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1.
Front Cell Dev Biol ; 12: 1416325, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915445

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease with a prognosis worse than lung cancer. It is a fatal lung disease with largely unknown etiology and pathogenesis, and no effective therapeutic drugs render its treatment largely unsuccessful. With continuous in-depth research efforts, the epigenetic mechanisms in IPF pathogenesis have been further discovered and concerned. As a widely studied mechanism of epigenetic modification, DNA methylation is primarily facilitated by DNA methyltransferases (DNMTs), resulting in the addition of a methyl group to the fifth carbon position of the cytosine base, leading to the formation of 5-methylcytosine (5-mC). Dysregulation of DNA methylation is intricately associated with the advancement of respiratory disorders. Recently, the role of DNA methylation in IPF pathogenesis has also received considerable attention. DNA methylation patterns include methylation modification and demethylation modification and regulate a range of essential biological functions through gene expression regulation. The Ten-Eleven-Translocation (TET) family of DNA dioxygenases is crucial in facilitating active DNA demethylation through the enzymatic conversion of the modified genomic base 5-mC to 5-hydroxymethylcytosine (5-hmC). TET2, a member of TET proteins, is involved in lung inflammation, and its protein expression is downregulated in the lungs and alveolar epithelial type II cells of IPF patients. This review summarizes the current knowledge of pathologic features and DNA methylation mechanisms of pulmonary fibrosis, focusing on the critical roles of abnormal DNA methylation patterns, DNMTs, and TET proteins in impacting IPF pathogenesis. Researching DNA methylation will enchance comprehension of the fundamental mechanisms involved in IPF pathology and provide novel diagnostic biomarkers and therapeutic targets for pulmonary fibrosis based on the studies involving epigenetic mechanisms.

2.
Sci Transl Med ; 16(736): eadg5116, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38416841

RESUMO

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE-/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.


Assuntos
Neuromielite Óptica , Humanos , Animais , Camundongos , Astrócitos/metabolismo , Aquaporina 4 , Proteômica , Apolipoproteínas E , Autoanticorpos
3.
Front Oncol ; 13: 1178945, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37188172

RESUMO

Rhabdomyosarcoma (RMS) is a prevalent form of soft tissue sarcoma that primarily affects children. Pediatric RMS is characterized by two distinct histological variants: embryonal (ERMS) and alveolar (ARMS). ERMS is a malignant tumor with primitive characteristics resembling the phenotypic and biological features of embryonic skeletal muscles. With the widespread and growing application of advanced molecular biological technologies, such as next-generation sequencing (NGS), it has been possible to determine the oncogenic activation alterations of many tumors. Specifically for soft tissue sarcomas, the determination of tyrosine kinase gene and protein related changes can be used as diagnostic aids and may be used as predictive markers for targeted tyrosine kinase inhibition therapy. Our study reports a rare and exceptional case of an 11-year-old patient diagnosed with ERMS, who tested positive for MEF2D-NTRK1 fusion. The case report presents a comprehensive overview of the clinical, radiographic, histopathological, immunohistochemical, and genetic characteristics of a palpebral ERMS. Furthermore, this study sheds light on an uncommon occurrence of NTRK1 fusion-positive ERMS, which may provide theoretical basis for therapy and prognosis.

4.
CNS Neurosci Ther ; 29(1): 317-330, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36440924

RESUMO

BACKGROUND: Epilepsy is a neurological condition that causes unprovoked, recurrent seizures. Accumulating evidence from clinical and experimental studies indicates that neuroinflammation exacerbates seizure activity. METHODS: We investigated the transcriptional changes occurring in specific brain domains of a seizure mouse model, using 10× Genomics spatial transcriptomics. Differential gene expression and pathway analysis were applied to investigate potential signaling targets for seizure, including CCL5/CCR5 pathway. Maraviroc, an FDA-approved C-C chemokine receptor 5 (CCR5) antagonist, was used to verify the impact of CCL5/CCR5 signaling in seizure mice. RESULTS: We found distinguished regional transcriptome features in the hippocampus of seizure mice. The hippocampus exhibited unique inflammatory gene signatures, including glia activation, apoptosis, and immune response in seizure mice. Especially, we observed notable expression of C-C chemokine ligand 5 (CCL5) throughout the entire seizure hippocampus. Blockade of CCL5/CCR5 signaling via maraviroc prevented microglia activation and neuron degeneration in seizure mice. CONCLUSIONS: This study supports the potential of CCL5/CCR5 signaling for targeting neuroinflammation after seizure.


