images compared to RD-FBP images. Better subjective image quality and CNR as well as lower objective noise were found in LD-IMR images (all, P<0.05). Two small lesions with the diameter less than 1 cm were missed in LD-FBP images, which were able to be observed in LD-IMR images. CONCLUSIONS: IMR is able to help more than half of reduction of radiation dose without compromising the quality of diagnostic information in patients after treatment of malignant tumors to chest and abdomen CT for response assessment.
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Recombinant antiepidermal growth factor receptorinternalizing arginineglycineaspartic acid (antiEGFR singledomain antibody fused with iRGD peptide) protein efficiently targets the EGFR extracellular domain and integrin αvß/ß5, and shows a high penetration into cells. Thus, this protein may improve penetration of conjugated drugs into the deep zone of gastric cancer multicellular 3D spheroids. In the present study, a novel tumortargeting contrast agent for magnetic resonance imaging (MRI) was developed, by coupling gadoliniumdiethylene triamine pentaacetate (GdDTPA) with the bispecific recombinant antiEGFRiRGD protein. The antiEGFRiRGD protein was extracted from Escherichia coli and Gd was loaded onto the recombinant protein by chelation using DTPA anhydride. Singletargeting agent antiEGFRDTPAGd, which served as the control, was also prepared. The results of the present study showed that antiEGFRiRGDDTPAGd exhibited no significant cyto-toxicity to human gastric carcinoma cells (BGC823) under the experimental conditions used. Compared with a conventional contrast agent (Magnevist), antiEGFRiRGDDTPAGd showed higher T1 relaxivity (10.157/mM/sec at 3T) and better tumortargeting ability. In addition, the signal intensity and the area under curve for the enhanced signal time in tumor, in vivo, were stronger than GdDTPA alone or the antiEGFRGd control. Thus, Gdlabelled antiEGFRiRGD has potential as a tumortargeting contrast agent for improved MRI.
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Anticorpos Biespecíficos/farmacocinética , Meios de Contraste/farmacocinética , Gadolínio DTPA/farmacocinética , Animais , Anticorpos Biespecíficos/toxicidade , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Contraste/toxicidade , Receptores ErbB/imunologia , Gadolínio DTPA/toxicidade , Humanos , Concentração Inibidora 50 , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/toxicidadeRESUMO
Primary spinal atypical teratoid/rhabdoid tumors are extremely rare and most commonly occur as intramedural or extramedural intradural. The location of extradural type is rarely reported. A 10-year-old girl presented with a 2-month history of nape pain. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an extradural tumor from C2-C5 with bony destruction of the C3 vertebral body. Subtotal removal of the tumor was performed and atypical teratoid/rhabdoid tumor was proven histologically. But 2 months after surgery, the neck pain became worse. There were metastasic lesions in bilateral lung fields and multiple enlarged lymph nodes around the carotid sheath. She died 8 months after the initial symptoms. The present case is the third detailed report of spinal extradural. We describe the CT and MRI findings of this case and review the literature describing this rare disease.