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1.
Wei Sheng Yan Jiu ; 49(5): 775-801, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070823

RESUMO

OBJECTIVE: To study the anti-apoptotic effect of cyanidin-3-O-glucoside(C3 G) on H_2O_2-induced injury in human embryonic kidney(HEK)-293 cells. METHODS: Hydrogen peroxide induced injury of HEK-293 cell was used as the research object. HEK-293 cells were pretreated with different concentrations of C3 G(1. 25, 5, 20 µmol/L). The anti-apoptotic effects of C3 G on injured cells were examined by the release rates of LDH and mitochondrial membrane potential(MMP). Western blot and qRT-PCR were used to detect the protein expression and mRNA expression of NF-κB P65. RESULTS: The result showed that the release rate of LDH was increased, MMP was decreased, the protein and mRNA of P65 was increased after H_2O_2 inducing. Whereas, the release rates of LDH were significantly lower than that of the injured group after 1. 25, 5, 20 µmol/L C3 G pretreatment of injured cells(P<0. 05). The MMP of C3 G group was significantly higher than injured group with concentration-dependent increases. The proteins and mRNA of P65 were also significantly lower than that of injured group(P<0. 05). CONCLUSION: Cyanidin-3-O-glucoside shows anti-apoptotic effect on H_2O_2-induced injury in HEK-293 cell. The mechanisms of anti-apoptotic effects may be to achieve by protecting cell biofilms, and inhibiting the activity of NF-κB signaling pathway.


Assuntos
Apoptose , NF-kappa B , Glucosídeos/farmacologia , Células HEK293 , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais
2.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-33011739

Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Glicosídeos Cardíacos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Animais , Antivirais/química , Betacoronavirus/patogenicidade , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Bufanolídeos/química , Bufanolídeos/farmacologia , Glicosídeos Cardíacos/química , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cloroquina/química , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Digoxina/química , Digoxina/farmacologia , Ensaios de Triagem em Larga Escala , Interações Hospedeiro-Patógeno/genética , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Pandemias , Fenantrenos/química , Fenantrenos/farmacologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
3.
Signal Transduct Target Ther ; 5(1): 186, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883951

RESUMO

Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients' blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.


Assuntos
Betacoronavirus/patogenicidade , Colesterol/biossíntese , Infecções por Coronavirus/genética , Síndrome da Liberação de Citocina/genética , Interações Hospedeiro-Patógeno/genética , Leucócitos Mononucleares/imunologia , Pneumonia Viral/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Regulação da Expressão Gênica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Unidades de Terapia Intensiva , Interleucina-1beta/genética , Interleucina-1beta/imunologia , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Cultura Primária de Células , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/imunologia , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/imunologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Anticancer Res ; 40(10): 5361-5369, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988855

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the role of toll-like receptor 2 (TLR2) in the proliferation of human lung cancer cells and identify the signaling pathway that mediates this effect. MATERIALS AND METHODS: Adenocarcinoma (A549 and H1650) and adenosquamous (H125) cells were treated with increasing doses of Pam3CSK4, a TLR2 agonist. Cell proliferation and NF-ĸB activation were evaluated. NF-ĸB was inhibited prior to treatment with Pam3CSK4 and proliferation was assessed. RESULTS: TLR2 expression was significantly higher in A549 and H1650 cells compared to H125 cells (p<0.001). TLR2 stimulation induced proliferation in adenocarcinoma cells only and led to a corresponding increase in NF-ĸB activity (p<0.05). Inhibition of NF-ĸB prior to treatment with Pam3CSK4 attenuated this proliferative response. CONCLUSION: TLR2 activation induced proliferation of lung adenocarcinoma cells through activation of NF-ĸB. Thus, the TLR2 signaling pathway may be a potential therapeutic target in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Lipopeptídeos/farmacologia , Receptor 2 Toll-Like/genética , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/genética , Receptor 2 Toll-Like/agonistas
5.
Am J Chin Med ; 48(6): 1369-1383, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32933311

RESUMO

Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.


