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1.
J Immunol ; 210(2): 180-190, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36458991

RESUMO

Acute pancreatitis (AP) can be complicated by inflammatory disorders of remote organs, such as lung injury, in which Jumonji domain-containing protein 3 (JMJD3) plays a vital role in proinflammatory responses. Currently, we found that JMJD3 expression was upregulated in the pancreas and lung in an AP male mouse model, which was also confirmed in AP patients. Further experiments revealed that the upregulation of JMJD3 and proinflammatory effects were possibly exerted by mitochondrial DNA (mtDNA) or oxidized-mtDNA from tissue injury caused by AP. The release of mtDNA and oxidized-mtDNA contributed to the infiltration of inflammatory monocytes in lung injury through the stimulator of IFN genes (STING)/TLR9-NF-κB-JMJD3-TNF-α pathway. The inhibition of JMJD3 or utilization of Jmjd3-cKO mice significantly alleviated pulmonary inflammation induced by AP. Blocking mtDNA oxidation or knocking down the TLR9/STING pathway effectively alleviated inflammation. Therefore, inhibition of JMJD3 or STING/TLR9 pathway blockage might be a potential therapeutic strategy to treat AP and the associated lung injury.


Assuntos
Lesão Pulmonar , Pancreatite , Masculino , Camundongos , Animais , Receptor Toll-Like 9/metabolismo , Doença Aguda , NF-kappa B/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo
2.
Part Fibre Toxicol ; 16(1): 18, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975174

RESUMO

BACKGROUND: Carbon nanomaterials are a growing family of materials featuring unique physicochemical properties, and their widespread application is accompanied by increasing human exposure. MAIN BODY: Considerable efforts have been made to characterize the potential toxicity of carbon nanomaterials in vitro and in vivo. Many studies have reported various toxicology profiles of carbon nanomaterials. The different results of the cytotoxicity of the carbon-based materials might be related to the differences in the physicochemical properties or structures of carbon nanomaterials, types of target cells and methods of particle dispersion, etc. The reported cytotoxicity effects mainly included reactive oxygen species generation, DNA damage, lysosomal damage, mitochondrial dysfunction and eventual cell death via apoptosis or necrosis. Despite the cellular toxicity, the immunological effects of the carbon-based nanomaterials, such as the pulmonary macrophage activation and inflammation induced by carbon nanomaterials, have been thoroughly studied. The roles of carbon nanomaterials in activating different immune cells or inducing immunosuppression have also been addressed. CONCLUSION: Here, we provide a review of the latest research findings on the toxicological profiles of carbon-based nanomaterials, highlighting both the cellular toxicities and immunological effects of carbon nanomaterials. This review provides information on the overall status, trends, and research needs for toxicological studies of carbon nanomaterials.


Assuntos
Carbono/toxicidade , Citocinas/metabolismo , Pulmão/efeitos dos fármacos , Nanoestruturas/toxicidade , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Carbono/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Nanoestruturas/química , Tamanho da Partícula , Propriedades de Superfície
3.
ACS Chem Neurosci ; 14(18): 3347-3356, 2023 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-37691264

RESUMO

Adamantinomatous craniopharyngioma (ACP) is a neuroendocrine tumor whose pathogenesis remains unclear. This study investigated the role of glioma-associated oncogene family zinc finger 1 (GLI1), a transcription factor in the sonic hedgehog (SHH) signaling pathway, in ACP. We discovered that GLI1 regulates the expression of IL-6, thereby triggering inflammatory responses in ACP and influencing the tumor's progression. Analyzing the Gene Expression Omnibus (GEO) database chip GSE68015, we found that GLI1 is overexpressed in ACP, correlating positively with the spite of ACP and inflammation markers. Knockdown of GLI1 significantly inhibited the levels of tumor necrosis factor α, interleukin-6 (IL-6), and IL-1ß in ACP cells, as well as cell proliferation and migration. We further identified a binding site between GLI1 and the promoter region of IL-6, demonstrating that GLI1 can enhance the expression of IL-6. These findings were verified in vivo, where activation of the SHH pathway significantly promoted GLI1 and IL-6 expressions in nude mice, inducing inflammation and tumor growth. Conversely, GLI1 knockdown markedly suppressed these processes. Our study uncovers a potential molecular mechanism for the occurrence of inflammatory responses and tumor progression in ACP.


Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Animais , Camundongos , Proteínas Hedgehog , Fatores de Transcrição , Interleucina-6 , Craniofaringioma/genética , Camundongos Nus , Proteína GLI1 em Dedos de Zinco/genética , Inflamação , Neoplasias Hipofisárias/genética
4.
Bone Res ; 10(1): 57, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028500

RESUMO

Ammonia plays an important role in cellular metabolism. However, ammonia is considered a toxic product. In bone marrow-derived mesenchymal stem cells, multipotent stem cells with high expression of glutamine synthetase (GS) in bone marrow, ammonia and glutamate can be converted to glutamine via glutamine synthetase activity to support the proliferation of MSCs. As a major nutritional amino acid for biosynthesis, glutamine can activate the Akt/mTOR/S6k pathway to stimulate cell proliferation. The activation of mTOR can promote cell entry into S phase, thereby enhancing DNA synthesis and cell proliferation. Our studies demonstrated that mesenchymal stem cells can convert the toxic waste product ammonia into nutritional glutamine via GS activity. Then, the Akt/mTOR/S6k pathway is activated to promote bone marrow-derived mesenchymal stem cell proliferation. These results suggest a new therapeutic strategy and potential target for the treatment of diseases involving hyperammonemia.

5.
Front Psychol ; 12: 771591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790157

RESUMO

This study conducts a scientific analysis of 249 literature on the application of brain-computer technology in emotion research. We find that existing researches mainly focus on engineering, computer science, neurosciences neurology and psychology. PR China, United States, and Germany have the largest number of publications. Authors can be divided into four groups: real-time functional magnetic resonance imaging (rtfMRI) research group, brain-computer interface (BCI) impact factors analysis group, brain-computer music interfacing (BCMI) group, and user status research group. Clustering results can be divided into five categories, including external stimulus and event-related potential (ERP), electroencephalography (EEG), and information collection, support vector machine (SVM) and information processing, deep learning and emotion recognition, neurofeedback, and self-regulation. Based on prior researches, this study points out that individual differences, privacy risk, the extended study of BCI application scenarios and others deserve further research.

6.
Front Bioeng Biotechnol ; 9: 764188, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900961

RESUMO

Phosphorus (P) is a nonrenewable resource, which is one of the major challenges for sustainable agriculture. Although phosphite (Phi) can be absorbed by the plant cells through the Pi transporters, it cannot be metabolized by plant and unable to use as P fertilizers for crops. However, transgenic plants that overexpressed phosphite dehydrogenase (PtxD) from bacteria can utilize phosphite as the sole P source. In this study, we aimed to improve the catalytic efficiency of PtxD from Ralstonia sp.4506 (PtxDR4506), by directed evolution. Five mutations were generated by saturation mutagenesis at the 139th site of PtxD R4506 and showed higher catalytic efficiency than native PtxDR4506. The PtxDQ showed the highest catalytic efficiency (5.83-fold as compared to PtxDR4506) contributed by the 41.1% decrease in the K m and 2.5-fold increase in the k cat values. Overexpression of PtxDQ in Arabidopsis and rice showed increased efficiency of phosphite utilization and excellent development when phosphite was used as the primary source of P. High-efficiency PtxD transgenic plant is an essential prerequisite for future agricultural production using phosphite as P fertilizers.

