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1.
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
2.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: covidwho-813983

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.
Mol Cell ; 80(1): 164-174.e4, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877642

RESUMO

SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Fosfatidilinositol 3-Quinase/genética , Receptores de Fatores de Crescimento/genética , Proteínas Virais/genética , Corticosteroides/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Células CACO-2 , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
4.
Mol Cell ; 80(1): 164-174.e4, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: covidwho-709380

RESUMO

SARS-CoV-2 infections are rapidly spreading around the globe. The rapid development of therapies is of major importance. However, our lack of understanding of the molecular processes and host cell signaling events underlying SARS-CoV-2 infection hinders therapy development. We use a SARS-CoV-2 infection system in permissible human cells to study signaling changes by phosphoproteomics. We identify viral protein phosphorylation and define phosphorylation-driven host cell signaling changes upon infection. Growth factor receptor (GFR) signaling and downstream pathways are activated. Drug-protein network analyses revealed GFR signaling as key pathways targetable by approved drugs. The inhibition of GFR downstream signaling by five compounds prevents SARS-CoV-2 replication in cells, assessed by cytopathic effect, viral dsRNA production, and viral RNA release into the supernatant. This study describes host cell signaling events upon SARS-CoV-2 infection and reveals GFR signaling as a central pathway essential for SARS-CoV-2 replication. It provides novel strategies for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Fosfatidilinositol 3-Quinase/genética , Receptores de Fatores de Crescimento/genética , Proteínas Virais/genética , Corticosteroides/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Células CACO-2 , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Receptores de Fatores de Crescimento/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
5.
Nature ; 584(7820): 252-256, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760004

RESUMO

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin4-6, which regulate aspects of social behaviour in mammals7. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions.


Assuntos
Transtorno Autístico/metabolismo , Transtorno Autístico/psicologia , Modelos Animais de Doenças , Ocitocina/metabolismo , Comportamento Social , Animais , Moléculas de Adesão Celular Neuronais/deficiência , Moléculas de Adesão Celular Neuronais/genética , Fator de Iniciação 4E em Eucariotos/metabolismo , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos
6.
PLoS One ; 15(8): e0236727, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750068

RESUMO

Low-power laser irradiation (LPLI) is clinically used to modulate inflammation, proliferation and apoptosis. However, its molecular mechanisms are still not fully understood. This study aimed to describe the effects of LPLI upon inflammatory, apoptotic and proliferation markers in submandibular salivary glands (SMGs) in an experimental model of chronic disorder, 24h after one time irradiation. Diabetes was induced in rats by the injection of streptozotocin. After 29 days, these animals were treated with LPLI in the SMG area, and euthanized 24h after this irradiation. Treatment with LPLI significantly decreased diabetes-induced high mobility group box 1 (HMGB1) and tumor necrosis factor alpha (TNF-α) expression, while enhancing the activation of the transcriptional factor cAMP response element binding (CREB) protein. LPLI also reduced the expression of bax, a mitochondrial apoptotic marker, favoring the cell survival. These findings suggest that LPLI can hamper the state of chronic inflammation and favor homeostasis in diabetic rats SMGs.


Assuntos
Diabetes Mellitus Experimental/radioterapia , Terapia com Luz de Baixa Intensidade , Transdução de Sinais/efeitos da radiação , Glândula Submandibular/efeitos da radiação , Animais , Apoptose , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
7.
Gene ; 760: 145003, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739587

RESUMO

Imiquimod (IMQ) is approved as a first-line treatment for genital warts caused by human papillomavirus (HPV) infection. However, the recurrence rate is very high. HPV E7 protein plays a critical role in HPV immune escape. However, the role of HPV11 E7 protein in genital warts recurrence during IMQ treatment is not clear. Here, we found that the expression profile of NHEK cells was obviously changed after IMQ treatment, and a large number of genes encoding cytokines and genes involved in cytokine-mediated signaling pathways and cellular metabolic signaling pathways were up- or downregulated. HPV11E7 overexpression inhibited the IMQ-induced production of of multiple chemokines and colony-stimulating factors in NHEK cells. Furthermore, we found that HPV11E7 could impair the activation of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, our results suggested that HPV11 E7 diminishes the production of chemokines, colony-stimulating factors and other cytokines via inhibition of the MAPK signaling pathway, which suppresses the therapeutic effect of IMQ and promotes the recurrence of diseases, such as condyloma acuminatum.


