Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Med Virol ; 96(3): e29504, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38445794

RESUMO

While most NOD-like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV-68), establish latent infection in B lymphocytes, which requires elevated NF-κB. This study shows that during latent EBV infection of human B cells, viral-encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1-induced-NF-κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF-κB activation by promoting the degradation of LMP1 in a proteasome-dependent manner. In vivo, MHV-68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3-deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis.


Assuntos
Infecções por Vírus Epstein-Barr , Latência Viral , Animais , Humanos , Camundongos , Herpesvirus Humano 4/genética , NF-kappa B , Linfócitos B , Peptídeos e Proteínas de Sinalização Intercelular
2.
Int J Pharm Pract ; 27(6): 501-509, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31140669

RESUMO

OBJECTIVES: To identify factors influencing Australian consumer decision-making and attitudes towards non-prescription medicine (NPM) purchases, pharmacy's role in providing these medications and views around sources of evidence for effectiveness of these products. METHODS: Cross-sectional survey of a general population sample of 1731 adults using an Australian online consumer panel stratified by gender, age and location (State/Territory). Beliefs about NPM purchases and evidence of their efficacy were assessed using a 5-point Likert scale (strongly disagree-strongly agree). Non-parametric measures (Ridit analysis and Mann-Whitney U-test) were used to explore associations between responses and previous experience with medicines. KEY FINDINGS: The most important factors when purchasing NPMs were effectiveness and safety. However, personal experience was the most common method of determining effectiveness. Most respondents believed buying NPMs in pharmacies gave access to advice, but were less likely to agree that pharmacies were associated with safe and effective treatments. Around half the respondents agreed that it is wrong to sell treatments lacking scientific evidence; many also agreed that it is up to consumers to decide what they want even without scientific evidence. Individuals experiencing an ineffective NPM were less likely to trust scientific evidence of efficacy as the sole source of effectiveness information; regular prescription medicine users often agreed that scientific evidence is needed to support effectiveness. CONCLUSIONS: Consumers have conflicting views regarding the need for scientific evidence and the desire for patient autonomy in NPM purchases. This presents a challenge for pharmacists wishing to maintain professional obligations to provide evidence-based treatments to consumers.


Assuntos
Comportamento de Escolha , Comportamento do Consumidor/estatística & dados numéricos , Medicamentos sem Prescrição/administração & dosagem , Farmacêuticos/organização & administração , Adulto , Austrália , Estudos Transversais , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Farmacêutica/organização & administração , Inquéritos e Questionários , Adulto Jovem
3.
J Microbiol ; 56(9): 683-689, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30141161

RESUMO

Human noroviruses are the causative agents of non-bacterial gastroenteritis worldwide. The rapid onset and resolution of disease symptoms suggest that innate immune responses are critical for controlling norovirus infection; however, no effective antivirals are yet available. The present study was conducted to examine the antiviral activities of Schizonepeta tenuifolia Briquet extract (STE) against noroviruses. Treatment of human norovirus replicon-bearing HG23 cells with STE at 5 and 10 mg/ml concentrations resulted in the reduction in the viral RNA levels by 77.2% and 85.9%, respectively. STE had no cytotoxic effects on HG23 cells. Treatment of RAW 264.7 cells infected with murine norovirus 1 (MNV-1), a surrogate virus of human noroviruses, with STE at 10 and 20 µg/ml concentrations resulted in the reduction of viral replication by 58.5% and 84.9%, respectively. STE treatment induced the expression of mRNAs for type I and type II interferons in HG23 cells and upregulated the transcription of interferon-ß in infected RAW 264.7 cells via increased phosphorylation of interferon regulatory factor 3, a critical transcription regulator for type I interferon production. These results suggest that STE inhibits norovirus replication through the induction of antiviral interferon production during virus replication and may serve as a candidate antiviral substance for treatment against noroviruses.


