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Alzheimer's disease (AD), the major cause of dementia, is a multifactoral progressive neurodegenerative disorder that currently affects over 43 million people worldwide. The interaction betweengenetic and environmental factors decides pathogenesis and pathological development. The chemical drugs designed for clinical applications on AD have not reached the expected preventive effect so far.Here, we obtained a new evodiamine (Evo) derivative, LE-42, which exhibited lower cytotoxicity in SH-SY5Y cells and HepaG2 cells than that of Evo. The LD50 of LE-42 in SH-SY5Y cells and HepaG2 cells was increased by 9 folds and 14 folds than Evo, respectively. The LE-42 also exhibited much more potent effects on anti-oxidation and anti-cytotoxicity of AßOs than Evo. The LE-42 significantly improved the working memory, spatial learning, and memory of the 3×Tg AD mice, and the pharmacodynamic dose of LE-42 on AD mice was increased by 500 folds than that of Evo. LE-42 significantly improved the Tau hyperphosphorylation, a typical pathological feature in 3×Tg AD mice. The LE-42 restored the JAK2/STAT3 pathway's dysfunction and upregulated the expression of GluN1, GluA2, SYN, and PSD95, subsequentially improving the synaptic integrity in 3×Tg mice. The activation of the JAK2/STAT3 axis by LE-42 was a possible mechanism for a therapeutic effect on the AD mice.
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Doença de Alzheimer , Disfunção Cognitiva , Quinazolinas , Sinapses , Animais , Quinazolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Camundongos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Humanos , Camundongos Transgênicos , Modelos Animais de Doenças , Masculino , Fator de Transcrição STAT3/metabolismo , Proteínas tau/metabolismo , Janus Quinase 2/metabolismo , Linhagem Celular Tumoral , Fosforilação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Lysosomes serve as regulatory hubs, and play a pivotal role in human diseases. However, the precise functions and mechanisms of action of lysosome-related genes remain unclear in preeclampsia and cancers. This study aimed to identify lysosome-related biomarkers in preeclampsia, and further explore the biomarkers shared between preeclampsia and cancers. MATERIALS AND METHODS: We obtained GSE60438 and GSE75010 datasets from the Gene Expression Omnibus database, pre-procesed them and merged them into a training cohort. The limma package in R was used to identify the differentially expressed mRNAs between the preeclampsia and normal control groups. Differentially expressed lysosome-related genes were identified by intersecting the differentially expressed mRNAs and lysosome-related genes obtained from Gene Ontology and GSEA databases. Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed using the DAVID database. The CIBERSORT method was used to analyze immune cell infiltration. Weighted gene co-expression analyses and three machine learning algorithm were used to identify lysosome-related diagnostic biomarkers. Lysosome-related diagnostic biomarkers were further validated in the testing cohort GSE25906. Nomogram diagnostic models for preeclampsia were constructed. In addition, pan-cancer analysis of lysosome-related diagnostic biomarkers were identified by was performed using the TIMER, Sangebox and TISIDB databases. Finally, the Drug-Gene Interaction, TheMarker and DSigDB Databases were used for drug-gene interactions analysis. RESULTS: A total of 11 differentially expressed lysosome-related genes were identified between the preeclampsia and control groups. Three molecular clusters connected to lysosome were identified, and enrichment analysis demonstrated their strong relevance to the development and progression of preeclampsia. Immune infiltration analysis revealed significant immunity heterogeneity among different clusters. GBA, OCRL, TLR7 and HEXB were identified as lysosome-related diagnostic biomarkers with high AUC values, and validated in the testing cohort GSE25906. Nomogram, calibration curve, and decision curve analysis confirmed the accuracy of predicting the occurrence of preeclampsia based on OCRL and HEXB. Pan-cancer analysis showed that GBA, OCRL, TLR7 and HEXB were associated with the prognosis of patients with various tumors and tumor immune cell infiltration. Twelve drugs were identified as potential drugs for the treatment of preeclampsia and cancers. CONCLUSION: This study identified GBA, OCRL, TLR7 and HEXB as potential lysosome-related diagnostic biomarkers shared between preeclampsia and cancers.
