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1.
Nucleic Acids Res ; 52(9): 5209-5225, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38636948

RESUMO

RNA silencing is a post-transcriptional gene-silencing mechanism mediated by microRNAs (miRNAs). However, the regulatory mechanism of RNA silencing during viral infection is unclear. TAR RNA-binding protein (TRBP) is an enhancer of RNA silencing that induces miRNA maturation by interacting with the ribonuclease Dicer. TRBP interacts with a virus sensor protein, laboratory of genetics and physiology 2 (LGP2), in the early stage of viral infection of human cells. Next, it induces apoptosis by inhibiting the maturation of miRNAs, thereby upregulating the expression of apoptosis regulatory genes. In this study, we show that TRBP undergoes a functional conversion in the late stage of viral infection. Viral infection resulted in the activation of caspases that proteolytically processed TRBP into two fragments. The N-terminal fragment did not interact with Dicer but interacted with type I interferon (IFN) signaling modulators, such as protein kinase R (PKR) and LGP2, and induced ER stress. The end results were irreversible apoptosis and suppression of IFN signaling. Our results demonstrate that the processing of TRBP enhances apoptosis, reducing IFN signaling during viral infection.


Assuntos
Apoptose , Caspases , Proteínas de Ligação a RNA , Humanos , Caspases/metabolismo , Linhagem Celular , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Estresse do Retículo Endoplasmático/genética , Células HEK293 , Células HeLa , Interferon Tipo I/metabolismo , Interferon Tipo I/genética , MicroRNAs/metabolismo , MicroRNAs/genética , Ribonuclease III/metabolismo , Ribonuclease III/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Viroses/genética , Viroses/metabolismo
2.
EMBO Rep ; 24(3): e54228, 2023 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-36633157

RESUMO

Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNß), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNß components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT-lymphotoxin beta receptor (LTßR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ERα-deficient mice. These findings indicate that estrogen derived from extragonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.


Assuntos
Encefalomielite Autoimune Experimental , Receptor alfa de Estrogênio , Camundongos , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Estrogênios/farmacologia , Fenótipo , Células Dendríticas/metabolismo , Camundongos Endogâmicos C57BL
3.
Cancer Sci ; 114(6): 2485-2498, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36854451

RESUMO

Cancer tissues generally have molecular oxygen and serum component deficiencies because of poor vascularization. Recently, we revealed that ICAM1 is strongly activated through lipophagy in ovarian clear cell carcinoma (CCC) cells in response to starvation of long-chain fatty acids and oxygen and confers resistance to apoptosis caused by these harsh conditions. CD69 is a glycoprotein that is synthesized in immune cells and is associated with their activation through cellular signaling pathways. However, the expression and function of CD69 in nonhematological cells is unclear. Here, we report that CD69 is induced in CCC cells as in ICAM1. Mass spectrometry analysis of phosphorylated peptides followed by pathway analysis revealed that CD69 augments CCC cell binding to fibronectin (FN) in association with the phosphorylation of multiple cellular signaling molecules including the focal adhesion pathway. Furthermore, CD69 synthesized in CCC cells could facilitate cell survival because the CD69-FN axis can induce epithelial-mesenchymal transition. Experiments with surgically removed tumor samples revealed that CD69 is predominantly expressed in CCC tumor cells compared with other histological subtypes of epithelial ovarian cancer. Overall, our data suggest that cancer cell-derived CD69 can contribute to CCC progression through FN.


Assuntos
Fibronectinas , Neoplasias Ovarianas , Humanos , Feminino , Oxigênio , Neoplasias Ovarianas/patologia , Transdução de Sinais , Lipídeos , Linhagem Celular Tumoral
4.
Biochem Biophys Res Commun ; 658: 122-127, 2023 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-37030066

