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1.
Mol Med Rep ; 22(1): 33-42, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32377730

RESUMO

Previous studies have shown that caspase-1 plays an important role in the acute inflammatory response of spinal cord injury (SCI). VX­765, a novel and irreversible caspase­1 inhibitor, has been reported to effectively intervene in inflammation. However, the effect of VX­765 on genome­wide transcription in acutely injured spinal cords remains unknown. Therefore, in the present study, RNA­sequencing (RNA­Seq) was used to analyze the effect of VX­765 on the local expression of gene transcription 8 h following injury. The differentially expressed genes (DEGs) underwent enrichment analysis of functions and pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. Parallel analysis of western blot confirmed that VX­765 can effectively inhibit the expression and activation of caspase­1. RNA­Seq showed that VX­765 treatment resulted in 1,137 upregulated and 1,762 downregulated DEGs. These downregulated DEGs and their associated signaling pathways, such as focal adhesion, cytokine­cytokine receptor interaction, leukocyte transendothelial migration, extracellular matrix­receptor interaction, phosphatidylinositol 3­kinase­protein kinase B, Rap1 and hypoxia inducible factor­1 signaling pathway, are mainly associated with inflammatory response, local hypoxia, macrophage differentiation, adhesion migration and apoptosis of local cells. This suggests that the application of VX­765 in the acute phase can improve the local microenvironment of SCI by inhibiting caspase­1. However, whether VX­765 can be used as a therapeutic drug for SCI requires further exploration. The sequence data have been deposited into the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/PRJNA548970).

2.
Genomics ; 112(2): 2092-2105, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31830526

RESUMO

MicroRNAs (miRNAs) are involved in a series of pathology of spinal cord injury (SCI). Although, locally expressed miRNAs have advantages in studying the pathological mechanism, they cannot be used as biomarkers. The "free circulation" miRNAs can be used as biomarkers, but they have low concentration and poor stability in body fluids. Exosomal miRNAs in body fluids have many advantages comparing with free miRNAs. Therefore, we hypothesized that the specific miRNAs in the central nervous system might be transported to the peripheral circulation and concentrated in exosomes after injury. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and subactue SCI rats were analyzed. The results showed that SCI can lead to changes of serum exosomal miRNAs. These changed miRNAs and their associated signaling pathways may explain the pathological mechanism of suacute SCI. More importantly, we found some valuable serum exosomal miRNAs for diagnosis and prognosis of SCI.

4.
Genomics ; 111(4): 986-996, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31307632

RESUMO

The underlying mechanisms of macrophage polarization have been detected by genome-wide transcriptome analysis in a variety of mammals. However, the transcriptome profile of rat genes in bone marrow-derived macrophages (BMM) at different activation statuses has not been reported. Therefore, we performed RNA-Sequencing to identify gene expression signatures of rat BMM polarized in vitro with different stimuli. The differentially expressed genes (DEGs) among unactivated (M0), classically activated pro-inflammatory (M1), and alternatively activated anti-inflammatory macrophages (M2) were analyzed by using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. In this study, not only we have identified the changes of global gene expression in rat M0, M1 and M2, but we have also made clear systematically the key genes and signaling pathways in the differentiation process of M0 to M1 and M2. These will provide a foundation for future researches of macrophage polarization.


Assuntos
Ativação de Macrófagos/genética , Macrófagos/imunologia , Transcriptoma , Animais , Células Cultivadas , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA , Transdução de Sinais
6.
Neural Regen Res ; 14(3): 542-552, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30539825

RESUMO

In traumatic brain injury, absent in melanoma 2 (AIM2) has been demonstrated to be involved in pyroptotic neuronal cell death. Although the pathophysiological mechanism of spinal cord injury is similar to that of brain injury, the expression and cellular localization of AIM2 after spinal cord injury is still not very clear. In the present study, we used a rat model of T9 spinal cord contusive injury, produced using the weight drop method. The rats were randomly divided into 1-hour, 6-hour, 1-day, 3-day and 6-day (post-injury time points) groups. Sham-operated rats only received laminectomy at T9 without contusive injury. Western blot assay revealed that the expression levels of AIM2 were not significantly different among the 1-hour, 6-hour and 1-day groups. The expression levels of AIM2 were markedly higher in the 1-hour, 6-hour and 1-day groups compared with the sham, 3-day and 7-day groups. Double immunofluorescence staining demonstrated that AIM2 was expressed by NeuN+ (neurons), GFAP+ (astrocytes), CNPase+ (oligodendrocytes) and CD11b+ (microglia) cells in the sham-operated spinal cord. In rats with spinal cord injury, AIM2 was also found in CD45+ (leukocytes) and CD68+ (activated microglia/macrophages) cells in the spinal cord at all time points. These findings indicate that AIM2 is mainly expressed in neurons, astrocytes, microglia and oligodendrocytes in the normal spinal cord, and that after spinal cord injury, its expression increases because of the infiltration of leukocytes and the activation of astrocytes and microglia/macrophages.