Assuntos
Imiquimode/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas/metabolismo , Fatores Estimuladores de Colônias/biossíntese , Fatores Estimuladores de Colônias/metabolismo , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Papillomavirus Humano 11/metabolismo , Humanos , Imiquimode/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
8.
PLoS One ; 15(8): e0237540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804965

RESUMO

The yeast MAP kinase Hog1 pathway activates transcription of several hundreds genes. Large-scale gene expression and DNA binding assays suggest that most Hog1-induced genes are regulated by the transcriptional activators Msn2/4, Hot1 and Sko1. These studies also revealed the target genes of each activator and the putative binding sites on their promoters. In a previous study we identified a group of genes, which we considered the bona fide targets of Hog1, because they were induced in response to expression of intrinsically active mutant of Hog1, in the absence of any stress. We previously analyzed the promoter of the most highly induced gene, STL1, and noticed that some promoter properties were different from those proposed by large-scale data. We therefore continue to study promoters individually and present here analyses of promoters of more Hog1's targets, RTC3, HSP12, DAK1 and ALD3. We report that RTC3 and HSP12 promoters are robust and are induced, to different degrees, even in cells lacking all four activators. DAK1 and ALD3 promoters are not robust and fully depend on a single activator, DAK1 on Sko1 and ALD3 on Msn2/4. Most of these observations could not be inferred from the large-scale data. Msn2/4 are involved in regulating all four promoters. It was assumed, therefore, that the promoters are spontaneously active in ras2Δ cells, in which Msn2/4 are known to be de-repressed. Intriguingly, the promoters were not active in BY4741ras2Δ cells, but were de-repressed, as expected, in ras2Δ cells of other genetic backgrounds. This study describes two phenomena. One, some Hog1's target promoters are most robust, backupped by many activators. Second, in contrast to most laboratory strains, the widely used BY4741 strain does not induce Msn2/4 activity when the Ras/cAMP cascade is downregulated.


Assuntos
Proteínas de Choque Térmico/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Fatores de Transcrição de Zíper de Leucina Básica/genética , Sítios de Ligação , Proteínas de Ligação a DNA/genética , Regulação Fúngica da Expressão Gênica , Proteínas de Choque Térmico/química , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/genética
9.
Chemosphere ; 255: 126999, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679628

RESUMO

Currently there are few reports on the combined immunotoxicity of zearaleone (ZEA) and deoxynivalenol (DON). Since the two coexist naturally, it is necessary to understand the immunotoxicity caused by the two mycotoxins alone and in combination. To examine T lymphocytes activation and immune effect during activation, we used mouse primary spleen T lymphocytes as the experimental material and concanavalin (Con A) as the stimulator. The effects of ZEA, DON, and their combined exposure on T lymphocytes immune related function and the relationship between the activation of the mitogen-activated protein kinase (MAPK) signaling pathway and mycotoxin induced T lymphocytes apoptosis were studied in vitro. Specifically, T lymphocytes were isolated from primary mouse splenic lymphocytes, activated by Con A and then exposed to different concentrations of ZEA, DON, and their combinations. Our results showed that ZEA and DON alone and their combinations (20:1) can decrease the cell viability of T lymphocytes activated by Con A. The inhibitory effect of the combined groups was greater than that of the single mycotoxins, showing a synergistic effect. In addition, single or combined mycotoxins can lead to intracellular and surface ultrastructure damage of T lymphocytes, inhibit the expression of CD25 and CD278 and inhibit the synthesis of effect molecules poreforming protein (PFP), granzyme A (GZMA), and tumor necrosis factor-α (TNF-α). Meanwhile, the single mycotoxin or combined mycotoxins can promote the apoptosis of T lymphocytes which was accompanied by the overactivation of MAPK. After using the inhibitors of extracellular regulated protein kinases (ERK) and c-Jun N-terminal kinase (JNK) in the MAPK pathway, we found that the apoptosis of the cells induced by the ZEA was significantly decreased, and the apoptosis of the cells induced by DON had no significant changes. This suggests that the activation of MAPK induced by ZEA can promote the apoptosis of T lymphocytes, but the activation of MAPK induced by DON is not directly related to T cell apoptosis.


