Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over ...other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system.
Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than ...75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients. Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9. Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G＞A, c.1747C＞T, c.313＋1G＞A, c.400T＞C, and APOB c.10579C＞T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants. Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients.
•After ultrasonic pretreatment, the total production of VFA increased markedly.•Ultrasonic significantly increased the COD and protein of supernatant of food waste.•Ultrasonic increased the amount of ...reducing sugars dissolved out of food waste.•Ultrasonic markedly decreased the amount of fat dissolved out of food waste.
This paper describes a series of studies on the effects of food waste disintegration using an ultrasonic generator and the production of volatile fatty acids (VFAs) by anaerobic hydrolysis. The results suggest that ultrasound treatment can significantly increase COD chemical oxygen demand, proteins and reducing sugars, but decrease that of lipids in food waste supernatant. Ultrasound pre-treatment boosted the production of VFAs dramatically during the fermentation of food waste. At an ultrasonic energy density of 480W/L, we treated two kinds of food waste (total solids (TS): 40 and 100g/L, respectively) with ultrasound for 15min. The amount of COD dissolved from the waste increased by 1.6–1.7-fold, proteins increased by 3.8–4.3-fold, and reducing sugars increased by 4.4–3.6-fold, whereas the lipid content decreased from 2 to 0.1g/L. Additionally, a higher VFA yield was observed following ultrasonic pre-treatment.
Cell-derived exosomes are leading candidates for in vivo drug delivery carriers. In particular, exosomes derived from 293T cells are used most frequently, although exosome dosing has varied greatly ...among studies. Considering their biological origin, it is crucial to characterize the molecular composition of exosomes if large doses are to be administered in clinical settings. In this study, we present the first comprehensive analysis of the protein, messenger RNA and microRNA profiles of 293T cell-derived exosomes; then, we characterized these data using Gene Ontology annotation and Kyoto Encyclopedia for Genes and Genomes pathway analysis. Our study will provide the basis for the selection of 293T cell-derived exosome drug delivery systems. Profiling the exosomal signatures of 293T cells will lead to a better understanding of 293T exosome biology and will aid in the identification of any harmful factors in exosomes that could cause adverse clinical effects.
An increased population of CD4＋CD25highFoxp3＋ regulatory T cells （Tregs） in the tumor-associated microenvi- ronment plays an important role in cancer immune evasion. However, the underlying mechanism ...remains unclear. Here we observed an increased secretion of miR-214 in various types of human cancers and mouse tumor models. Tumor-secreted miR-214 was sufficiently delivered into recipient T cells by microvesicles （MVs）. In targeted mouse peripheral CD4＋ T cells, tumor-derived miR-214 efficiently downregulated phosphatase and tensin homolog （PTEN） and promoted Treg expansion. The miR-214-induced Tregs secreted higher levels of IL-10 and promoted tumor growth in nude mice. Furthermore, in vivo studies indicated that Treg expansion mediated by cancer cell-secreted miR-214 resulted in enhanced immune suppression and tumor implantation/growth in mice. The MV delivery of anti-miR-214 antisense oligonucleotides （ASOs） into mice implanted with tumors blocked Treg expansion and tumor growth. Our study reveals a novel mechanism through which cancer cell actively manipulates immune response via promoting Treg expansion.
The Exosome complex (EXOSC) is a multiprotein complex that was originally discovered as the machinery of RNA degradation. Interestingly, recent studies have reported that EXOSC family members ...(EXOSCs) are associated with various human diseases, including cancers. It will be interesting to investigate whether EXOSCs are related to the processes of hepatocellular carcinoma (HCC). In this study, multiple public databases and experimental validation were utilized to systemically investigate the role of EXOSCs, especially EXOSC5, in HCC. It is worth considering that the mRNA and protein levels of many EXOSCs were elevated in HCC, although there were some differences in the results from different database analyses. The over-expression of EXOSCs could predict HCC to some extent, as evidenced by the positive correlation between the elevated EXOSCs and alpha fetoprotein (AFP) levels, as well as with a high accuracy, as shown by the receiver operating characteristic curve analysis. Additionally, higher mRNA expressions of specific EXOSCs were significantly related to clinical cancer stage, shorter overall survival and disease-free survival in HCC patients. A moderate mutation rate of EXOSCs was also observed in HCC. Furthermore, a gene functional enrichment analysis indicated that EXOSCs were mainly involved in the metabolism of RNA. Moreover, we revealed that the expression of EXOSCs is remarkably related to immune cell infiltration. Finally, EXOSC5 was upregulated in HCC tissues and cell lines, promoting cell growth and proliferation via activated signal transducer and activator of transcription 3 (STAT3). The bioinformatic analyses, following verification in situ and in vitro, provided a direction for further functions and underlying mechanism of EXOSCs in HCC.
