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Clinical trials of hypothermia after pediatric cardiac arrest (CA) have not seen robust improvement in functional outcome, possibly because of the long delay in achieving target temperature. Previous work in infant piglets showed that high nasal airflow, which induces evaporative cooling in the nasal mucosa, reduced regional brain temperature uniformly in half the time needed to reduce body temperature. Here, we evaluated whether initiation of hypothermia with high transnasal airflow provides neuroprotection without adverse effects in the setting of asphyxic CA. Anesthetized piglets underwent sham-operated procedures (n = 7) or asphyxic CA with normothermic recovery (38.5°C; n = 9) or hypothermia initiated by surface cooling at 10 (n = 8) or 120 (n = 7) min or transnasal cooling initiated at 10 (n = 7) or 120 (n = 7) min after resuscitation. Hypothermia was sustained at 34°C with surface cooling until 20 h followed by 6 h of rewarming. At 4 days of recovery, significant neuronal loss occurred in putamen and sensorimotor cortex. Transnasal cooling initiated at 10 min significantly rescued the number of viable neurons in putamen, whereas levels in putamen in other hypothermic groups remained less than sham levels. In sensorimotor cortex, neuronal viability in the four hypothermic groups was not significantly different from the sham group. These results demonstrate that early initiation of high transnasal airflow in a pediatric CA model is effective in protecting vulnerable brain regions. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field or emergency room for early initiation of brain cooling after pediatric CA.NEW & NOTEWORTHY The onset of therapeutic hypothermia after cardiac resuscitation is often delayed, leading to incomplete neuroprotection. In an infant swine model of asphyxic cardiac arrest, initiation of high transnasal airflow to maximize nasal evaporative cooling produced hypothermia sufficient to provide neuroprotection that was not inferior to body surface cooling. Because of its simplicity and portability, this technique may be of use in the field or emergency room for rapid brain cooling in pediatric cardiac arrest victims.
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Modelos Animais de Doenças , Parada Cardíaca , Hipotermia Induzida , Animais , Hipotermia Induzida/métodos , Parada Cardíaca/terapia , Parada Cardíaca/fisiopatologia , Suínos , Neuroproteção/fisiologia , Animais Recém-Nascidos , Feminino , MasculinoRESUMO
Two series of lanthanoid (Ln)-containing polyoxometalates (POMs) {[Ln6(ampH)4(H2O)24-n(ampH2)n(PW11O39)2]·21H2O (Ln = Tb, n = 0 (1), Ln = Er, n = 1 (2)) and K2[Ln6(ampH)4(H2O)22(SiW11O39)2]·23H2O (Ln = Tb (3), Er (4)) (ampH2 = (aminomethyl) phosphonic acid)} have been synthesized with tri-lacunary Keggin-type POMs containing different types of heteroatoms. Compounds 1 and 2 display neutral organic-inorganic hybrid POM molecules containing {Ln6(ampH)4} ({Ln6}) cores sandwiched by two {PW11O39} units. By changing the heteroatoms from PV to SiIV, the extended 2D networks of 3 and 4 were successfully isolated where the adjacent {Ln6} clusters were connected by {SiW11O39} moieties. Luminescence performances and magnetic properties of 1-4 have been systematically surveyed. The solid-state fluorescence spectra of 1-4 display characteristic emissions of Ln components resulting from the 4f-4f transitions, and energy transfer from the POM segments to Ln3+ centers in 1 and 3 has been observed based on the lifetime decay behaviors. Furthermore, all compounds can be utilized as electrocatalysts toward reduction of nitrite with high stability.
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Neutron and γ-ray irradiation damages to transistors are found to be non-additive, and this is denoted as the irradiation synergistic effect (ISE). Its mechanism is not well-understood. The recent defect-based model [Song and Wei, ACS Appl. Electron. Mater. 2, 3783 (2020)] for silicon bipolar junction transistors (BJTs) achieves quantitative agreement with experiments, but its assumptions on the defect reactions are unverified. Going beyond the model requires directly representing the effect of γ-ray irradiation in first-principles calculations, which was not feasible previously. In this work, we examine the defect-based model of the ISE by developing a multiscale method for the simulation of the γ-ray irradiation, where the γ-ray-induced electronic excitations are treated explicitly in excited-state first-principles calculations. We find the calculations agree with experiments, and the effect of the γ-ray-induced excitation is significantly different from the effects of defect charge state and temperature. We propose a diffusion-based qualitative explanation of the mechanism of positive/negative ISE in NPN/PNP BJTs in the end.