Assuntos
Envelhecimento , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , NF-kappa B/genética , NF-kappa B/metabolismo , Fitoterapia , Animais , Anti-Inflamatórios , Colágeno/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais , Volume Sistólico/efeitos dos fármacos
6.
Sci Adv ; 6(31)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32937590

RESUMO

The outbreak of the highly contagious and deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease 2019 (COVID-19), has posed a serious threat to public health across the globe, calling for the development of effective diagnostic markers and therapeutics. Here, we report a highly reliable severity diagnostic biomarker, acetylated 676th lysine transforming growth factor-beta-induced protein (TGFBIp K676Ac). TGFBIp K676Ac was consistently elevated in the blood of patients with SARS-CoV-2 pneumonia (n = 113), especially in patients in the intensive care unit (ICU) compared to non-ICU patients. Patients' blood samples showed increased cytokines and lymphopenia, which are exemplary indicators of SARS-CoV-2 pneumonia. Treatment with TGFBIp neutralizing antibodies suppressed the cytokine storm. The increased level of TGFBIp K676Ac in ICU patients suggests the promise of this protein as a reliable severity diagnostic biomarker for severe SARS-CoV-2 disease.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Síndrome da Liberação de Citocina/diagnóstico , Proteínas da Matriz Extracelular/imunologia , Leucócitos Mononucleares/imunologia , Pneumonia Viral/diagnóstico , Processamento de Proteína Pós-Traducional , Insuficiência Respiratória/diagnóstico , Fator de Crescimento Transformador beta/imunologia , Acetilação , Anticorpos Neutralizantes/farmacologia , Betacoronavirus/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Proteínas da Matriz Extracelular/antagonistas & inibidores , Proteínas da Matriz Extracelular/genética , Expressão Gênica , Humanos , Unidades de Terapia Intensiva , Contagem de Leucócitos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Lisina/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Cultura Primária de Células , Prognóstico , Insuficiência Respiratória/sangue , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/patologia , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/genética
7.
DNA Cell Biol ; 39(10): 1779-1788, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32865424

RESUMO

Today, mesenchymal stem cells (MSCs) are candidates for various autoimmune disease treatments due to immunomodulatory activity in these cells. Much research has recently been done to improve the immunomodulatory activity of MSCs. Genetic variation is one of these methods. microRNAs (miRNAs) are small noncoding RNAs that control most of the cell's biological activities. Recent studies have shown that miRNAs play a significant role in the regulation of MSC immunomodulatory activity. Pomegranate is a fruit that has antioxidant, anti-inflammatory, and anticancer properties and has been used for many years for therapeutic purposes. The objective of this research is to evaluate the immunoregulatory-related miRNAs level of adipose-derived MSCs (Ad-MSCs) obtained from adipose tissue in the presence or lack of pomegranate (Punica granatum) extract (PGE). Our results showed that miRNA-23 and miRNA-126 were upregulated by PGE treatment in MSCs, and in contrast, miRNA-21 and miRNA-155 were downregulated by PGE treatment in MSCs. In addition this research shows that PGE can downregulate the expression of PI3K\AKT1\NF-[Formula: see text]B in Ad-MSCs. Our bioinformatics data have shown that the target of these four miRNAs and the signaling pathways, in which these targets are involved, can play an important role in regulating the immunomodulation function of stem cells. In conclusion, PGE can inhibit the expression of PI3K\AKT1\NF-[Formula: see text]B genes involved in inflammatory pathways via miRNA-23 and miRNA-126 overexpression or miRNA-21 and miRNA-155 downregulation that plays a role in the pathways of immune modulation in Ad-MSCs. These results may provide insight into the mechanism underlying the regulation of the immunomodulatory activity of Ad-MSCs by PGE.