Assuntos
Epilepsia , Doenças Neuroinflamatórias , Camundongos , Animais , Maraviroc/uso terapêutico , Ligantes , Convulsões/tratamento farmacológico
6.
Z Naturforsch C J Biosci ; 76(5-6): 187-192, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33909958

RESUMO

Alzheimer's disease (AD) is a common neurodegenerative disease with high morbidity among elderly people. A genetic attribution has been extensively proved. Here, we propose to further prioritize genes that harbor single nucleotide variation (SNV) or structural variation (SV) for AD and explore the underlying potential mechanisms through exploiting their expression and methylation spectra. A high-confidence AD-associated candidate gene list was obtained from the ClinVar and Human Gene Mutation Database (HGMD). Genome-wide methylation and expression profiles of AD and normal subjects were downloaded from the Gene Expression Omnibus (GEO). Through comprehensive comparison of expression and methylation levels between AD and normal samples, as well as different stages of AD samples, SORL1 was identified as the most plausible gene for AD incidence and progression. Gene Set Enrichment Analysis (GSEA) revealed significant activation of the ABC (ATP binding cassette) transporter with the aberrant up-regulation of SORL1 within AD samples. This study unfolds the expression and methylation spectra of previously probed genes with SNV or SV in AD for the first time, and reports an aberrant activation of the ABC transporter pathway that might contribute to AD progression. This should shed some light on AD diagnosis and precision treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Doença de Alzheimer/patologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Metilação de DNA , Bases de Dados Genéticas , Regulação para Baixo , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único
7.
Biosci Rep ; 40(8)2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32744319

RESUMO

PURPOSE: The present study aimed to investigate the comprehensive differential expression profile of microRNAs (miRNAs) by screening for miRNA expression in ischemic stroke and normal samples. METHODS: Differentially expressed miRNA (DEM) analysis was conducted using limma R Bioconductor package. Target genes of DEMs were identified from TargetScanHuman and miRTarBase databases. Functional enrichment analysis of the target genes was performed using clusterProfiler R Bioconductor package. The miRNA-based ischemic stroke diagnostic signature was constructed via logistic regression analysis. RESULTS: Compared with the normal cohort, a total of 14 DEMs, including 5 up-regulated miRNAs and 9 down-regulated miRNAs, were identified in ischemic stroke patients. These DEMs have 1600 regulatory targets. Using a logistic regression model, the top five miRNAs were screened for constructing an miRNA-based ischemic stroke diagnostic signature. Using the miRNA-mRNA interaction pairs, two target genes (specificity protein 1 (SP1) and Argonaute 1 (AGO1)) were speculated to be the primary genes of ischemic stroke. DISCUSSION AND CONCLUSION: Here, several potential miRNAs biomarkers were identified and an miRNA-based diagnostic signature for ischemic stroke was established, which can be a valuable reference for future clinical researches.


Assuntos
Biologia Computacional , Perfilação da Expressão Gênica , AVC Isquêmico/diagnóstico , MicroRNAs/genética , Transcriptoma , Proteínas Argonautas/genética , Estudos de Casos e Controles , Bases de Dados Genéticas , Fatores de Iniciação em Eucariotos/genética , Redes Reguladoras de Genes , Humanos , AVC Isquêmico/genética , Modelos Logísticos , Aprendizado de Máquina , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Fator de Transcrição Sp1/genética
8.
J Cell Biochem ; 120(7): 11241-11247, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30790324

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized progressive memory loss and cognitive impairment. In previous studies, the activities of extracts of Chinese medicinal herbs to treat brain function disorders caused by AD have already been reported. ZiShen prescription was a traditional Chinese medicine (TCM) compound prescription reformed for AD disease based on the basic theory of TCM. To explore the effect of ZiShen (kidney-reinforcing) prescription on the learning and memory abilities, we made compound AD model rats by injecting d-galactose and ibotenic acid into the abdominal cavity to damage both sides of the nucleus basalis of Meynert with ibotenic acid. The trisected Y-maze was used to test the learning and memory abilities of AD model rats before and after treatment by ZiShen prescription and Piracetam. To investigate the mechanism of ZiShen prescription, the expressions of apoptosis-related genes (Bcl-2/Bax) in the cortex and hippocampus of compound AD model rats were detected in the cortex and hippocampus. The results show that, comparing with Piracetam, a clinical medicine to promote the thinking and memory for AD patients, ZiShen prescription significantly increased the learning and memory abilities of the compound AD model rats. After the treatment of ZiShen prescription, the expression of Bcl-2 was upregulated, along with a downregulation of Bax in the cortex and hippocampus of compound AD model rats. And the results indicated that the clinical benefits of ZiShen prescription were slightly better than Piracetam. Still, further well-designed studies are required to ensure the clinical effect of ZiShen.