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KDM4 histone demethylases mainly catalyze the removal of methyl marks from H3K9 and H3K36 to epigenetically regulate chromatin structure and gene expression. KDM4 expression is strictly regulated to ensure proper function in a myriad of biological processes, including transcription, cellular proliferation and differentiation, DNA damage repair, immune response, and stem cell self-renewal. Aberrant expression of KDM4 demethylase has been documented in many types of blood and solid tumors, and thus, KDM4s represent promising therapeutic targets. In this chapter, we summarize the current knowledge of the structures and regulatory mechanisms of KDM4 proteins and our understanding of their alterations in human pathological processes with a focus on development and cancer. We also review the reported KDM4 inhibitors and discuss their potential as therapeutic agents.
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Histona Desmetilases com o Domínio Jumonji , Neoplasias , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Reparo do DNA , Proliferação de Células , Diferenciação Celular , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Histona Desmetilases/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêuticoRESUMO
Decidualization is necessary for the successful establishment of early pregnancy in rodents and humans. Disturbed decidualization results in recurrent implantation failure, recurrent spontaneous abortion, and preeclampsia. Tryptophan (Trp), one of the essential amino acids in humans, has a positive effect on mammalian pregnancy. Interleukin 4-induced gene 1 (IL4I1) is a recently identified enzyme that can metabolize L-Trp to activate aryl hydrocarbon receptor (AHR). Although IDO1-catalyzed kynurenine (Kyn) from Trp has been shown to enhance human in vitro decidualization via activating AHR, whether IL4I1-catalyzed metabolites of Trp are involved in human decidualization is still unknown. In our study, human chorionic gonadotropin stimulates IL4I1 expression and secretion from human endometrial epithelial cells through ornithine decarboxylase-induced putrescine production. Either IL4I1-catalyzed indole-3-pyruvic acid (I3P) or its metabolite indole-3-aldehyde (I3A) from Trp is able to induce human in vitro decidualization by activating AHR. As a target gene of AHR, Epiregulin induced by I3P and I3A promotes human in vitro decidualization. Our study indicates that IL4I1-catalyzed metabolites from Trp can enhance human in vitro decidualization through AHR-Epiregulin pathway.
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Interleucina-4 , Receptores de Hidrocarboneto Arílico , Animais , Humanos , Epirregulina , Receptores de Hidrocarboneto Arílico/metabolismo , Triptofano/metabolismo , Cinurenina/metabolismo , Gonadotropina Coriônica , Mamíferos/metabolismo , L-Aminoácido OxidaseRESUMO
MgB2-type superconductors are of great interest in chemistry and condensed matter physics due to their superconductivity dominated by the structural unit of graphene-like B. However, this kind of material is absent in phosphides resulting from the inherent lone pair electrons of phosphorus. Here, we report that a pressure-stabilized LaP2, isostructural to MgB2, shows superconductivity with a predicted Tc of 22.2 K, which is the highest among those of already known transition metal phosphides. Besides the electron-phonon coupling of graphene-like P, alike the role of the B layer in MgB2, La 5d/4f electrons are also responsible for the superconducting transition. The distinct P atomic arrangement is attributed to its sp2 hybridization and out-of-plane symmetric distribution of lone pair electrons. On the other hand, its dynamically stabilized pressure reaches as low as 7 GPa, a desirable feature of pressure-induced superconductors. Although P is isoelectronic to N and As, we hereby find the different stable stoichiometries, structures, and electronic properties of La phosphides compared with La nitrides/arsenides at high pressures.
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NXPH4 is discovered to be a neuropeptide-like glycoprotein, belonging to the Neurexophilins (Nxphs) family. NXPH4 shares a similar domain structure with NXPH1, which, however, is poorly understood in terms of its function. Bioinformatics analysis and experimental verification in this study confirmed the abnormal high expression of NXPH4 in non-small cell lung cancer (NSCLC) tissues and cells. Knockdown of NXPH4 by siRNA can inhibit the proliferation and migration of cells, resulting in significant cell cycle arrest in S1 phase. Furthermore, in NSCLC cells, NXPH4 was regulated by transcriptional activation of enhancer of zeste homolog 2 (EZH2) in its upstream. While downstream, NXPH4 could interact with CDKN2A and downregulate its protein stability, thus participating in the cell cycle regulation through interacting with cyclinD-CDK4/6-pRB-E2F signaling pathway. To sum up, the present study reveals a regulatory pathway of EZH2/NXPH4/CDKN2A in NSCLC, providing possible reference for understanding the function of NXPH4 in tumors.