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Neoplasias , Pré-Eclâmpsia , Feminino , Gravidez , Humanos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Receptor 7 Toll-Like , Lisossomos/genética , Biomarcadores , Biologia Computacional , Aprendizado de Máquina , Neoplasias/diagnóstico , Neoplasias/genéticaRESUMO
BACKGROUND: Previous evidence suggests that higher blood uric acid (UA) levels are associated with adverse cardiovascular outcomes during pregnancy and subsequent birth outcomes. However, it has been relatively unclear whether these associations persist in normotensive pregnant women. METHODS: The study was based on a retrospective analysis of 18,250 mother-infant pairs in a large obstetric center in China. Serum UA concentrations in early pregnancy (median: 17.6, IQR: 16.3, 18.6 gestational weeks) were assessed. Hyperuricemia was defined as ≥ one standard deviation (SD) of the reference value for the corresponding gestational age. Outcomes of gestational diabetes mellitus (GDM), preterm birth (PB), low birth weight (LBW), macrosomia, small for gestational age (SGA) and large for gestational age (LGA) were extracted from the medical records. RESULTS: The mean maternal UA level was 0.22 ± 0.05 mmol/L, and 2,896 (15.9%) subjects had hyperuricemia. After adjustment for several covariates, UA was associated with several adverse outcomes. The ORs (95%CI) per one SD increase in serum UA concentration were 1.250 (1.136, 1.277) for GDM, 1.137 (1.060, 1.221) for PB, 1.134 (1.051, 1.223) for LBW, and 1.077 (1.020, 1.137) for SGA, respectively. Similar adverse associations were found between hyperuricemia and GDM, PB (ORs: 1.394 and 1.385, P < 0.001), but not for LBW, macrosomia, SGA, and LGA. Adverse associations tended to be more pronounced in subjects with higher BMI for outcomes including PB, LBW, and SGA (P interaction = 0.001-0.028). CONCLUSION: Higher UA levels in early pregnancy were associated with higher risk of GDM, PB, LBW, and SGA in normotensive Chinese women.
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Diabetes Gestacional , Hiperuricemia , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Diabetes Gestacional/epidemiologia , Macrossomia Fetal/epidemiologia , Macrossomia Fetal/etiologia , Ácido Úrico , Estudos Retrospectivos , Resultado da Gravidez/epidemiologia , Hiperuricemia/epidemiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Aumento de Peso , Retardo do Crescimento FetalRESUMO
Multiple enzymes perform moonlighting functions distinct from their main roles. UDP-glucose epimerases (UGEs), a subclass of isomerases, catalyze the interconversion of UDP-glucose (UDP-Glc) and UDP-galactose (UDP-Gal). We identified a rice male-sterile mutant, osuge1, with delayed tapetum degradation and abortive pollen. The mutant osuge1 protein lacked UDP-glucose epimerase activity, resulting in higher UDP-Gal content and lower UDP-Glc levels in the osuge1 mutant compared with the wild type. Interestingly, we discovered that OsUGE1 participates in the TIP2/bHLH142-TDR-EAT1/DTD transcriptional regulatory cascade involved in tapetum degradation, in which TIP2 and TDR regulate the expression of OsUGE1 while OsUGE1 regulates the expression of EAT1. In addition, we found that OsUGE1 regulates the expression of its own gene by directly binding to an E-box element in the OsUGE1 promoter. Collectively, our results indicate that OsUGE1 not only functions as a UDP-glucose epimerase but also moonlights as a transcriptional activator to promote tapetum degradation, revealing a novel regulatory mechanism of rice reproductive development.