7.
Exp Mol Med ; 53(8): 1207-1217, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34385569

RESUMO

Compelling evidence has indicated the vital role of lysine-specific demethylase 4 A (KDM4A), hypoxia-inducible factor-1α (HIF1α) and the mechanistic target of rapamycin (mTOR) signaling pathway in nasopharyngeal carcinoma (NPC). Therefore, we aimed to investigate whether KDM4A affects NPC progression by regulating the HIF1α/DDIT4/mTOR signaling pathway. First, NPC and adjacent tissue samples were collected, and KDM4A protein expression was examined by immunohistochemistry. Then, the interactions among KDM4A, HIF1α and DDIT4 were assessed. Gain- and loss-of-function approaches were used to alter KDM4A, HIF1α and DDIT4 expression in NPC cells. The mechanism of KDM4A in NPC was evaluated both in vivo and in vitro via RT-qPCR, Western blot analysis, MTT assay, Transwell assay, flow cytometry and tumor formation experiments. KDM4A, HIF1α, and DDIT4 were highly expressed in NPC tissues and cells. Mechanistically, KDM4A inhibited the enrichment of histone H3 lysine 9 trimethylation (H3K9me3) in the HIF1α promoter region and thus inhibited the methylation of HIF1α to promote HIF1α expression, thus upregulating DDIT4 and activating the mTOR signaling pathway. Overexpression of KDM4A, HIF1α, or DDIT4 or activation of the mTOR signaling pathway promoted SUNE1 cell proliferation, migration, and invasion but inhibited apoptosis. KDM4A silencing blocked the mTOR signaling pathway by inhibiting the HIF1α/DDIT4 axis to inhibit the growth of SUNE1 cells in vivo. Collectively, KDM4A silencing could inhibit NPC progression by blocking the activation of the HIF1α/DDIT4/mTOR signaling pathway by increasing H3K9me3, highlighting a promising therapeutic target for NPC.


Assuntos
Carcinogênese/patologia , Movimento Celular , Histona Desmetilases com o Domínio Jumonji/metabolismo , Carcinoma Nasofaríngeo/enzimologia , Carcinoma Nasofaríngeo/patologia , Adulto , Idoso , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Histonas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Lisina/metabolismo , Masculino , Metilação , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Invasividade Neoplásica , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima/genética , Adulto Jovem
8.
Theranostics ; 10(10): 4589-4605, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292516

RESUMO

Rationale: The adverse health effects of nano-particulate pollutants have attracted much attention in recent years. Carbon nanomaterials are recognized as risk factors for prolonged inflammatory responses and diffuse alveolar injury. Previous research indicated a central role of alveolar macrophages in the pathogenesis of particle-related lung disease, but the underlying mechanism remains largely unknown. Methods: C57BL/6 mice were intratracheally instilled with carbon black nanoparticles (CBNPs). Cell necrosis and the infiltrated neutrophils in the lungs were detected by flow cytometry. Release of mitochondria was observed with Mito Tracker and mitochondrial DNA (mtDNA) was quantified by qPCR via Taqman probes. TLR9-p38 MAPK signaling pathway was detected by Western blotting. The production of lipid chemoattractant leukotriene B4 (LTB4) in the supernatant and bronchoalveolar lavage fluid (BALF) was quantitated using an enzyme immunoassay (EIA). Results: In the present study, we found that a single instillation of CBNPs induced neutrophil influx in C57BL/6 mice as early as 4 h post-exposure following the rapid appearance of cell damage indicators in BALF at 30 min. Macrophages exposed to CBNPs showed necrotic features and were characterized by lysosome rupture, cathepsin B release, reactive oxygen species generation, and reduced intracellular ATP level. Necrosis was partly inhibited by a specific lysosomal cathepsin B inhibitor CA074 Me. Further analyses suggested that the resulting leakage of mtDNA from the necrotic cells activated neutrophils and triggered severe inflammation in vivo. Pulmonary neutrophilic inflammation induced by mtDNA was reduced in TLR9-/- mice. Additionally, mtDNA induced LTB4 production from macrophages, which may contribute to neutrophil recruitment. Conclusion: We demonstrated here that CBNPs induce acute cell necrosis through lysosomal rupture and that mtDNA released from necrotic cells functions as a key event mediating pulmonary neutrophilic inflammation. This study described a novel aspect of the pathogenesis of particle-induced inflammatory response and provided a possible therapeutic target for the regulation of inflammation.