Assuntos
Anti-Inflamatórios/farmacologia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , MicroRNAs/genética , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Romã (Fruta)/química , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
8.
Nucleic Acids Res ; 48(15): 8724-8739, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32735645

RESUMO

T cell activation is a well-established model for studying cellular responses to exogenous stimulation. Motivated by our previous finding that intron retention (IR) could lead to transcript instability, in this study, we performed BruChase-Seq to experimentally monitor the expression dynamics of nascent transcripts in resting and activated CD4+ T cells. Computational modeling was then applied to quantify the stability of spliced and intron-retained transcripts on a genome-wide scale. Beyond substantiating that intron-retained transcripts were considerably less stable than spliced transcripts, we found a global stabilization of spliced mRNAs upon T cell activation, although the stability of intron-retained transcripts remained relatively constant. In addition, we identified that La-related protein 4 (LARP4), an RNA-binding protein (RBP) known to enhance mRNA stability, was involved in T cell activation-dependent mRNA stabilization. Knocking out Larp4 in mice destabilized Nfκb1 mRNAs and reduced secretion of interleukin-2 (IL2) and interferon-gamma (IFNγ), two factors critical for T cell proliferation and function. We propose that coordination between splicing regulation and mRNA stability may provide a novel paradigm to control spatiotemporal gene expression during T cell activation.


Assuntos
Interferon gama/genética , Interleucina-2/genética , Proteínas/genética , Estabilidade de RNA/genética , Transcriptoma/genética , Processamento Alternativo/genética , Animais , Humanos , Íntrons/genética , Ativação Linfocitária/genética , Camundongos , NF-kappa B/genética , Ligação Proteica/genética , RNA Mensageiro/genética , Linfócitos T/metabolismo
9.
Virology ; 548: 117-123, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838932

RESUMO

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in immune evasion. While VSV has been thought to suppress the interferon (IFN) response primarily by inhibiting host cell transcription and translation, our recent findings indicate that the M protein also targets NF-κB activation. Therefore, the M protein may utilize two distinct mechanisms to limit expression of antiviral genes, inhibiting both host gene expression and NF-κB activation. Here we characterize a recently reported mutation in the M protein [M(D52G)] of VSV isolate 22-20, which suppressed IFN mRNA and protein production despite activating NF-κB. 22-20 inhibited reporter gene expression from multiple promoters, suggesting that 22-20 suppressed the IFN response via M-mediated inhibition of host cell transcription. We propose that suppression of the IFN response and regulation of NF-κB are independent, genetically separable functions of the VSV M protein.


Assuntos
Interferon beta/imunologia , NF-kappa B/imunologia , Estomatite Vesicular/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Proteínas da Matriz Viral/imunologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Interferon beta/genética , Camundongos , NF-kappa B/genética , Estomatite Vesicular/genética , Estomatite Vesicular/virologia , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/fisiologia , Proteínas da Matriz Viral/genética
10.
Virology ; 548: 31-38, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32838944

RESUMO

Entering the nucleus is important for Porcine circovirus type 2 (PCV2) replication. Karyopherins (KPNs) mediate the nuclear import of many cytoplasmic proteins. Our previous study showed that KPNA3 is involved in interferon production during PCV2 infection induced by Poly I:C and ISD (Interferon stimulatory DNA). However, it remains unclear whether PCV2 replication is associated with KPNA3. In the present study, knockdown of KPNA3 promoted the replication of PCV2, whereas overexpression of KPNA3 inhibited PCV2 replication in PK-15 cells. Furthermore, KPNA3 knockdown inhibited IRF3 and reduced the expression of antiviral genes including IFN-ß, ISG54, Mx1 and ISG56, while the opposite results were obtained after KPNA3 overexpression. KPNA3 knockdown also promoted p65 nuclear translocation and increased the mRNA expression of IL-10 and IL-1ß. These results suggested that KPNA3 facilitates IRF3 entry into the nucleus and the production of an antiviral response, resulting in PCV2 replication inhibition and blockage of NF-κB signal activation.