7.
Int J Mol Med ; 43(1): 209-220, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30431059

RESUMO

The present study aimed to investigate the effect of microRNA­183 (miR­183) on substantia nigra neurons by targeting oncostatin M receptor (OSMR) in a mouse model of Parkinson's disease (PD). The positive expression rates of OSMR and the apoptosis of substantia nigra neurons were detected by immunohistochemistry and terminal deoxynucleotidyl transferase­mediated dUTP­biotin nick end­labeling, respectively. Substantia nigra neurons in normal and PD mice were cultured in vitro. The association between miR­183 and OSMR was verified using a dual luciferase reporter gene assay. The expression of miR­183 and the phosphoinositide 3­kinase­Akt signaling pathway­associated genes were detected by reverse transcription­quantitative polymerase chain reaction and western blot analysis, respectively. Cell apoptosis was detected by flow cytometry. OSMR is the target gene of miR­183. The number of OSMR­positive cells and the apoptotic rate of substantia nigra neurons were increased in the PD group. Neurons transfected with miR­183 mimic exhibited elevated expression levels of miR­183, B­cell lymphoma 2 (Bcl­2)­associated X protein (Bax) and caspase­9 and increased apoptotic rate, and reduced expression levels of OSMR, Akt, phosphorylated (p­)Akt, glycogen synthase kinase­3 (GSK­3ß), p­GSK­3ß, Bcl­2, insulin­like growth factor 1 (IGF­1), mammalian target of rapamycin (mTOR) and p­mTOR. The miR­183 inhibitor decreased the expression levels of miR­183, Bax and caspase­9 and the apoptotic rate; however, increased the expression of OSMR, Akt, p­Akt, GSK­3ß, p­GSK­3ß, Bcl­2, IGF­1, mTOR and p­mTOR. The results of the present study provide evidence that the overexpression of miR­183 promotes the apoptosis of substantia nigra neurons by inhibiting the expression of OSMR.


Assuntos
Apoptose/genética , MicroRNAs/genética , Neurônios/patologia , Doença de Parkinson/genética , Receptores de Oncostatina M/antagonistas & inibidores , Substância Negra/patologia , Animais , Sequência de Bases , Comportamento Animal , Caspase 9/metabolismo , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Oncostatina M/genética , Receptores de Oncostatina M/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína X Associada a bcl-2/metabolismo
8.
J Neurosci Res ; 96(7): 1265-1276, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29377294

RESUMO

Ceruloplasmin (Cp), an enzyme containing six copper atoms, has important roles in iron homeostasis and antioxidant defense. After spinal cord injury (SCI), the cellular components in the local microenvironment are very complex and include functional changes of resident cells and the infiltration of leukocytes. It has been confirmed that Cp is elevated primarily in astrocytes and to a lesser extent in macrophages following SCI in mice. However, its expression in other cell types is still not very clear. In this manuscript, we provide a sensible extension of these findings by examining this system within a female Sprague-Dawley rat model and expanding the scope of inquiry to include additional cell types. Quantitative reverse transcription polymerase chain reaction and Western blot analysis revealed that the Cp mRNA and protein in SCI tissue homogenates were quite consistent with prior publications. However, we observed that Cp was expressed not only in GFAP+ astrocytes (consistent with prior reports) but also in CD11b+ microglia, CNPase+ oligodendrocytes, NeuN+ neurons, CD45+ leukocytes, and CD68+ activated microglia/macrophages. Quantitative analysis proved that infiltrated leukocytes, activated microglia/macrophages, and astrocytes should be the major sources of increased Cp.


Assuntos
Astrócitos/enzimologia , Ceruloplasmina/biossíntese , Microglia/enzimologia , Traumatismos da Medula Espinal/patologia , 2',3'-Nucleotídeo Cíclico Fosfodiesterases/metabolismo , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígenos Nucleares/metabolismo , Astrócitos/patologia , Antígeno CD11b/metabolismo , Ceruloplasmina/metabolismo , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/enzimologia , Leucócitos/patologia , Macrófagos/enzimologia , Macrófagos/patologia , Camundongos , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/enzimologia , Neurônios/fisiologia , Oligodendroglia/enzimologia , Oligodendroglia/patologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/induzido quimicamente
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