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Oryza , UDPglucose 4-Epimerase , UDPglucose 4-Epimerase/genética , UDPglucose 4-Epimerase/química , UDPglucose 4-Epimerase/metabolismo , Oryza/genética , Oryza/metabolismo , Fertilidade , Glucose , Difosfato de UridinaRESUMO
The dependence of bendability on crystallographic orientations and texture evolution was investigated in a strongly textured Mg-9Al extrusion plate by bending along four directions. Results show that the bars have relatively small and reasonably close bendability when bent along the extrusion direction, transverse direction, and through-thickness direction. In contrast, the bendability of the 45° bar is much larger. Microstructure examination indicates that twins are prevalent in all bars. Furthermore, a detailed analysis of deformation mechanisms suggests that the initial texture transforms towards a basal texture during bending. Nevertheless, the texture transformation efficiency is drastically lower when basal slip-in contrast to tensile twinning-is the dominant deformation mechanism. The difference in texture evolution efficiency was used to rationalize the varied bendability along different directions. The findings of this provide insights into improving the bendability of magnesium alloys.
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In this paper, the influence of long-period stacked ordered (LPSO) phases on the electrochemical impedance spectroscopy (EIS) of a Mg-Gd-Y-Zn-Zr-Ag alloy in 0.9 wt.% NaCl was investigated. The Mg-6Gd-3Y-1Zn-0.5Zr-0.3Ag (wt.%) alloy samples with and without LPSO phases in the grain interior (HOMO and LPSO, respectively) were prepared using different heat treatments. The EIS results showed that both the HOMO and LPSO samples' Nyquist diagrams contained two inductive loops. However, in the Nyquist plots of the LPSO samples, the inductive loops at 1.71-0.67 Hz appeared in the first quadrant rather than the fourth quadrant. Analysis of the fitting parameters illustrated that the abnormal shape of the inductive loops is related to greater values of the surface film capacitance Cf and double layer capacitance Cdl in the LPSO samples. Further investigations through corrosion morphology observation indicated that the greater values of Cf and Cdl in the LPSO samples resulted from the existence of intragranular LPSO phases that created more film-free areas. The above results show that a better understanding of the relationship between the inductive impedance and corrosion morphology of a Mg-6Gd-3Y-1Zn-0.5Zr-0.3Ag alloy in 0.9 wt.% NaCl solution was attained.
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Nanograins were obtained in the AZ31 Mg alloy bars with different initial grain sizes via cold rotary swaging. Microstructure evolution during deformation was investigated through electron backscatter diffraction analysis and transmission electron microscopy studies. The results indicate that initial grain size had little effect on the mechanism of grain refinement during swaging. The nanocrystallization process of the alloys with different initial grain sizes included extensive twinning followed by the further refinement of the twin lamellae through the formation of massive dislocation arrays. However, as the initial grain size decreased, the formation rate of nanograins increased, resulting in a higher degree of nanocrystallization after the same swaging pass. The mean grain size and yield strength of the sample with the smallest initial grain size were about 91 nm and 489 MPa, respectively. The slower rate and lower degree of nanocrystallization in the alloy with a larger initial grain size were mainly attributed to the less grain boundary areas and higher activity of twinning.
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Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blot assay data shown in Figs. 1C and 6A were strikingly similar to data appearing in different form in another article written by different authors. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 13: 22212228, 2016; DOI: 10.3892/mmr.2016.4788].
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KEY MESSAGE: OsFLA1 positively regulates pollen exine development, and locates in the cellular membrane. Arabinogalactan proteins are a type of hydroxyproline-rich glycoprotein that are present in all plant tissues and cells and play important roles in plant growth and development. Little information is available on the participation of fasciclin-like arabinogalactan proteins in sexual reproduction in rice. In this study, a rice male-sterile mutant, osfla1, was isolated from an ethylmethanesulfonate-induced mutant library. The osfla1 mutant produced withered, shrunken, and abortive pollen. The gene OsFLA1 encoded a FLA protein and was expressed strongly in the anthers in rice. Subcellular localization showed that OsFLA1 was located in the cellular membrane. In the osfla1 mutant, abnormal Ubisch bodies and a discontinuous nexine layer of the microspore wall were observed, which resulted in pollen abortion and ultimately in male sterility. The results show the important role that OsFLA1 plays in male reproductive development in rice.