Assuntos
Núcleo Celular/metabolismo , Infecções por Circoviridae/veterinária , Circovirus/fisiologia , Doenças dos Suínos/metabolismo , alfa Carioferinas/metabolismo , Animais , Núcleo Celular/genética , Infecções por Circoviridae/genética , Infecções por Circoviridae/metabolismo , Infecções por Circoviridae/virologia , Circovirus/genética , Interações Hospedeiro-Patógeno , Interleucina-10/genética , Interleucina-10/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transporte Proteico , Transdução de Sinais , Suínos , Doenças dos Suínos/genética , Doenças dos Suínos/virologia , Replicação Viral , alfa Carioferinas/genética
12.
Adv Biol Regul ; 77: 100741, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773102

RESUMO

Pandemic coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and poses an unprecedented challenge to healthcare systems due to the lack of a vaccine and specific treatment options. Accordingly, there is an urgent need to understand precisely the pathogenic mechanisms underlying this multifaceted disease. There is increasing evidence that the immune system reacts insufficiently to SARS-CoV-2 and thus contributes to organ damage and to lethality. In this review, we suggest that the overwhelming production of reactive oxygen species (ROS) resulting in oxidative stress is a major cause of local or systemic tissue damage that leads to severe COVID-19. It increases the formation of neutrophil extracellular traps (NETs) and suppresses the adaptive arm of the immune system, i.e. T cells that are necessary to kill virus-infected cells. This creates a vicious cycle that prevents a specific immune response against SARS-CoV-2. The key role of oxidative stress in the pathogenesis of severe COVID-19 implies that therapeutic counterbalancing of ROS by antioxidants such as vitamin C or NAC and/or by antagonizing ROS production by cells of the mononuclear phagocyte system (MPS) and neutrophil granulocytes and/or by blocking of TNF-α can prevent COVID-19 from becoming severe. Controlled clinical trials and preclinical models of COVID-19 are needed to evaluate this hypothesis.


Assuntos
Antioxidantes/uso terapêutico , Infecções por Coronavirus/epidemiologia , Armadilhas Extracelulares/imunologia , Linfopenia/epidemiologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Acetilcisteína/uso terapêutico , Ácido Ascórbico/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfopenia/tratamento farmacológico , Linfopenia/imunologia , Linfopenia/virologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
13.
PLoS One ; 15(7): e0236928, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735610

RESUMO

The rabbit retinal vein occlusion (RVO) model is an experimental system that mimics retinal ischemic diseases in humans. The rabbit RVO model is widely used to assess the therapeutic efficacy of various experimental surgical procedures. In the present study, we measured temporal retinal expression of Vegfa, which is known as an ischemic response gene, in rabbit RVO. This analysis revealed that the retinal Vegfa transcriptional response began 7 days after generation of RVO, rather than immediately after induction of ischemia. Next, in order to analyze ischemia-induced changes in gene expression profiles, we performed microarray analysis of day 7 RVO retina versus control retina. The angiogenic regulators Dcn and Mmp1 and pro-inflammatory factors Mmp12 and Cxcl13 were significantly upregulated in RVO retinas. Further, we suggest that epigenetic regulation via the REST/cofactor-complex could contribute to RVO pathology. Among human homologous genes in rabbits, genes associated with hypoxia, angiogenesis, and inflammation were significantly upregulated in RVO retinas. Components of the Tumor necrosis factor-alpha (TNFα) and Nuclear factor-kappa B (NF-κB) pathways, which play regulatory roles in angiogenesis and inflammation, were significantly upregulated in RVO, and the expression levels of downstream factors, such as the transcription factor AP-1 and chemokines, were increased. Further, connectivity map analyses suggested that inhibitors of the NF-κB pathway are potential therapeutic agents for retinal ischemic disease. The present study revealed new insights into the pathology of retinal ischemia using the rabbit RVO model, which accurately recapitulates human disease.