Assuntos
Antivirais/farmacologia , Infecções por Caliciviridae/tratamento farmacológico , Interferons/metabolismo , Lamiaceae/química , Norovirus/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Infecções por Caliciviridae/virologia , Linhagem Celular/efeitos dos fármacos , Monoterpenos Cicloexânicos , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Mentol/farmacologia , Camundongos , Monoterpenos/farmacologia , Norovirus/patogenicidade , Vírus Norwalk , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Sesquiterpenos Policíclicos , Células RAW 264.7 , RNA Viral , Sesquiterpenos/farmacologia , Replicação Viral/efeitos dos fármacos
4.
Nucleic Acids Res ; 46(17): 9011-9026, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30137501

RESUMO

DExD/H-box helicase 9 (DHX9), or RNA helicase A (RHA), is an abundant multifunctional nuclear protein. Although it was previously reported to act as a cytosolic DNA sensor in plasmacytoid dendritic cells (pDCs), the role and molecular mechanisms of action of DHX9 in cells that are not pDCs during DNA virus infection are not clear. Here, a macrophage-specific knockout and a fibroblast-specific knockdown of DHX9 impaired antiviral innate immunity against DNA viruses, leading to increased virus replication. DHX9 enhanced NF-κB-mediated transactivation in the nucleus, which required its ATPase-dependent helicase (ATPase/helicase) domain, but not the cytosolic DNA-sensing domain. In addition, DNA virus infection did not induce cytoplasmic translocation of nuclear DHX9 in macrophages and fibroblasts. Nuclear DHX9 was associated with a multiprotein complex including both NF-κB p65 and RNA polymerase II (RNAPII) in chromatin containing NF-κB-binding sites. DHX9 was essential for the recruitment of RNAPII rather than NF-κB p65, to the corresponding promoters; this function also required its ATPase/helicase activity. Taken together, our results show a critical role of nuclear DHX9 (as a transcription coactivator) in the stimulation of NF-κB-mediated innate immunity against DNA virus infection, independently of DHX9's DNA-sensing function.


Assuntos
RNA Helicases DEAD-box/genética , DNA Viral/genética , Interações Hospedeiro-Patógeno/genética , Imunidade Inata , NF-kappa B/genética , RNA Polimerase II/genética , Animais , Chlorocebus aethiops , RNA Helicases DEAD-box/deficiência , RNA Helicases DEAD-box/imunologia , DNA Viral/imunologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Feminino , Gammaherpesvirinae/genética , Gammaherpesvirinae/crescimento & desenvolvimento , Gammaherpesvirinae/imunologia , Regulação da Expressão Gênica , Células HEK293 , Células HeLa , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Macrófagos/imunologia , Macrófagos/virologia , Masculino , Camundongos , Camundongos Transgênicos , Células-Tronco Embrionárias Murinas/imunologia , Células-Tronco Embrionárias Murinas/virologia , NF-kappa B/imunologia , Células NIH 3T3 , Cultura Primária de Células , RNA Polimerase II/imunologia , Transdução de Sinais , Células Vero , Replicação Viral
5.
Exp Mol Med ; 44(6): 378-86, 2012 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-22391335

RESUMO

12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid (12- HHT) is an enzymatic product of prostaglandin H(2) (PGH(2)) derived from cyclooxygenase (COX)-mediated arachidonic acid metabolism. Despite the high level of 12-HHT present in tissues and bodily fluids, its precise function remains largely unknown. In this study, we found that 12-HHT treatment in HaCaT cells remarkably down-regulated the ultraviolet B (UVB) irradiation-induced synthesis of interleukin-6 (IL-6), a pro-inflammatory cytokine associated with cutaneous inflammation. In an approach to identify the down-stream signaling mechanism by which 12-HHT down-regulates UVB-induced IL-6 synthesis in keratinocytes, we observed that 12-HHT inhibits the UVB-stimulated activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB). In addition, we found that 12-HHT markedly up-regulates MAPK phosphatase-1 (MKP-1), a critical negative regulator of p38 MAPK. When MKP-1 was suppressed by siRNA knock-down, the 12-HHT-mediated inhibitory effects on the UVB-stimulated activation of p38 MAPK and NF-κB, as well as the production of IL-6, were attenuated in HaCaT cells. Taken together, our results suggest that 12-HHT exerts anti-inflammatory effect via up-regulation of MKP-1, which negatively regulates p38 MAPK and NF-κB, thus attenuating IL-6 production in UVB-irradiated HaCaT cells. Considering the critical role of IL-6 in cutaneous inflammation, our findings provide the basis for the application of 12-HHT as a potential anti-inflammatory therapeutic agent in UV-induced skin diseases.