Urgent demands to reduce the harmful electromagnetic radiation and improve weapons survivability made it necessary to develop high-efficiency microwave absorption materials, especially those ...operating in frequency range of 2–12 GHz. In this work, Fe3O4/Ag composites were synthesized by one-step hydrothermal method. Microwave absorbing performance can be flexibly tuned by varying Fe3O4/Ag molar ratio from 2:1, 3:1, to 4:1. An increase in Fe3O4/Ag molar ratio would lead to an enhanced permeability over the frequency region of 4–12 GHz. Meanwhile, real part of permittivity remains almost unchanged whereas the imaginary part drastically decreases, making impedance matching and attenuation capacity increase dramatically. In this way, splendid microwave absorption performance with broad absorption bandwidth within a range of 4.88–9.76 GHz and minimum reflection loss of −63.2 dB could be achieved at composite thickness of 3.6 mm.
Identifying the yarn end from the package surface is integral to the textile process. Using the automatic method based on negative pressure adsorption instead of the traditional manual method to ...capture the yarn end is an excellent solution to the time-consuming and inefficient problems caused by the latter. To clarify the influence of process parameters on the process of the yarn end being adsorbed to break away from the package surface by the suction nozzle, this paper first establishes a kinetic model of the yarn attached to the package surface. Next, the air-yarn interaction is solved using the momentum exchanged-based immersed boundary-lattice Boltzmann method (IB-LBM). Then, the effect of the distance between the suction nozzle and the package, the rotational speed of the package, and the airflow velocity in the suction nozzle duct on the movement of the yarn end with the airflow field are studied. Further, the regression model for the depth of the yarn end sucked into the suction nozzle duct when the package turns through a fixed angle is solved. Finally, with the goal of a high success rate, large distance, high efficiency, and energy saving, a multi-parameter optimization is performed using the Central Composite Design-based response surface methodology. The work has been proven effective through experimental validation and practical production applications. It provides a theoretical basis for the automatic process of yarn-end-capturing from the package in the textile field.
•The kinetic model of the yarn end being adsorbed to break away from the package surface by airflow is established.•The air-yarn interaction is solved using the momentum exchanged-based immersed boundary-lattice Boltzmann method (IB-LBM).•The effects of several process parameters on the movement of the yarn end with the airflow field are studied emphatically.•Multi-parameter and multi-objective optimization are performed by the Central Composite Design-based response surface method.
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new ...therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.
Cholangiocarcinoma (CCA) is a malignant tumor originating in the bile duct and its branching epithelium. Due to its high heterogeneity, there are no specific clinical indications at the early stage, ...the diagnosis is often in advanced CCA. With surgical resection, the 5-year postoperative survival rate (long-term survival rate) is very poor. The regimen of gemcitabine combined with platinum has been used as the first-line chemotherapy for advanced patients. In recent years, targeted therapy for a variety of malignant tumors has made great progress, showing good efficacy and safety in advanced CCA. However, the current targeted therapy of CCA still has many challenges, such as adverse reactions, drug resistance, and individual differences. Therefore, the researches need to further explore the targeted therapy mechanism of CCA malignancies in depth, develop more effective and safe drugs, and accurately formulate plans based on patient characteristics to further improve patient prognosis in the future. This article reviews the recent progress of targeted therapy for CCA, aiming to provide a strategy for the research and clinical work of targeted therapy for CCA.
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