Assuntos
Isquemia/metabolismo , Retina/patologia , Oclusão da Veia Retiniana , Indutores da Angiogênese/metabolismo , Animais , Quimiocinas/metabolismo , Conectoma , Modelos Animais de Doenças , Epigênese Genética , Angiofluoresceinografia , Regulação da Expressão Gênica , Hipóxia/metabolismo , Inflamação/metabolismo , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 12 da Matriz/genética , Metaloproteinase 12 da Matriz/metabolismo , Análise em Microsséries , NF-kappa B/genética , NF-kappa B/metabolismo , Coelhos , Oclusão da Veia Retiniana/genética , Oclusão da Veia Retiniana/metabolismo , Transcriptoma , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
J Pharmacol Sci ; 144(2): 69-75, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32713799

RESUMO

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.


Assuntos
Anti-Inflamatórios , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Fatores Imunológicos , Papaverina/farmacologia , Papaverina/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamação , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
15.
J Environ Radioact ; 220-221: 106292, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32658641

RESUMO

This study investigated the fluctuation of NF-KB and HIF-1a gene expression between inhabitants of a high-level background radiation area (HBRA) and a normal-level background radiation area (NBRA) of Ramsar, Iran. Sixty participants with the mean age of 48 ± 15 years were selected and divided into two groups. The group receiving a dose of ≤1.5 mGy/year (NBRA) was considered the control group and the target group (HBRA) received a dose of >1.5 mGy/year. These two groups were from neighbor regions to minimize socioeconomic differences between the participants. Blood samples were collected from each group and NF-KB and HIF-1a expression levels were compared using quantitative real-time PCR (qPCR) based on the stem loop method. The effects of residency duration in the respective areas and gender on the expression of NF-KB and HIF-1a was also examined. The HIF-1a expression level was statistically lower in the HLBRA region (P < 0.0002), while NF-KB expression was upregulated (P < 0.0001). Although the under-expression of HIF-1a in response to dose rate was significant in females (P < 0.0004), it was not different in males (P = 0.74), indicating a significant difference between sexes (P = 0.0047). The upregulation of NF-KB expression related to dose level was also significant for the female group (P < 0.0001), whereas it was not for the male group (P = 0.72). Notably and as expected, there was a significant relation between longer residency in the HBRA and HIF-1A under-expression (P < 0.026), while there was no effect of increasing residency time for NF-KB over-expression level (P = 0.29). The dwellers of the HBRA those noted that despite receiving an elevated radiation level were seemingly good in general health, showed some alterations in their molecular mechanisms, specifically HIF-1a and NF-KB expression levels. It is not clear if this is indicative of a beneficial adaptive response and more research is recommended.


Assuntos
Radiação de Fundo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , NF-kappa B/genética , Monitoramento de Radiação , Feminino , Humanos , Irã (Geográfico) , Masculino
16.
PLoS One ; 15(7): e0235717, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658905

RESUMO

Vernonia amygdalina (VA) has been reported to have antioxidant potential; however, its DNA protection and anti-inflammatory properties remain unclear. We aimed to investigate whether aqueous (WEVAL) and alcoholic (EEVAL) VA extracts exert similar antioxidant, DNA protection and anti-inflammatory effects and attempted to explore the mechanism underlying the anti-inflammatory effects. These results demonstrated that WEVAL had greater polyphenolic and flavonoid contents, as well as a stronger reducing power, DPPH radical scavenging and DNA protective activity. Moreover, both extracts reduced lipopolysaccharide (LPS)-induced expression of COX-II, iNOS, pro-inflammatory factors, including NO, TNF-α, IL-1ß, and IL-10. Compared with WEVAL, EEVAL was a more potent inflammatory inhibitor. Both extracts similarly inhibited LPS-induced MAPK (p38) and NF-κB expression. Our findings indicate that WEVAL and EEVAL have diverse antioxidant and anti-inflammatory effects. WEVAL had a stronger antioxidant and DNA protection activity; contrastingly, EEVAL had a stronger anti-inflammatory ability. The anti-inflammatory activity involves reduced pro-inflammatory cytokines through NF-κB down-regulation and MAPK inhibition. These results demonstrated that production of WEVAL and EEVAL from VA leaves may provide a safe and efficacious source of pharmaceutical applications, with antioxidant, DNA protective and anti-inflammation activities.