Assuntos
Ácidos Graxos Insaturados/farmacologia , Interleucina-6/biossíntese , Queratinócitos/metabolismo , Raios Ultravioleta , Anti-Inflamatórios não Esteroides/farmacologia , Linhagem Celular , Fosfatase 1 de Especificidade Dupla/biossíntese , Fosfatase 1 de Especificidade Dupla/genética , Ativação Enzimática , Humanos , Queratinócitos/efeitos da radiação , NF-kappa B/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptores do Leucotrieno B4/genética , Transdução de Sinais/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Am J Respir Cell Mol Biol ; 39(2): 208-17, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18314542

RESUMO

The mechanisms by which corticosteroids reduce airway inflammation are not completely understood. Traditionally, corticosteroids were thought to inhibit cytokines exclusively at the transcriptional level. Our recent evidence, obtained in airway smooth muscle (ASM), no longer supports this view. We have found that corticosteroids do not act at the transcriptional level to reduce TNF-alpha-induced IL-6 gene expression. Rather, corticosteroids inhibit TNF-alpha-induced IL-6 secretion by reducing the stability of the IL-6 mRNA transcript. TNF-alpha-induced IL-6 mRNA decays at a significantly faster rate in ASM cells pretreated with the corticosteroid dexamethasone (t(1/2) = 2.4 h), compared to vehicle (t(1/2) = 9.0 h; P < 0.05) (results are expressed as decay constants [k] [mean +/- SEM] and half-life [h]). Interestingly, the underlying mechanism of inhibition by corticosteroids is via the up-regulation of an endogenous mitogen-activated protein kinase (MAPK) inhibitor, MAPK phosphatase-1 (MKP-1). Corticosteroids rapidly up-regulate MKP-1 in a time-dependent manner (44.6 +/- 10.5-fold increase after 24 h treatment with dexamethasone; P < 0.05), and MKP-1 up-regulation was temporally related to the inhibition of TNF-alpha-induced p38 MAPK phosphorylation. Moreover, TNF-alpha acts via a p38 MAPK-dependent pathway to stabilize the IL-6 mRNA transcript (TNF-alpha, t(1/2) = 9.6 h; SB203580 + TNF-alpha, t(1/2) = 1.5 h), exogenous expression of MKP-1 significantly inhibits TNF-alpha-induced IL-6 secretion and MKP-1 siRNA reverses the inhibition of TNF-alpha-induced IL-6 secretion by dexamethasone. Taken together, these results suggest that corticosteroid-induced MKP-1 contributes to the repression of IL-6 secretion in ASM cells.


Assuntos
Dexametasona/farmacologia , Fosfatase 1 de Especificidade Dupla/biossíntese , Glucocorticoides/farmacologia , Interleucina-6/biossíntese , Miócitos de Músculo Liso/efeitos dos fármacos , Brônquios/citologia , Brônquios/metabolismo , Células Cultivadas , Humanos , Imidazóis/farmacologia , Miócitos de Músculo Liso/metabolismo , Piridinas/farmacologia , Processamento Pós-Transcricional do RNA , Ativação Transcricional , Fator de Necrose Tumoral alfa/farmacologia , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...