Assuntos
Pulmão , Macrófagos/efeitos dos fármacos , Nanopartículas/efeitos adversos , Neutrófilos/efeitos dos fármacos , Pneumonia/induzido quimicamente , Fuligem/efeitos adversos , Animais , Células Cultivadas , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Lisossomos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Necrose/induzido quimicamente , Neutrófilos/patologia
9.
Signal Transduct Target Ther ; 5(1): 6, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-32296026

RESUMO

Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor ß (FRß) is overexpressed in TAMs. However, the clinical significance of FRß-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRß overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRß-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRß-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.


Assuntos
Receptor 2 de Folato/genética , Ácido Fólico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos Associados a Tumor/efeitos dos fármacos , Células A549 , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptor 2 de Folato/antagonistas & inibidores , Ácido Fólico/química , Humanos , Lipossomos/química , Lipossomos/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Microambiente Tumoral/efeitos dos fármacos
10.
Protein Cell ; 10(12): 864-882, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31701394

RESUMO

In recent years, many studies have shown that histone methylation plays an important role in maintaining the active and silent state of gene expression in human diseases. The Jumonji domain-containing protein D3 (JMJD3), specifically demethylate di- and trimethyl-lysine 27 on histone H3 (H3K27me2/3), has been widely studied in immune diseases, infectious diseases, cancer, developmental diseases, and aging related diseases. We will focus on the recent advances of JMJD3 function in human diseases, and looks ahead to the future of JMJD3 gene research in this review.


Assuntos
Envelhecimento/metabolismo , Doenças Transmissíveis/metabolismo , Doenças do Sistema Imunitário/metabolismo , Histona Desmetilases com o Domínio Jumonji/fisiologia , Neoplasias/metabolismo , Animais , Linhagem Celular , Desenvolvimento Embrionário , Humanos
11.
Cell Prolif ; 52(3): e12579, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851061

RESUMO

OBJECTIVES: Neutrophils are thought to release neutrophil extracellular traps (NETs) to form in response to exogenous bacteria, viruses and other pathogens. However, the mechanisms underlying NET formation during sterile inflammation are still unclear. In this study, we would like to identify neutrophil extracellular traps formation during sterile inflammation and tissue injury and associated pathways and its mechanism. MATERIALS AND METHODS: We identified different injuries such as chemical-induced and trauma-induced formation of NETs and investigated mechanism of the formation of NETs in vitro and in vivo during the treatment of mtDNA. RESULTS: Here, we find the release of mitochondrial DNA (mtDNA) and oxidized mtDNA in acute peripheral tissue trauma models or other chemically induced lung injury, and moreover, endogenous mtDNA and oxidized mtDNA induce the formation of NETs and sterile inflammation. Oxidized mtDNA is a more potent inducer of NETs. Mitochondrial DNA activates neutrophils via cyclic GMP-AMP synthase (cGAS)-STING and the Toll-like receptor 9 (TLR9) pathways and increases the production of neutrophil elastase and extracellular neutrophil-derived DNA in NETs. Mitochondrial DNA also increases the production of reactive oxygen species (ROS) and expression of the NET-associated proteins Rac 2 and peptidylarginine deiminase 4 (PAD4). CONCLUSIONS: Altogether, these findings highlight that endogenous mitochondrial DNA inducted NETs formation and subsequent sterile inflammation and the mechanism associated with NET formation.