Assuntos
Imunotoxinas/toxicidade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Tricotecenos/toxicidade , Zearalenona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2 , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Micotoxinas/toxicidade , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa
10.
Nat Commun ; 11(1): 3494, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661402

RESUMO

Cellular processes are inherently noisy, and the selection for accurate responses in presence of noise has likely shaped signalling networks. Here, we investigate the trade-off between accuracy of information transmission and its energetic cost for a mitogen-activated protein kinase (MAPK) signalling cascade. Our analysis of the pheromone response pathway of budding yeast suggests that dose-dependent induction of the negative transcriptional feedbacks in this network maximizes the information per unit energetic cost, rather than the information transmission capacity itself. We further demonstrate that futile cycling of MAPK phosphorylation and dephosphorylation has a measurable effect on growth fitness, with energy dissipation within the signalling cascade thus likely being subject to evolutionary selection. Considering optimization of accuracy versus the energetic cost of information processing, a concept well established in physics and engineering, may thus offer a general framework to understand the regulatory design of cellular signalling systems.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Animais , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas Tirosina Fosfatases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/genética , Saccharomycetales/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
11.
Am J Chin Med ; 48(5): 1103-1120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668965

RESUMO

Centella asiatica (L.) Urb. (C. asiatica) has been widely treated for inflammation-related diseases in China for thousands of years. While C. asiatica showed relevant effects as traditional medicine, the mechanism of C. asiatica suppressing inflammation has not been thoroughly investigated. Therefore, this study was conducted to reveal the anti-inflammatory mechanism of methanol fraction from C. asiatica (MCA) at the molecular level in murine macrophages. Levels of inflammation-related mediators were observed with treatment of MCA. MCA significantly suppressed nitric oxide production and iNOS expression in RAW 264.7 macrophages. Prostaglandin E2 production was alleviated by MCA via the downregulation of cyclooxygenase-2. MCA treatment also reduced pro-inflammatory tumor necrosis factor-[Formula: see text] and interleukin (IL)-6 levels. LPS/D-GalN-induced acute hepatitis in mouse was alleviated by MCA treatment. In addition, MCA decreased the phosphorylation of inhibitory [Formula: see text]B[Formula: see text] (I[Formula: see text]B[Formula: see text]) at Ser32/36 and thereby blocked I[Formula: see text]B[Formula: see text] degradation. TXY motif phosphorylation in the activation loops of mitogen-activated protein kinases (MAPKs) was also suppressed by MCA treatment. Further investigation revealed that MCA inhibited transforming growth factor-[Formula: see text]-activated kinase 1 (TAK1) phosphorylation and IL-1 receptor-associated kinase (IRAK1) degradation, the upstream kinases activating nuclear factor [Formula: see text]B and MAPKs. Taken together, MCA exhibited anti-inflammatory properties via the downregulation of IRAK1-TAK1 signaling pathways.


Assuntos
Anti-Inflamatórios , Centella/química , Regulação para Baixo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/metabolismo , Animais , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Células RAW 264.7
12.
Am J Chin Med ; 48(5): 1121-1140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668966

RESUMO

Achillea millefolium L. (AM) is an aromatic herb with a variety of pharmacological properties, such as anti-inflammatory and anti-allergic activities. However, AM's effects on atopic dermatitis (AD) have not been investigated. This study evaluates the anti-AD activity of 50% ethanol-extracted AM in murine macrophage Raw 264.7 cells, in tumor necrosis factor-alpha/interferon-gamma (TNF-[Formula: see text]/IFN-[Formula: see text])-stimulated human immortal keratinocyte HaCaT cells in vitro, and in Biostir-AD-treated NC/Nga mice in vivo. The results showed that AM significantly downregulated expression of pro-inflammatory cytokines, such as INOS, COX-2, and interleukin (IL)-6 in lipopolysaccharide (LPS)-treated Raw 264.7 cells. The mRNA expressions of INOS, COX-2, and IL-6 decreased by 76.1%, 69.3%, and 31.8%, respectively. Overexpression of chemokines, such as activation-regulated chemokine and macrophage-derived chemokine, regulated on activation of normal T-cell expressed and secreted, and IL-8 was inhibited by 70.01%, 52.91%, 73.53%, and 18.93%, respectively, in TNF-[Formula: see text]/IFN-[Formula: see text]-stimulated HaCaT cells by downregulating the mitogen-activated protein kinase, I[Formula: see text]B[Formula: see text], and the signal transducer and activator of transcription 1 signaling pathways. AD-like symptoms, such as elevated serum immunoglobin E levels, epidermal thickening, high dermatitis severity score, transepidermal water loss, and reduced skin hydration, were relieved by the dietary administration of AM in Biostir-AD-treated NC/Nga mice. In addition, filaggrin expression increased significantly in AM-treated groups. These results suggest that AM could be a useful candidate for AD treatment.