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Carcinoma Pulmonar de Células não PequenasRESUMO
Endometrial decidualization plays a pivotal role during early pregnancy. Compromised decidualization has been tightly associated with recurrent implantation failure (RIF). Primary cilium is an antenna-like sensory organelle and acts as a signaling nexus to mediate Hh, Wnt, TGFß, BMP, FGF, and Notch signaling. However, whether primary cilium is involved in human decidualization is still unknown. In this study, we found that primary cilia are present in human endometrial stromal cells. The ciliogenesis and cilia length are increased by progesterone during in vitro and in vivo decidualization. Primary cilia are abnormal in the endometrium of RIF patients. Based on data from both assembly and disassembly of primary cilia, it has been determined that primary cilium is essential to human decidualization. Trichoplein (TCHP)-Aurora A signaling mediates cilia disassembly during human in vitro decidualization. Mechanistically, primary cilium modulates human decidualization through PTEN-PI3K-AKT-FOXO1 signaling. Our study highlights primary cilium as a novel decidualization-related signaling pathway.
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Cílios , Proteínas Proto-Oncogênicas c-akt , Gravidez , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cílios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Endométrio/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Decídua/metabolismoRESUMO
There are around 300 million adolescent pregnancies worldwide, accounting for 11% of all births worldwide. Accumulating evidence demonstrates that many adverse perinatal outcomes are associated with adolescent pregnancies. However, how and why these abnormalities occur remain to be defined. In this study, pregnancy at different stages was compared between 25- and 30- day-old and mature female mice. We found that the litter size of adolescent pregnancy is significantly decreased from F1 to F3 generations compared to mature pregnancy. On days 8 and 12 of pregnancy, multiple abnormalities in decidual and placental development appear in F3 adolescent pregnancy. On days 5 and 8, uterine endoplasmic reticulum stress is dysregulated in F3 adolescent pregnancy. Embryo implantation and decidualization are also compromised in adolescent pregnancy. Many genes are abnormally expressed in adolescent estrous uteri. The abnormal endocrine environment and abnormal implantation from uterine immaturity may result in multiple pregnancy failures in adolescent pregnancy. The aim of this study is to shed light on human adolescent pregnancy.
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Gravidez na Adolescência , Adolescente , Animais , Decídua , Implantação do Embrião , Feminino , Humanos , Camundongos , Placenta , Gravidez , Reprodução , ÚteroRESUMO
BACKGROUND: Decidualization is essential to the successful pregnancy in mice. The molecular mechanisms and effects of Aurora kinase A (Aurora A) remain poorly understood during pregnancy. This study is the first to investigate the expression and role of Aurora A during mouse decidualization. METHODS: Quantitative real time polymerase chain reaction, western blotting and in situ hybridization were used to determine the expression of Aurora A in mouse uteri. Aurora A activity was inhibited by Aurora A inhibitor to explore the role of Aurora A on decidualization via regulating the Aurora A/Stat3/Plk1/Cdk1 signaling pathway. RESULTS: Aurora A was strongly expressed at implantation sites compared with inter-implantation sites. Furthermore, Aurora A was also significantly increased in oil-induced deciduoma compared with control. Both Aurora A mRNA and protein were significantly increased under in vitro decidualization. Under in vitro decidualization, Prl8a2, a marker of mouse decidualization, was significantly decreased by TC-S 7010, an Aurora A inhibitor. Additionally, Prl8a2 was reduced by Stat3 inhibitor, Plk1 inhibitor and Cdk1 inhibitor, respectively. Moreover, the protein levels of p-Stat3, p-Plk1 and p-Cdk1 were suppressed by TC-S 7010. The protein levels of p-Stat3, p-Plk1 and p-Cdk1 were also suppressed by S3I-201, a Stat3 inhibitor). SBE 13 HCl (Plk1 inhibitor) could reduce the protein levels of p-Plk1 and p-Cdk1. Collectively, Aurora A could regulate Stat3/Plk1/Cdk1 signaling pathway. CONCLUSION: Our study shows that Aurora A is expressed in decidual cells and should be important for mouse decidualization. Aurora A/Stat3/Plk1/Cdk1 signaling pathway may be involved in mouse decidualization.