Assuntos
Antioxidantes/farmacologia , DNA/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Vernonia/química , Proliferação de Células , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Flavonoides/farmacologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais
17.
PLoS One ; 15(7): e0235295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687504

RESUMO

Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/- provides a new model to study atopic dermatitis.


Assuntos
Dermatite Atópica/genética , Inflamação/genética , Queratina-14/genética , Proteínas do Tecido Nervoso/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Animais , Apoptose/genética , Artrite/genética , Artrite/patologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Imunoglobulina E/genética , Inflamação/patologia , Integrases/genética , Interleucina-18/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , NF-kappa B/genética , Fenótipo , Transdução de Sinais
18.
Nat Rev Immunol ; 20(9): 515-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32728221

Assuntos
Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Pulmão/imunologia , Neutrófilos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Acetilcisteína/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/genética , Citocinas/imunologia , Quimioterapia Combinada , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Regulação da Expressão Gênica , Glicina/análogos & derivados , Glicina/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/virologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Neutrófilos/imunologia , Neutrófilos/virologia , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Secretadas Inibidoras de Proteinases/uso terapêutico , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Sulfonamidas/uso terapêutico , Superóxido Dismutase/genética , Superóxido Dismutase/imunologia
19.
J Vet Sci ; 21(3): e50, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32476323

RESUMO

BACKGROUND: Porcine parvovirus (PPV) is a single-stranded DNA virus that causes porcine reproductive failure. It is of critical importance to study PPV pathogenesis for the prevention and control of the disease. NS1, a PPV non-structural protein, is participated in viral DNA replication, transcriptional regulation, and cytotoxicity. Our previous research showed that PPV can activate nuclear factor kappa B (NF-κB) signaling pathway and then up-regulate the expression of interleukin (IL)-6. OBJECTIVES: Herein, the purpose of this study is to determine whether the non-structural protein NS1 of PPV also has the same function. METHODS: Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay, western blot, immunofluorescence assay and small interfering RNA (siRNA) were used. RESULTS: Our findings demonstrated that PPV NS1 protein can up-regulate the expression levels of IL-6 and tumor necrosis factor-alpha in a dose-dependent manner. Moreover, PPV NS1 protein was found to induce the phosphorylation of IκBα, then leading to the phosphorylation and nuclear translocation of NF-κB. In addition, the NS1 protein activated the upstream pathways of NF-κB. Meanwhile, TLR2-siRNA assay showed TLR2 plays an important role in the activation of NF-κB signaling pathway induced by PPV-NS1. CONCLUSIONS: These findings indicated that PPV NS1 protein induced the up-regulated of IL-6 expression through activating the TLR2 and NF-κB signaling pathways. In conclusion, these findings provide a new avenue to study the innate immune mechanism of PPV infection.


Assuntos
NF-kappa B/metabolismo , Infecções por Parvoviridae/veterinária , Parvovirus Suíno/fisiologia , Transdução de Sinais , Doenças dos Suínos/genética , Receptor 2 Toll-Like/metabolismo , Proteínas não Estruturais Virais/genética , Animais , Regulação da Expressão Gênica/imunologia , NF-kappa B/genética , Infecções por Parvoviridae/genética , Infecções por Parvoviridae/metabolismo , Parvovirus Suíno/genética , Suínos , Doenças dos Suínos/metabolismo , Receptor 2 Toll-Like/genética , Proteínas não Estruturais Virais/metabolismo
20.
PLoS Pathog ; 16(6): e1008538, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32544190

RESUMO

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.


Assuntos
Síndrome de Guillain-Barré , Proteínas Nucleares/antagonistas & inibidores , Peptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Infecção por Zika virus , Zika virus/metabolismo , Animais , Linhagem Celular , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/genética , Síndrome de Guillain-Barré/metabolismo , Síndrome de Guillain-Barré/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transdução de Sinais/genética , Trofoblastos/metabolismo , Trofoblastos/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Zika virus/genética , Infecção por Zika virus/tratamento farmacológico , Infecção por Zika virus/genética , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia
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