Assuntos
Achillea/química , Anti-Inflamatórios , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
13.
Mol Immunol ; 125: 15-22, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619930

RESUMO

PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.


Assuntos
Células Epiteliais Alveolares/metabolismo , Caderinas/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Células A549 , Células Epiteliais Alveolares/patologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
14.
Life Sci ; 258: 118139, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32721463

RESUMO

AIMS: Atopic dermatitis is a chronic inflammatory disease characterized by eczematous lesions and has become a serious health problem worldwide. Pseudoephedrine (PSE) is a nasal decongestant to treat the common cold. PSE has been reported that is beneficial to allergic diseases. However, whether PSE has the potential in atopic dermatitis remains to be elucidated. MAIN METHODS: Male BALB/c mice were challenged with 2,4-dinitrochlorobenzene (DNCB) to induce atopic dermatitis-like lesion and orally administrated with PSE for two weeks. The skin hydration and the scratching behavior were detected. The skin lesions and histopathological changes were evaluated and inflammatory factors levels were detected. Human Keratinocytes (HaCaT cells) were stimulated by TNF-α/IFN-γ after PSE-pretreatment. The transcriptions of inflammatory factors were detected. KEY FINDINGS: PSE decreased skin lesion area and skin thickness in atopic dermatitis mice. PSE improved skin hydration and scratching. Histologically, PSE reduced mast cell and CD4+ cell infiltration. PSE suppressed serum TNF-α and IgE levels, reducing cytokines (IL-1ß, IL-4, IL-6, IL-13, IL-33, TSLP, and IL-23) and neutrophil migration factors (CCL2 and MMP-9) in skin tissues. In addition, PSE inhibited TNF-α/IFN-γ-induced release of inflammatory factors (TNF-α, IL-1ß, and IL-23) in HaCaT cells. Furthermore, PSE suppressed the activation of MAPKs and NF-κB signaling pathways in vivo and in vitro. SIGNIFICANCE: These results demonstrate that PSE could inhibit inflammatory responses in atopic dermatitis models. PSE may serve as a viable alternatives drug for the treatment of atopic dermatitis.


Assuntos
Dermatite Atópica/tratamento farmacológico , Inflamação/tratamento farmacológico , Pseudoefedrina/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Dermatite Atópica/sangue , Dermatite Atópica/enzimologia , Dermatite Atópica/patologia , Humanos , Imunoglobulina E/sangue , Inflamação/sangue , Inflamação/patologia , Interferon gama/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Pseudoefedrina/química , Pseudoefedrina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/farmacologia
15.
Nat Commun ; 11(1): 3171, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576833

RESUMO

Precise regulation of gene expression in response to environmental changes is crucial for cell survival, adaptation and proliferation. In eukaryotic cells, extracellular signal integration is often carried out by Mitogen-Activated Protein Kinases (MAPK). Despite a robust MAPK signaling activity, downstream gene expression can display a great variability between single cells. Using a live mRNA reporter, here we monitor the dynamics of transcription in Saccharomyces cerevisiae upon hyper-osmotic shock. We find that the transient activity of the MAPK Hog1 opens a temporal window where stress-response genes can be activated. We show that the first minutes of Hog1 activity are essential to control the activation of a promoter. Chromatin repression on a locus slows down this transition and contributes to the variability in gene expression, while binding of transcription factors increases the level of transcription. However, soon after Hog1 activity peaks, negative regulators promote chromatin closure of the locus and transcription progressively stops.