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Aurora Quinase A/biossíntese , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/metabolismo , Decídua/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Animais , Aurora Quinase A/antagonistas & inibidores , Proteína Quinase CDC2/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Células Cultivadas , Decídua/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Camundongos , Gravidez , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Quinase 1 Polo-LikeRESUMO
Glucocorticoids (GCs), stress-induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress-induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox-2 expression. Cort-induced collagen disorder also suppresses decidualization through regulating mesenchymal-epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.
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Anti-Inflamatórios/toxicidade , Corticosterona/toxicidade , Decídua/patologia , Implantação do Embrião/efeitos dos fármacos , Estresse Fisiológico , Útero/patologia , Animais , Decídua/efeitos dos fármacos , Feminino , Masculino , Camundongos , Gravidez , Útero/efeitos dos fármacosRESUMO
Two novel polynuclear dysprosium (Dy)-containing polytungstoarsenates, CsK7Na16[(AsW9O33)6Dy6W10O24(H2O)23]·40H2O (1) and Cs2K18Na18[(AsW9O33)7Dy7W8O21(H2O)17(µ3-OH)(OH)]·78H2O (2), have been synthesized via the reaction of the preformed polyoxometalate (POM) precursor [As2W19O67(H2O)]14- and Dy3+ ions through controlling pH. The polyanion of 1 can be described as a dimer of two similar trimers {(AsW9O33)3Dy2W5O12(H2O)6} that are linked by Dy cation and two µ2-oxo groups, and the Dy(III) ions in 1 are arranged in a linear fashion. Compound 2 presenting an interesting W-shaped structure, assembly composed of a dimeric {(AsW9O33)2W3Dy2O8(H2O)7}, a trimer {(AsW9O33)3W4Dy2O11(OH)(H2O)3}, and a particular sandwiched {(AsW9O33)2WDy3O4(µ3-OH)(H2O)7} segment concatenated by µ2-oxo groups. The solid-state luminescence performances and lifetime decay behaviors of 1 and 2 were systematically researched at ambient temperature, and time-resolved fluorescence spectra of 1 and 2 indicate energy transfer (ET) from the photoexcitation Oâ¯â M ligand to the metal charge-transfer (LMCT) bands of the POM ligands to Dy3+ ions. Moreover, the dynamic magnetic measurement indicates that 1 and 2 exhibit slow relaxation of the magnetization.
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Solids undergo displacement damage (DD) when interacting with energetic particles, which may happen during the fabrication of semiconductor devices, in harsh environments and in certain analysis techniques. Simulations of DD generation are usually carried out using classical molecular dynamics (MD), but classical MD does not account for all the effects in DD, as demonstrated by ab initio calculations of model systems in the literature. A complete ab initio simulation of DD generation is impractical due to the large number of atoms involved. In my previous paper [Yang, Phys. Chem. Chem. Phys., 2020, 22, 19307], I developed an adaptive-center (AC) method for the adaptive-partitioning (AP) of quantum mechanics/molecular mechanics (QM/MM) simulations, allowing the active region centers and the QM/MM partition to be determined on-the-fly for energy-conserving AP-QM/MM methods. I demonstrated that the AC-AP-QM/MM is applicable to the simulation of DD generation, so that the active regions can be treated using an ab initio method. The AC method could not be used to identify the fast-moving recoil ions in DD generation as active region centers, however, and the accuracy is negatively affected by the rapid change in the QM/MM partition of the system. In this paper, I extend the AC method and develop a speed-dependent adaptive-center (SDAC) method for accurate AP-QM/MM simulations of DD. The SDAC method is applicable to general problems with speed-dependent active regions, and is compatible with all existing energy-conserving partitioning-by-distance AP-QM/MM methods. The artifact due to the speed-dependent potential energy surface can be made small by choosing suitable criteria. I demonstrate the SDAC method by simulations of DD generation in bulk silicon.
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A novel strategy combining visible-light and enzyme catalysis in one pot for the synthesis of 4H-pyrimido[2,1-b] benzothiazole derivatives from alcohols is described for the first time. Fourteen 4H-pyrimido[2,1-b] benzothiazole derivatives were prepared with yields of up to 98% under mild reaction conditions by a simple operation. The photoorgano catalyst rose Bengal (rB) was employed to oxyfunctionalise alcohols to aldehydes. Compared with aldehydes, alcohols with more stable properties and lower cost, thus we used photocatalysis to oxidize alcohols into aldehydes. Next, the enzyme was used to further catalyze the reaction of Biginelli to produce the target product of 4H-pyrimidine [2,1-b] benzothiazole. Experimental results show that this method provides a more efficient and eco-friendly strategy for the synthesis of 4H-pyrimido[2,1-b] benzothiazole derivatives.
