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Maternal inflammation can lead to premature birth and fetal brain damage. CircRNA_19038 and lncRNA-AK016022 have been shown to be significantly reduced in brain tissues of preterm mice, while whether they are involved in the regulation of preterm white matter injury remains to be explored. Pregnant mice were intraperitoneally injected with lipopolysaccharide (LPS) to establish a preterm brain injury model. Healthy mice born at term served as controls. Lentivirus-mediated circ_19038 overexpression vector (LV-circ_19038), LV-lnc-AK016022, LV-Sirt1 and LV-sh-Sirt1 were administered to preterm mice through the ventricles. The expression levels of circ_19038, lnc-AK016022 and Sirt1 in the brain tissues of preterm mice were significantly lower than those of full-term healthy mice, and circ_19038 and lnc-AK016022 were co-localized in the brain tissues. Upregulation of circ_19038 or/and lnc-AK016022 promoted remyelination and alleviated white matter structural damage, neuroinflammation, and long-term cognitive and motor deficits in preterm mice, and the combined effect of circ_19038 and lnc-AK016022 showed better results. Primary mouse neuronal cells were isolated to investigate the regulatory effects of circ_19038 and lnc-AK016022 on Sirt1. Circ_19038 and lnc-AK016022 jointly promoted the expression of Sirt1 by adsorbing miR-1b and miR-328, respectively. Moreover, silencing Sirt1 antagonized the beneficial effects of circ_19038 or/and lnc-AK016022 on brain white matter injury in preterm mice. In conclusion, circ_19038 and lnc-AK016022 synergistically regulated Sirt1 expression to promote remyelination and alleviate white matter injury in preterm mice.
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BACKGROUND: Despite ongoing research, the underlying causes of schizophrenia remain unclear. Aspartate and asparagine, essential amino acids, have been linked to schizophrenia in recent studies, but their causal relationship is still unclear. This study used a bidirectional two-sample Mendelian randomization (MR) method to explore the causal relationship between aspartate and asparagine with schizophrenia. METHODS: This study employed summary data from genome-wide association studies (GWAS) conducted on European populations to examine the correlation between aspartate and asparagine with schizophrenia. In order to investigate the causal effects of aspartate and asparagine on schizophrenia, this study conducted a two-sample bidirectional MR analysis using genetic factors as instrumental variables. RESULTS: No causal relationship was found between aspartate and schizophrenia, with an odds ratio (OR) of 1.221 (95%CI: 0.483-3.088, P-value = 0.674). Reverse MR analysis also indicated that no causal effects were found between schizophrenia and aspartate, with an OR of 0.999 (95%CI: 0.987-1.010, P-value = 0.841). There is a negative causal relationship between asparagine and schizophrenia, with an OR of 0.485 (95%CI: 0.262-0.900, P-value = 0.020). Reverse MR analysis indicates that there is no causal effect between schizophrenia and asparagine, with an OR of 1.005(95%CI: 0.999-1.011, P-value = 0.132). CONCLUSION: This study suggests that there may be a potential risk reduction for schizophrenia with increased levels of asparagine, while also indicating the absence of a causal link between elevated or diminished levels of asparagine in individuals diagnosed with schizophrenia. There is no potential causal relationship between aspartate and schizophrenia, whether prospective or reverse MR. However, it is important to note that these associations necessitate additional research for further validation.
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Asparagina , Esquizofrenia , Humanos , Asparagina/genética , Ácido Aspártico/genética , Esquizofrenia/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Estudos ProspectivosRESUMO
BACKGROUND: Programmed death ligand-1 (PD-L1) is involved in the negative regulation of immune responses in a variety of diseases. We evaluated the contribution of PD-L1 to the activation of immune cells that promote atherosclerotic lesion formation and inflammation. METHODS AND RESULTS: Compared to ApoE-/- mice that were provided a high-cholesterol diet in combination with anti-PD-L1 antibody developed a larger lipid burden with more abundant CD8+ T cells. The anti-PD-L1 antibody increased the abundance of CD3+PD-1+, CD8 + PD-1+,CD3+IFN-γ+ and CD8+IFN-γ+ T cell under high-cholesterol diet, as well as the serum tumor necrosis factor-α (TNF-a), IFN-γ, PF, GNLY, Gzms B and LTA. Interestingly, the anti-PD-L1 antibody increased the serum level of sPD-L1. In vitro, blocking of PD-L1 on the surface of mouse aortic endothelial cells with anti-PD-L1 antibody stimulated the activation and secretion of cytokines, including IFN-γ, PF, GNLY, Gzms B and LTA, from cytolytic CD8+IFN-γ+ T cell. However, the concentration of sPD-L1 was lower after treatment of the MAECs with anti-PD-L1 antibody. CONCLUSIONS: Our findings highlighted that blocking of PD-L1 promoted up-regulation of CD8 + IFN-γ + T cell-mediated immune responses, leading to the secretion of inflammatory cytokine that exacerbated the atherosclerotic burden and promoted inflammation. However, further studies are needed to gain insight into whether PD-L1 activation could be a novel immunotherapy strategy for atherosclerosis.