Assuntos
Cromatina/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Regulação Fúngica da Expressão Gênica , Pressão Osmótica/fisiologia , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais
16.
Ecotoxicol Environ Saf ; 201: 110806, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512418

RESUMO

The present study investigated the expressions of signalling molecules and inflammatory cytokines involved in copper-induced inflammatory responses of the mouse liver. A total of 240 institute of cancer research (ICR) mice (half male and half female) aged four weeks were randomly allocated to four groups treated with 0, 4, 8, and 16 mg/kg of [Cu] (Cu2+-CuSO4) for 42 days, respectively. [Cu] exceeding 4 mg/kg was found to induce inflammatory responses of the liver. Results showed significant up-regulation of mRNA and protein levels of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinases 3/6 (MEK3/6), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK), mitogen-activated protein kinase kinases 4/7 (MEK4/7), mitogen-activated protein kinase kinases 1/2 (MEK1/2), and extracellular signal-regulated protein kinases 1/2 (Erk1/2) due to Cu. By doing so, copper could activate the mitogen-activated protein kinases (MAPKs) signalling pathway. Concurrently, the nuclear factor-kappa B (NF-κB) signalling pathway was also activated in the Cu-treatment, as demonstrated by higher expressions of NF-κB and cyclooxygenase-2 (COX-2), activities of inducible nitric oxide synthase (iNOS), contents of nitric oxide (NO) and prostaglandin E2 (PGE2), and reducing levels of expression of inhibitory kappa B (IκB). High Cu intake also up-regulated expression levels of some pro-inflammatory mediators such as interleukin-2 (IL-2), interleukin-1ß (IL-1ß), and interleukin-8 (IL-8), and down-regulated the levels of expression of transforming growth factor beta (TGF-ß), an anti-inflammatory mediator. Additionally, our results indicated that Cu caused hepatic dysfunction, with evidence of occurrence of histopathological lesions and higher serum activities of alkaline phosphatase (AKP), aspartic acid transferase (AST), alanine amino transferase (ALT), and gamma-glutamyl transpeptidase (GGT), contents of albumin (ALB) and total bilirubin (TBIL). Altogether, the aforementioned results indicate that [Cu], at more than 4 mg/kg, induces the inflammatory responses in the liver via NF-κB and MAPKs signalling pathways, subsequently inducing hepatic dysfunction.


Assuntos
Cobre/toxicidade , Interleucina-1beta/metabolismo , Interleucina-2/metabolismo , Fígado/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Feminino , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos ICR , Distribuição Aleatória , Transdução de Sinais
17.
Nat Commun ; 11(1): 3003, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532972

RESUMO

The arms race between entomopathogenic bacteria and their insect hosts is an excellent model for decoding the intricate coevolutionary processes of host-pathogen interaction. Here, we demonstrate that the MAPK signaling pathway is a general switch to trans-regulate differential expression of aminopeptidase N and other midgut genes in an insect host, diamondback moth (Plutella xylostella), thereby countering the virulence effect of Bacillus thuringiensis (Bt) toxins. Moreover, the MAPK cascade is activated and fine-tuned by the crosstalk between two major insect hormones, 20-hydroxyecdysone (20E) and juvenile hormone (JH) to elicit an important physiological response (i.e. Bt resistance) without incurring the significant fitness costs often associated with pathogen resistance. Hormones are well known to orchestrate physiological trade-offs in a wide variety of organisms, and our work decodes a hitherto undescribed function of these classic hormones and suggests that hormonal signaling plasticity is a general cross-kingdom strategy to fend off pathogens.


Assuntos
Bacillus thuringiensis/metabolismo , Toxinas Bacterianas/metabolismo , Hormônios de Inseto/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mariposas/metabolismo , Transdução de Sinais , Animais , Bacillus thuringiensis/fisiologia , Proteínas de Bactérias/metabolismo , Antígenos CD13/classificação , Antígenos CD13/genética , Antígenos CD13/metabolismo , Endotoxinas/metabolismo , Regulação da Expressão Gênica , Proteínas Hemolisinas/metabolismo , Interações Hospedeiro-Patógeno , Proteínas de Insetos/classificação , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Resistência a Inseticidas/genética , Mariposas/genética , Mariposas/microbiologia , Filogenia , Células Sf9 , Spodoptera
18.
Proc Natl Acad Sci U S A ; 117(27): 15846-15851, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32561648

RESUMO

Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells' apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.