Assuntos
Armadilhas Extracelulares/metabolismo , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Neutrófilos/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , DNA Mitocondrial/metabolismo , Feminino , Humanos , Técnicas In Vitro , Elastase de Leucócito/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Modelos Biológicos , Ativação de Neutrófilo , Nucleotidiltransferases/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Ferimentos e Lesões/metabolismo
13.
Atherosclerosis ; 183(1): 95-100, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16216592

RESUMO

It has been demonstrated that higher degree of arteriolar retinopathy is associated with greater cardiovascular risk, and hyperhomocysteinaemia is also related to increased cardiovascular risk, but interacts with other risk factors, particularly smoking. It still remains unclear regarding relationships of smoking, fasting plasma total homocysteine (tHcy) levels and arteriolar retinopathy. This study was aimed to investigate the relationship and influence of smoking and tHcy levels on degree of arteriolar retinopathy. Two hundred and forty-three subjects were enrolled from an annual health examination. The arteriolar retinopathy was examined by direct ophthalmoscopy. Dundett ANOVA showed that geometric mean of tHcy levels were 11.5+/-1.54 versus 11.2+/-1.41 versus 17.6+/-1.92 (P1=0.883, P2=0.001) in subjects with no arteriolar retinopathy (as control group), grades I and II retinopathy, respectively. Furthermore, multiple linear regression analysis showed that only smoking consumption (P<0.001), gender (P=0.012) and presence of hypertension (P=0.041) were independent determinants of plasma tHcy levels. After females were excluded, T-test showed a significant differences in tHcy levels (15.6+/-1.56 micromol/L versus 12.4+/-1.45 micromol/L, P=0.003) and in prevalence of grade II retinopathy (25.4% versus 9.3%, P=0.029), but no difference in other variables or prevalence of overall retinopathy between smokers and non-smokers. Finally, logistic regression showed that smoking (OR 4.19, 95% CI 1.17-15.0) was a stronger predictor than hyperhomocysteinaemia (OR 2.14, 95% CI 0.85-5.41) for presence of grade II retinopathy. This study showed that smoking was related to increased plasma tHcy levels in subjects with grade II retinopathy, and it could independently contribute to facilitating the progression of arteriolar retinopathy.


Assuntos
Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Doenças Retinianas/etiologia , Vasos Retinianos/patologia , Fumar/efeitos adversos , Adulto , Arteríolas/patologia , China/epidemiologia , Estudos Transversais , Progressão da Doença , Feminino , Humanos , Hiper-Homocisteinemia/epidemiologia , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Oftalmoscopia , Prevalência , Doenças Retinianas/sangue , Doenças Retinianas/diagnóstico , Doenças Retinianas/epidemiologia , Fatores de Risco , Estudos de Amostragem , Índice de Gravidade de Doença
14.
Int J Clin Exp Pathol ; 8(9): 11452-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617874

RESUMO

BACKGROUND: Promoter methylation is an alternative mechanism of gene silencing in human tumorigenesis. Although a number of methylated genes have been found in non small cell lung cancer (NSCLC), useful methylation markers for early prognostic evaluation of NSCLC remain largely unknown. METHODS: Using methylation-specific PCR (MSP), we examined promoter methylation status of PAX6 gene, and explored their association with clinical features in NSCLC via chi-square test. NSCLC patient survival was assessed by Kaplan-Meier analyses and a Cox proportional hazard model was employed for multivariate analyses. RESULTS: The methylation level of PAX6 gene was higher in tumor tissues than that in normal tissues. In addition, PAX6 promoter methylation showed a very significant correlation with differentiation (P = 0.002), distant metastasis (P = 0.024), and TNM stage (P = 0.002). PAX6 gene promoter hyper-methylation was found to be significantly associated with poor overall survival (P = 0.018) and to serve as an independent marker for prognosis using multivariate Cox regression analysis (HR: 2.254, 95% CI: 1.088-4.667, P = 0.029). CONCLUSION: We found that PAX6 gene was specifically methylated in NSCLC, and demonstrated the effect of promoter methylation of PAX6 gene on clinical outcome in NSCLC, indicating the methylated PAX6 may be useful biomarkers for prognostic evaluation in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , Fator de Transcrição PAX6/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Fator de Transcrição PAX6/genética , Reação em Cadeia da Polimerase , Prognóstico , Regiões Promotoras Genéticas/genética , Modelos de Riscos Proporcionais
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