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Aterosclerose , Linfócitos T CD8-Positivos , Camundongos , Animais , Receptor de Morte Celular Programada 1/metabolismo , Células Endoteliais/metabolismo , Ligantes , Interferon gama/metabolismo , Citocinas/metabolismo , Apoptose , Aterosclerose/metabolismo , Inflamação/metabolismo , Colesterol/metabolismoRESUMO
The perinatal period is the key period for the development of brain and central nervous system, and different events in this period will have a profound influence on brain development. Glucocorticoids, antibiotics, magnesium sulfate, caffeine, pulmonary surfactant, and mild hypothermia treatment are commonly used drugs or treatment methods in the perinatal period and are closely associated with the prognosis of neonatal neurodevelopment. This article reviews the latest research on the effect of perinatal treatments on neonatal neurodevelopment, so as to provide a reference for clinical decision making.
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Encéfalo , Feminino , Humanos , Recém-Nascido , GravidezRESUMO
OBJECTIVE: To determine the association of circular RNA (circRNA) and circRNA-microRNA (miRNA) network regulation with brain injury induced by inflammation in preterm mice. METHODS: Pregnant mice were treated with intraperitoneally injected lipopolysaccharide to establish a preterm mouse model of brain injury induced by inflammation (inflammation preterm group with 3 mice). Preterm mice born to normal pregnant mice by cesarean section were selected as controls (non-inflammation preterm group with 3 mice). The gene microarray technique was used to screen out the circRNAs associated with brain injury in preterm mice. The miRNA target prediction software was used to predict the binding sites between circRNAs and miRNAs and analyze the regulatory mechanism. RESULTS: A total of 365 differentially expressed circRNAs were screened out between the inflammation preterm and non-inflammation preterm groups (fold change > 1.5, P < 0.05), among which there were 206 upregulated circRNAs and 159 downregulated circRNAs. Further analysis of the circRNAs with a fold change of > 4 showed that these circRNAs could bind to miRNAs and regulate their activity, thereby regulating the expression of the genes associated with the nervous system. CONCLUSIONS: Inflammation induces a significant change in the expression profile of circRNAs in the brain tissue of mice, and the change in the expression of circRNAs plays an important role in brain injury induced by inflammation and subsequent brain development in preterm mice.
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Lesões Encefálicas , MicroRNAs , Animais , Cesárea , Feminino , Perfilação da Expressão Gênica , Inflamação/genética , Camundongos , MicroRNAs/genética , Gravidez , RNA/genética , RNA CircularRESUMO
The complex anatomy of petrous part of temporal bone makes the craniotomy around this area challenging. To avoid damaging the interior structures of petrous part of temporal bone, the authors used computed tomography to get the projection of the petrous part of temporal bone on skulls, making the external contours of petrous part clear, thus protecting its interior structure as a reference in craniotomy. The objective of this study was to find out the three-dimensional location of 4 points of petrous part of temporal bone. Parameters of 120 patients (240 observations) between 25 and 65 years who were free of abnormalities and pathological changes in temporal bone were measured on high-resolution spiral multiple slice computed tomographic multiple planar reconstruction images that were parallel to the base plane. The data were analyzed by SPSS, statistical software with the comparison between sides and sexes. The authors found the accurate locations that 4 points of petrous part of temporal bone with mastoidale as the origin. Then the authors connect the 3 vertexes of underside and the petrous apex and lengthen it until intersect with skulls to get the external landmarks. In the end, the authors get the safe range that can be applied to the clinical surgery.