Assuntos
Apoptose/efeitos dos fármacos , Mutação , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/efeitos dos fármacos , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Animais , Morte Celular , Linhagem Celular Tumoral , Neoplasias do Colo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Imidazóis/farmacologia , Melanoma/genética , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oximas/farmacologia , Piridonas/farmacologia , Pirimidinonas/farmacologia , Neoplasias da Glândula Tireoide/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Environ Pathol Toxicol Oncol ; 39(1): 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479014

RESUMO

Helicobacter pylori causes a Gram-negative bacterial infection that can increase the risk of gastric cancer. Consequently, meticulous prevention of an H. pylori infection is significant for averting gastric cancer in humans. Nobiletin, an important dietary polymethoxylated flavonoid in citrus fruits, possesses multidimensional pharmaceutical properties, including its ability to act as an anticancer, anti-inflammatory, antioxidative, cardiovascularly defensive, neuroprotective, and antimetabolic agent. Our study evaluates the role of nobiletin in inflammation-mediated gastric carcinogenic signaling of H. pylori-arbitrated coculture in the human gastric epithelial (GES)-1 cell line. Our results show that the culture system of H. pylori-tainted GES-1 cells demonstrates maximum fabrication of reactive oxygen species (ROS), mediating DNA injury and augmenting nuclear fragmentations. Treatment with nobiletin reduces ROS levels and apoptotic morphological changes by dual staining and decreases levels of lipid peroxides and glutathione content in H. pylori-infected GES-1 cells. Phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/phosphatase and tensin homolog signaling have been implicated to affect cell endurance, inflammation, proliferation, and carcinogenic activity in gastric GES-1 cells. We find that nobiletin strongly impedes tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, PI3K, AKT, and mitogen-activated protein kinase molecules, including p38, extracellular receptor kinase 1, and c-Jun amino-terminal expression in H. pylori-infected GES-1 cells. We conclude that nobiletin potentially impedes H. pylori infection and its related activation, likely preventing H. pylori infection-mediated gastric cancer.


Assuntos
Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Flavonas/farmacologia , Infecções por Helicobacter/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Inflamação/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/microbiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-32353676

RESUMO

Peppermint (Mentha × piperita L.) is a flavoring additive used worldwide, and Trichoderma species are beneficial fungi that can stimulate growth and disease resistance of these plants. Here the growth conditions and metabolic processes of essential oil (EO) biosynthesis in response to inoculation with Trichoderma viride Tv-1511 were investigated. The results showed that T. viride Tv-1511 was able to colonize roots of peppermint to promote its growth and photosynthetic activity and induce higher levels of glandular trichomes and elevated EO yield and composition. GC-MS analysis showed that T. viride Tv-1511-inoculated peppermint produced higher concentrations of menthone, menthol, and pulegone and lower concentrations of menthofuran than un-inoculated seedlings, and qRT-PCR showed that T. viride Tv-1511 inoculation induced upregulation of Pr (pulegone reductase encoding gene) and Mr (menthone reductase encoding gene), whereas it led to the downregulation of Mfs (menthofuran synthase encoding gene). Furthermore, a mitogen-activated protein kinase (MAPK) in peppermint, which was determined to be an analog of Arabidopsis MPK6 protein, was found to be responsible for the modulation of EO metabolism at the transcriptional level and for enzymatic activation in the T. viride Tv-1511-inoculated peppermint. Notably, NADPH oxidase-dependent reactive oxygen species (ROS) production played vital roles in the root colonization of T. viride Tv-1511 and was also involved in the induction of MAPK activation. These data showed the beneficial effects of T. viride Tv-1511 on the seedling growth and EO yield of peppermint, and they elucidated that T. viride Tv-1511 improved the quantity and quality of EOs by regulating the genes that encode the enzymes involved in EO metabolism through a potential MAPK-mediated signaling pathways.


Assuntos
Mentha piperita , Proteínas Quinases Ativadas por Mitógeno , Óleos Voláteis , Espécies Reativas de Oxigênio , Trichoderma , Ativação Enzimática , Mentha piperita/enzimologia , Mentha piperita/microbiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Óleos Voláteis/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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