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Benzotiazóis/química , Enzimas/metabolismo , Luz , Benzotiazóis/síntese química , Benzotiazóis/metabolismo , Biocatálise , Candida/enzimologia , Catálise , Enzimas/química , Proteínas Fúngicas/metabolismo , Humanos , Lipase/metabolismo , OxirreduçãoRESUMO
An efficient and green method, combining enzymatic and visible-light catalysis for synthesis of the widely applicable 2-substituted benzothiazoles, has been developed. This method features a relay catalysis protocol consisting of biocatalytic promiscuity and visible-light-induced subsequent oxidization of 2-phenyl benzothiazolines. The whole reaction process is very high-efficiency, achieving 99% yield in just 10 min, under an air atmosphere, nearly 100% atomic utilization, and the 2-substituted benzothiazole products were obtained in good to excellent yields with a wide range of substrates. This reaction is the other example of combining the non-natural catalytic activity of hydrolases with visible-light catalysis for organic synthesis and the catalytic system does not require additional oxidants or metals, which is good for the environment.
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Benzotiazóis/síntese química , Hidrolases/metabolismo , Luz , Benzotiazóis/química , Benzotiazóis/metabolismo , Catálise , Oxirredução , Fármacos Fotossensibilizantes/química , Solventes/química , Especificidade por SubstratoRESUMO
Decidualization is essential to the establishment of pregnancy in rodents and primates. Laminin A5 (encoding by Laminin α5) is a member of the laminin family, which is mainly expressed in the basement membranes. Although laminins regulate cellular phenotype maintenance, adhesion, migration, growth, and differentiation, the expression, function, and regulation of laminin A5 during early pregnancy are still unknown. Therefore, we investigated the expression and role of laminin A5 during mouse and human decidualization. Laminin A5 is highly expressed in mouse decidua and artificially induced deciduoma. Laminin A5 is significantly increased under in vitro decidualization. Laminin A5 knockdown significantly inhibits the expression of Prl8a2, a marker for mouse decidualization. Progesterone stimulates the expression of laminin A5 in ovariectomized mouse uterus and cultured mouse stromal cells. We also show that progesterone regulates laminin A5 through the PKA-CREB-C/EBPß pathway. Laminin A5 is also highly expressed in human pregnant decidua and cultured human endometrial stromal cells during in vitro decidualization. Laminin A5 knockdown by siRNA inhibits human in vitro decidualization. Collectively, our study reveals that laminin A5 may play a pivotal role during mouse and human decidualization via the PKA-CREB-C/EBPß pathway.
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Decídua/metabolismo , Laminina/metabolismo , Adulto , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Decídua/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Laminina/genética , Masculino , Camundongos Endogâmicos ICR , Modelos Biológicos , Gravidez , Progesterona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
Aberrant activation of the hedgehog (Hh) signaling pathway is associated with the formation of medulloblastoma (MB), the most common malignant pediatric brain tumor. However, tumor cells from human and mouse MB can not be passaged or preserved after being adherently cultured. Moreover, Hh signaling in MB cells is inactivated in such culture. Here we demonstrate that MB cells are capable of forming tumoroids (tumor spheroids) in vitro under optimized conditions, which can be further passaged and cryopreserved. More importantly, MB cells maintain Hh pathway activation and cell proliferation in tumoroids. Our studies further reveal that tumoroids-forming capacity of MB cells relies on astrocytes, a major component of the MB microenvironment. Astrocytes facilitate the formation of MB tumoroids by secreting sonic hedgehog (Shh) and generating astrocyte-derived extracellular matrix. These findings demonstrate the critical role of stromal astrocytes in supporting the survival and proliferation of MB cells in vitro. This study establishes a valid model for long-term culture of primary MB cells, which could be greatly beneficial for future investigation of MB tumorigenicity and the development of improved approaches to treat MB.