9.
Sci Rep ; 6: 21776, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26878912

RESUMO

BRD7 was originally identified as a novel bromodomain gene and a potential transcriptional factor. BRD7 was found to be extensively expressed in multiple mouse tissues but was highly expressed in the testis. Furthermore, BRD7 was located in germ cells during multiple stages of spermatogenesis, ranging from the pachytene to the round spermatid stage. Homozygous knockout of BRD7 (BRD7(-/-)) resulted in complete male infertility and spermatogenesis defects, including deformed acrosomal formation, degenerative elongating spermatids and irregular head morphology in postmeiotic germ cells in the seminiferous epithelium, which led to the complete arrest of spermatogenesis at step 13. Moreover, a high ratio of apoptosis was determined by TUNEL analysis, which was supported by high levels of the apoptosis markers annexin V and p53 in knockout testes. Increased expression of the DNA damage maker λH2AX was also found in BRD7(-/-) mice, whereas DNA damage repair genes were down-regulated. Furthermore, no or lower expression of BRD7 was detected in the testes of azoospermia patients exhibiting spermatogenesis arrest than that in control group. These data demonstrate that BRD7 is involved in male infertility and spermatogenesis in mice, and BRD7 defect might be associated with the occurrence and development of human azoospermia.


Assuntos
Proteínas Cromossômicas não Histona/deficiência , Infertilidade Masculina , Espermatogênese , Animais , Apoptose , Enzimas Reparadoras do DNA/genética , Regulação para Baixo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testículo/patologia
10.
PLoS One ; 10(9): e0138955, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406239

RESUMO

Breast cancer has become the leading cause of cancer-related death among women. A large number of patients become resistant to drug chemotherapy. Paclitaxel (Taxol) is an effective chemotherapeutic agent used to treat cancer patients. Taxol has been widely used in human malignancies including breast cancer because it can stabilize microtubules resulting in cell death by causing an arrest during the G2/M phase of the cell cycle. Pro-apoptotic Bcl-2 antagonist killer 1 (Bak) plays an important role in Taxol-induced apoptosis in breast cancer. In our present study, we investigated the expression of the Bak protein and clinicopathological correlations in a large sample of breast cancer tissues by immunohistochemistry. We found that the percentage of high scores of Bak expression in breast cancer was significantly lower than that of the non-cancerous breast control tissue. In addition, lower Bak expression was positively associated with the clinical TNM stage of breast cancer with a significant decrease in overall survival compared with those with higher Bak expression especially in the Luminal and HER2 subtypes. Importantly, higher Bak expression predicted a favorable clinical outcome in the cases treated with Taxol indicated by a higher overall survival than that of patients with lower Bak expression especially in Luminal and HER2 subtypes. Furthermore, these results were confirmed in vitro since overexpression of Bak sensitized breast cancer cells to Taxol by inhibiting proliferation and promoting apoptosis; in contrast, downregulation of Bak through siRNA transfection inhibited Taxol induced-apoptosis. Therefore, our results demonstrate that Bak acts as a sensitive biomarker and favorable prognostic factor for Taxol treatment in breast cancer. The restoration of Bak expression would be therapeutically beneficial for Taxol resistant breast cancer patients.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Paclitaxel/farmacologia , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Adulto , Idoso , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Masculino , Pessoa de Meia-Idade , Paclitaxel/uso terapêutico , Prognóstico , Análise de Sobrevida , Regulação para Cima , Adulto Jovem
11.
Behav Brain Res ; 286: 1-10, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25721744

RESUMO

BRD7 is a bromodomain-containing protein (BCP), and recent evidence implicates the role of BCPs in the initiation and development of neurodevelopmental disorders. However, few studies have investigated the biological functions of BRD7 in the central nervous system. In our study, BRD7 was found to be widely expressed in various regions of the mouse brain, including the medial prefrontal cortex (mPFC), caudate putamen (CPu), hippocampus (Hip), midbrain (Mb), cerebellum (Cb), and mainly co-localized with neuron but not with glia. Using a BRD7 knockout mouse model and a battery of behavioral tests, we report that disruption of BRD7 results in impaired cognitive behavior leaving the emotional behavior unaffected. Moreover, a series of proteins involved in synaptic plasticity were decreased in the medial prefrontal cortex and there was a concomitant decrease in neuronal spine density and dendritic branching in the medial prefrontal cortex. However, no significant difference was found in the hippocampus compared to the wild-type mice. Thus, BRD7 might play a critical role in the regulation of synaptic plasticity and affect cognitive behavior.


Assuntos
Proteínas Cromossômicas não Histona/deficiência , Transtornos Cognitivos/fisiopatologia , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/fisiopatologia , Animais , Ansiedade/patologia , Ansiedade/fisiopatologia , Western Blotting , Proteínas Cromossômicas não Histona/genética , Transtornos Cognitivos/patologia , Dendritos/patologia , Dendritos/fisiologia , Depressão/patologia , Depressão/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes Neuropsicológicos , Percepção Olfatória/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Córtex Pré-Frontal/patologia , Reconhecimento Psicológico/fisiologia , Percepção Social
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