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Oryza , Regulação da Expressão Gênica de Plantas , Mucoproteínas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , PólenRESUMO
The good performance conditions for determination of EU priority PAHs in coffee samples were established to evaluate the effects of roasting degree on the PAHs in coffee beans and the brewing methods on the PAHs transfer from coffee beans to their brews. The consumption risk of the PAHs in coffee products was also assessed. The PAHs levels of the roasted coffee beans were in the order: 923.65 ng/g (dark roast) > 132.20 ng/g (medium roast) > 69.28 ng/g (light roast). Compared with general brewing with the drip bag (PAHs content, 0.30-0.62 ng/mL in coffee brews), the coffee machine brewing (set at 4 bar) induced higher PAHs release into coffee brews (PAHs content, 0.36-2.14 ng/g). The PAHs amounts of the commercial brewed and canned coffee products were 0.32-1.23 ng/g and 0.16-0.46 ng/g, respectively. The consumption risk of the PAHs in the coffee brews and products is a low level of concern.
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Temperatura Alta , Hidrocarbonetos Policíclicos Aromáticos , Cromatografia Líquida de Alta Pressão/métodos , Manipulação de Alimentos/métodos , Sementes/química , Hidrocarbonetos Policíclicos Aromáticos/análiseRESUMO
Nanocrystalline materials exhibit many unique physical and chemical properties with respect to their coarse-grained counterparts due to the high volume fraction of grain boundaries. Research interests on nanocrystalline materials around the world have been lasting over the past decades. In this study, we explored the room temperature strain rate sensitivity and creep behavior of the nanocrystalline Mg-Gd-Y-Zr alloy by using a nanoindentation technique. Results showed that the hardness and creep displacements of the nanocrystalline Mg-Gd-Y-Zr alloy decreased with increasing loading strain rate. That is, the nanocrystalline Mg-Gd-Y-Zr alloy showed negative strain rate sensitivity and its creep behavior also exhibited negative rate dependence. It was revealed that the enhanced twinning activities at higher loading strain rates resulted in reduced hardness and creep displacements. The dominant creep mechanism of the nanocrystalline Mg-Gd-Y-Zr alloy is discussed based on a work-of-indentation theory in this paper.
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When Mg-Gd-Y-Zr alloy is cold forged, a large number of nano-micro shear bands are formed inside the grains. It is observed that micro-shear bands hinder the sliding of dislocations, resulting in an increase in tensile strength at elevated temperatures. The subsequent aging treatment further strengthens the alloy. Compared with unforged aged alloys, aged samples with pre-generated micro-shear bands exhibit higher strength at room temperature to 250 °C, but exhibit similar properties at higher temperatures. Microstructure characterization and fracture behavior analysis indicate that the transformation of deformation mode from dislocation sliding to grain boundary activity is mainly due to the change of mechanical properties with temperature. In addition, the alloy precipitates with the aid of dislocations during tension, and exhibits higher strength at 200 °C than that at room temperature.
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BACKGROUND: To compare the maternal and neonatal outcomes of placenta previa (PP) with and without coverage of a uterine scar in Foshan, China. METHODS: A retrospective cohort study comparing all singleton pregnancies with PP was conducted at a tertiary, university-affiliated medical center from 1 January 2012 to 31 April 2017 in Foshan, China. Demographic, clinical and laboratory data were extracted from electronic medical records (EMRs). Maternal and neonatal outcomes of PP with and without coverage of a uterine scar were compared by statistical method. RESULTS: There were 58,062 deliveries during the study period, of which 726 (1.25%) were complicated PP in singleton pregnancies and were further classified into two groups: the PP with coverage of a uterine scar group (PPCS, n=154) and the PP without coverage of a uterine scar group (Non-PPCS, n=572). Overall, premature birth (<37 weeks, 67.5% vs 54.8%; P=0.019), cesarean section (100% vs 97.6%; P=0.050), intraoperative blood loss >1000 mL (77.9% vs 16.0%; P<0.001) or >3000mL (29.9% vs 3.0%; P<0.001), bleeding within 2-24 hours after delivery (168.2±370.1 ml vs 49.9±58.4 ml; P<0.001), postpartum hemorrhage (48.7% vs 15.7%; P<0.001), transfusion (34.6% vs 16.1%; P<0.001), hemorrhage shock (7.8% vs 1.9%; P<0.001), hysterectomy (2.6% vs 0.5%; P=0.019), fetal distress (35.7% vs 12.1%; P<0.001) and APGAR score at 1 min (15.2% vs 7.1%; P=0.002) had a significant difference between PPCS group and Non-PPCS group. After grouping by whether complicated with placenta accreta spectrum disorders (PASD), we found that PPCS was significant associated with more intraoperative blood loss >1000mL, intraoperative blood loss >3000mL, bleeding within 2-24 hours after delivery and fetal distress than the Non-PPCS group. CONCLUSION: The PPCS group had poorer maternal and neonatal outcomes than the Non-PPCS group after grouping by whether pregnancies complicated with PASD or with different placental positions.