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Astrócitos/metabolismo , Neoplasias Cerebelares/genética , Matriz Extracelular/metabolismo , Proteínas Hedgehog/genética , Meduloblastoma/genética , Transdução de Sinais/genética , Animais , Astrócitos/patologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patologia , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Receptor Patched-2/genética , Receptor Patched-2/metabolismo , Microambiente Tumoral/genética , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
Lysine acetyltransferases (KATs) are a highly diverse group of epigenetic enzymes that play important roles in various cellular processes including transcription, signal transduction, and cellular metabolism. However, our knowledge of the genomic and transcriptomic alterations of KAT genes and their clinical significance in human cancer remains incomplete. We undertook a metagenomic analysis of 37 KATs in more than 10 000 cancer samples across 33 tumor types, focusing on breast cancer. We identified associations among recurrent genetic alteration, gene expression, clinicopathologic features, and patient survival. Loss-of-function analysis was carried out to examine which KAT has important roles in growth and viability of breast cancer cells. We identified that a subset of KAT genes, including NAA10, KAT6A, and CREBBP, have high frequencies of genomic amplification or mutation in a spectrum of human cancers. Importantly, we found that 3 KATs, NAA10, ACAT2, and BRD4, were highly expressed in the aggressive basal-like subtype, and their expression was significantly associated with disease-free survival. Furthermore, we showed that depletion of NAA10 inhibits basal-like breast cancer growth in vitro. Our findings provide a strong foundation for further mechanistic research and for developing therapies that target NAA10 or other KATs in human cancer.
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Genoma Humano/genética , Lisina Acetiltransferases/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteína de Ligação a CREB/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Intervalo Livre de Doença , Proteína p300 Associada a E1A/genética , Dosagem de Genes , Expressão Gênica , Histona Acetiltransferases/genética , Humanos , Lisina Acetiltransferases/metabolismo , Mutação , Acetiltransferase N-Terminal A/genética , Acetiltransferase N-Terminal A/metabolismo , Acetiltransferase N-Terminal E/genética , Acetiltransferase N-Terminal E/metabolismo , Neoplasias/mortalidade , Prognóstico , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Fatores de Transcrição/genéticaRESUMO
The striatal, primary sensorimotor cortical, and thalamic neurons are highly vulnerable to hypoxia-ischemia (HI) in term newborns. In a piglet model of HI that exhibits similar selective regional vulnerability, we tested the hypothesis that early treatment with sulforaphane, an activator of the Nrf2 transcription factor, protects vulnerable neurons from HI injury. Anesthetized piglets (aged 3-7 days) were subjected to 45 min of hypoxia and 7 min of airway occlusion. At 15 min after resuscitation, the piglets received intravenous vehicle or sulforaphane. At 4 days of recovery, the density of viable neurons in the putamen of vehicle-treated piglets was 31 ± 34% (±SD) that of sham-operated controls. Treatment with sulforaphane significantly increased viability to 77 ± 31%. In the sensorimotor cortex, neuronal viability was also increased; it was 59 ± 35% in the vehicle-treated and 89 ± 15% in the sulforaphane-treated animals. Treatment with sulforaphane increased the nuclear Nrf2 and γ-glu-tamylcysteine synthetase expression at 6 h of recovery in these regions. We conclude that systemic administration of sulforaphane 15 min after HI can induce the translocation of Nrf2 to the nucleus, increase expression of an enzyme involved in glutathione synthesis, and salvage neurons in the highly vulnerable putamen and sensorimotor cortex in a large-animal model of HI. Therefore, targeting Nrf2 activation soon after recovery from HI is a feasible approach for neuroprotection in the newborn brain.
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Encéfalo/efeitos dos fármacos , Hipóxia-Isquemia Encefálica/patologia , Isotiocianatos/farmacologia , Fármacos Neuroprotetores/farmacologia , Sulfóxidos/farmacologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Masculino , SuínosRESUMO
Embryo implantation and decidualization are crucial steps during early pregnancy. We recently showed that nucleolar stress is involved in embryo implantation. This study was to explore whether nucleolar stress participates in mouse and human decidualization. Our data demonstrated that a low dose of actinomycin D (ActD) could induce nucleolar stress in stroma cells. Nucleolar stress promotes the stromal-epithelial transition during mouse in vitro decidualization through nucleophosmin1 (NPM1). Under nucleolar stress, Wnt family member 4 (Wnt4), a decidualization marker, is significantly increased, but decidua/trophoblast prolactin-related protein (Dtprp/Prl8a2) expression remains unchanged. For translational significance, we also examined the effects of nucleolar stress on human decidualization. Nucleolar stress stimulated by a low dose of ActD enhances human stromal-epithelial transition during human decidualization, but has no effects on the expression of insulin-like growth factor-binding protein 1 (IGFBP1). Our study indicates that nucleolar stress may promote only the mesenchymal-epithelial transition (MET), but not for all the molecular changes during decidualization.