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Interpretação de Imagem Assistida por Computador , Osso Petroso/anatomia & histologia , Crânio/anatomia & histologia , Osso Temporal/anatomia & histologia , Tomografia Computadorizada Espiral , Adulto , Cefalometria , Feminino , Humanos , Masculino , Osso Petroso/cirurgia , Valores de Referência , Fatores Sexuais , Crânio/cirurgia , Osso Temporal/cirurgiaRESUMO
The aim of this study was to investigate how the concentration of interleukin-13 (IL-13) affects the regulation of endothelial cell migration after injury. The incubation of recombinant human interleukin-13 (rhIL-13) strongly increased the content of reactive oxygen species (ROS) in HUVECs via the JAK-1/STAT-3/NOX-4 signaling pathway. Antagonizing the high intracellular ROS that was induced by rhIL-13 promoted the migration of HUVECs. Furthermore, IL-13 neutralization not only inhibited intimal hyperplasia, but also promoted the migration of endothelial cells (ECs) after injury. The results suggest that IL-13 inhibition is a potential means of stimulating endothelial cells recovery after injury. Therefore, the attenuation of IL-13 activation may have therapeutic value for vascular disease.
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Células Endoteliais , Interleucina-13 , Humanos , Hiperplasia/patologia , Proliferação de Células , Células Endoteliais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Transdução de SinaisRESUMO
Immune checkpoint blockade therapy against programmed death protein-1 and its ligand (PD-1/PD-L1) has been accepted as a promising approach to activate the immune system's anti-tumor response. Although small interfering RNA (siRNA) or antibodies can block the PD-1/PD-L1 pathway, the effect of this blockade is temporary and reversible. Here, we developed a nano-delivery system to achieve permanent disruption of the PD-L1 gene based on Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated nuclease 9 (Cas9) gene editing technology. In this system, the CRISPR/Cas9 plasmid was delivered into melanoma B16F10 cells using a nucleobase-modified polyamidoamine (PAMAM) derivative namely AP-PAMAM, which was constructed through the modification with 2-amino-6-chloropurine. Meanwhile, the carrier could efficiently facilitate the endosomal escape of CRISPR/Cas9 plasmid and thereby inhibit PD-L1 expression in cancer cells. Moreover, the intravenous injection of AP-PAMAM/plasmid nanoparticles could recruit and activate CD8+ T cells at the tumor site, promoting the secretion of cytokines and the killing of tumor cells. Overall, this nano-delivery system for genome editing provided a promising strategy to block the PD-1/PD-L1 pathway and obtain effective tumor immunotherapy.
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Edição de Genes , Neoplasias , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Poliaminas , Receptor de Morte Celular Programada 1 , RNA Interferente Pequeno/farmacologiaRESUMO
Highly invasive and rapidly fatal, small-cell lung cancer (SCLC) has been an insurmountable gulf since discovery. Innate immunity plays a vital role in anti-tumor response, among which macrophages contribute to an indispensable character. Here, we found that macrophage infiltration in SCLC reduced significantly in a stage-dependent manner, attributed to the decreased expression of CCL2, a potent chemoattractant for monocytes. Validated by ChIP-qPCR and MassArray methylation analysis, CCL2 expression was inhibited by EZH2-mediated H3K27me3 in the enhancer regions and DNMT1-mediated DNA methylation in the promoter regions, the process of which could be reversed by small-molecular compounds, EPZ011989 and Decitabine. Direct cell-cell contact between SCLC cells and macrophages skewed the phenotype of macrophages to be more M1-like. Furthermore, in an ectopic engraft model of SCLC, disruption of EZH2/DNMT1 function using the combination treatment of EPZ011989 and Decitabine potently abrogated the inhibition of macrophage infiltration and thus suppressed tumor growth, the effect of which was impaired by CCL2 neutralization or macrophage depletion. Overall, this work provides new insights into the role of macrophages in SCLC and establishes a rationale for constructing novel therapeutic avenues for SCLC patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quimiocina CCL2/genética , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Macrófagos Associados a Tumor/imunologia , Adolescente , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/imunologia , Quimiocina CCL2/metabolismo , Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/imunologia , Decitabina/farmacologia , Decitabina/uso terapêutico , Elementos Facilitadores Genéticos/genética , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/imunologia , Feminino , Histonas/genética , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Fagocitose/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Análise Serial de Tecidos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Efficient borylation reaction of diazonium salts in water is realized for the first time by using easily prepared, highly emissive and crystalline carbon dots. Electron-donating and electron-withdrawing groups on diazonium salts were well tolerated with moderate to good conversion efficiency. Compared with widely used metal complexes, organic dyes and quantum dots, the approach presented herein uses carbon dots, which are nontoxic and possess good biological and medicinal compatibility and high reactivity. Therefore, this approach presents a new prospective use for carbon dots in green chemistry.