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This study aimed to explore effects of Sevoflurane on ischemia-reperfusion (I/R) injury after total knee arthroplasty (TKA). To explore potential molecular mechanism, Ras related dexamethasone induced 1 (RASD1), a Protein kinase A (PKA) activator, frequently associated with various models of I/R injury, was also investigated. In vivo mouse models with I/R injury after TKA and in vitro cell models with I/R injury were induced. Contents of creatinine kinase (CK), lactic dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), serum levels of inflammatory factors, expression of PKA pathway-related genes and cell proliferation and apoptosis were measured. RASD1 was altered and PKA pathway was inhibited in mice and cells to elucidate the involvement of RASD1 and PKA pathway in Sevoflurane treatment on I/R injury. RASD1 was upregulated in I/R injury after TKA. Sevoflurane treatment or silencing RASD1 reduced RASD1 expression, CK, LDH and MDA contents, inflammation, apoptosis, but increased proliferation, SOD content, cAMP expression, and extents of PKA and cAMP responsive element binding protein (CREB) phosphorylation in skeletal muscle cells of I/R injury. Additionally, PKA pathway activation potentiated the therapeutic effect of Sevoflurane on I/R injury after TKA. Altogether, Sevoflurane treatment confines I/R injury after TKA via RASD1-mediated PKA pathway activation.
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Proliferação de Células/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Sevoflurano/farmacologia , Proteínas ras/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Artroplastia do Joelho/métodos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Camundongos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/metabolismoRESUMO
Mg-Gd-Y-Zr alloy was subjected to torsion of various strain levels at room temperature. Obvious traces of basal slip were observed in the twisted alloy. Dislocations of
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BACKGROUND: Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.
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Cisplatino/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/metabolismo , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Reparo do DNA por Junção de Extremidades , Neoplasias do Endométrio/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Mitochondria are vital regulators of plant growth and development, constitute the predominant source of ATP, and participate in multiple anabolic and catabolic metabolic pathways. But the mechanism by which dysfunctional mitochondria affect plant growth remains unknown, and more mitochondria-defective mutants need to be identified. RESULTS: A mitochondria-defective mutant decreased vascular bundle 1 (dvb1) was isolated from rice mutant library mutagenized by EMS (ethylmethane sulfonate), which shows dwarfism, narrow leaves, short branches, few vascular bundles, and low fertility. Map-based cloning, genetic complementation, and phylogenetic analysis revealed that DVB1 encodes a structural protein classified in the Mic10 family and is required for the formation of cristae in mitochondria, and was primarily expressed in vascular bundles. The DVB1 protein is partially localized in the mitochondria and capable of forming dimers and polymers. Comparing with the wild type, disruption of amino acid metabolism and increased auxin synthesis were observed in dvb1 mutant which also showed increased sensitivity to the mitochondrial electron transport inhibitors. CONCLUSIONS: DVB1 belongs to Mic10 family and DVB1 is partially localized in the mitochondria. Further studies indicated that DVB1 is important for mitochondrial and plant development in rice.
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BACKGROUND: Exosomes are potential tools for disease control by regulating intercellular communication through carrying proteins and RNAs between cells or remote organs. Exosome activities have aroused wide concerns in cancer biology and malignancy control. AIMS: This study was performed to explore the roles of mesenchymal stem cell (MSC)-derived exosomes in colorectal cancer (CRC) progression. METHODS: MSC-exosomal microRNAs (miRNAs) in CRC tissues were analyzed, and aberrantly expressed miRNAs in CRC tissues were obtained from the data available on the GEO database. Altered expression of miR-3940-5p was introduced to identify its role in CRC invasion and metastasis in both cell and animal models. The binding relationship between miR-3940-5p and Integrin alpha6 (ITGA6) was predicted on TargetScan and validated through a luciferase assay. The effects of ITGA6 on CRC were figured out. RESULTS: MSC-derived exosomes carried miR-3940-5p into CRC cells. Up-regulation of miR-3940-5p inhibited epithelial-mesenchymal transition (EMT) and invasion of CRC cells, and suppressed the tumor metastasis and growth in vivo. miR-3940-5p was found to directly bind to ITGA6. Overexpression of ITGA6 promoted CRC cell invasion and EMT and tumor progression through upregulating the transforming growth factor-beta1 (TGF-ß1) signaling. A TGF-ß1-specific antagonist, Disitertide, blocked the functions of ITGA6 both in vivo and in vitro. CONCLUSION: MSC-exosomal miR-3940-5p inhibits invasion and EMT of CRC cells as well as growth and metastasis of tumors through targeting ITGA6 and the following TGF-ß1 inactivation. This study may provide novel insights into exosome-based treatment for CRC.
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Neoplasias Colorretais/metabolismo , Exossomos/metabolismo , Marcação de Genes/métodos , Integrina alfa6/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Exossomos/genética , Células HT29 , Humanos , Integrina alfa6/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/administração & dosagem , MicroRNAs/genéticaRESUMO
OBJECTIVE: Serum response factor (SRF), a sequence-specific transcription factor, is closely related to metastasis of gastric cancer, a digestive tract cancer. Herein, we probed the effect of SRF on metastasis and progression of colon cancer (CC), another digestive tract disorder, and the detailed mechanism. METHODS: Microarray analysis was conducted on tumor and adjacent tissues to filter differentially expressed miRNA, followed by RT-qPCR validation in CC cell lines. The transcription factor and the target gene of microRNA-214 (miR-214) were predicted, and their binding relationships were tested by luciferase reporter assays and ChIP assays. Subsequently, SRF and protein tyrosine kinase 6 (PTK6) expression in CC patients and cells was evaluated by RT-qPCR, while JAK2 and STAT3 expression in cells by Western blot analysis. To further explore functions of miR-214, PTK6 and SRF on CC, CC cells were delivered with si-PTK6, miR-214 mimic and/or SRF overexpression. RESULTS: miR-214 expressed poorly in CC tissues and cell lines, which related to advanced TNM staging and survival. miR-214 mimic inhibited proliferation, migration, invasion, xenograft tumor growth and metastasis of CC cells. SRF, overexpressed in CC samples and cells, suppressed the transcription of miR-214. Meanwhile, SRF upregulation counteracted the inhibitory role of miR-214 mimic in CC cell growth. miR-214 negatively regulated PTK6 expression to impair the JAK2/STAT3 pathway activation, thereby halting CC cell proliferation, migration, invasion, xenograft tumor growth and metastasis. CONCLUSION: Altogether, miR-214 may perform as a tumor suppressor in CC, and the SRF/miR-214/PTK6/JAK2/STAT3 axis could be applied as a biomarker and potential therapeutic target.
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Forging at room temperature was applied on the per-extruded Mg-Gd-Y-Zr alloy to investigate the effect of cold forging on the microstructure, mechanical properties and corrosion resistance of the alloy. Abundant micro shear bands with misorientations of 2-15° were generated in the as forged alloys. Tremendous enhancement in tensile yield strength was achieved after forging. With a quantitative investigation, micro band boundaries were considered to provide a great contribution to the reinforcement. The ultrafine structure resulting from the formation of micro shear bands led to increased corrosion resistance of the alloy.