RESUMO

Viral infection induces diverse cellular immune responses. Some viruses induce the production of antiviral cytokines, alterations of endogenous gene expression, and apoptosis; however, other viruses replicate without inducing such responses, enabling them to persistently infect cells. Infection by Borna disease virus type 1 (BoDV-1) can result in fatal immune-mediated encephalitis, including in humans, yet infection of cells in vitro is generally persistent. The regulatory mechanisms underlying this persistent infection remain unclear. Here, we show that an enhancer of RNA-silencing, TRBP, positively regulates BoDV RNA level in human cells. Knockdown of TRBP decreased BoDV RNA levels in persistently-infected cells, whereas overexpression of TRBP increased BoDV RNA levels. To investigate the mechanism underlying this phenomenon, we performed immunoprecipitation assays and found that TRBP interacts with BoDV RNA. Furthermore, we performed cell fractionation, which revealed that persistent infection with BoDV does not alter the localization of TRBP and other RNA silencing factors in cells. Our results showed the regulation of persistent BoDV infection by RNA-silencing factors in human cells.


Assuntos
Doença de Borna , Vírus da Doença de Borna , Animais , Humanos , Vírus da Doença de Borna/genética , Doença de Borna/genética , Doença de Borna/metabolismo , Interferência de RNA , Infecção Persistente , RNA
5.
PLoS Pathog ; 17(12): e1010091, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34914813

RESUMO

There are strong incentives for human populations to develop antiviral systems. Similarly, genomes that encode antiviral systems have had strong selective advantages. Protein-guided immune systems, which have been well studied in mammals, are necessary for survival in our virus-laden environments. Small RNA-directed antiviral immune systems suppress invasion of cells by non-self genetic material via complementary base pairing with target sequences. These RNA silencing-dependent systems operate in diverse organisms. In mammals, there is strong evidence that microRNAs (miRNAs) regulate endogenous genes important for antiviral immunity, and emerging evidence that virus-derived nucleic acids can be directly targeted by small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNAs (tRNAs) for protection in some contexts. In this review, we summarize current knowledge of the antiviral functions of each of these small RNA types and consider their conceptual and mechanistic overlap with innate and adaptive protein-guided immunity, including mammalian antiviral cytokines, as well as the prokaryotic RNA-guided immune system, CRISPR. In light of recent successes in delivery of RNA for antiviral purposes, most notably for vaccination, we discuss the potential for development of small noncoding RNA-directed antiviral therapeutics and prophylactics.


Assuntos
Pequeno RNA não Traduzido/imunologia , Vírus/imunologia , Animais , Humanos
6.
Opt Express ; 31(5): 7492-7504, 2023 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-36859878

RESUMO

We have developed a method to combine morphological and chemical information for the accurate identification of different particle types using optical measurement techniques that require no sample preparation. A combined holographic imaging and Raman spectroscopy setup is used to gather data from six different types of marine particles suspended in a large volume of seawater. Unsupervised feature learning is performed on the images and the spectral data using convolutional and single-layer autoencoders. The learned features are combined, where we demonstrate that non-linear dimensional reduction of the combined multimodal features can achieve a high clustering macro F1 score of 0.88, compared to a maximum of 0.61 when only image or spectral features are used. The method can be applied to long-term monitoring of particles in the ocean without the need for sample collection. In addition, it can be applied to data from different types of sensor measurements without significant modifications.

7.
Int Arch Allergy Immunol ; 184(8): 797-807, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37231861

RESUMO

INTRODUCTION: Asthma is an inflammatory reaction mediated by type 2 helper T (Th2) cells and is known to increase eosinophil levels. Our previous study showed that stress-related asthma can cause neutrophilic and eosinophilic airway inflammation by suppressing immune tolerance. However, the mechanism of stress-induced neutrophilic and eosinophilic airway inflammation remains unclear. Therefore, to elucidate the cause of neutrophilic and eosinophilic inflammation, we investigated the immune response during the induction of airway inflammation. In addition, we focused on the relationship between immune response modulation immediately after stress exposure and the development of airway inflammation. METHODS: Asthmatic mice were induced by three phases using female BALB/c mice. During the first phase, the mice were made to inhale ovalbumin (OVA) to induce immune tolerance before sensitization. Some mice were exposed to restraint stress during the induction of immune tolerance. In the second phase, the mice were sensitized with OVA/alum intraperitoneal injections. In the final phase, onset of asthma was induced through OVA exposure. Asthma development was evaluated based on airway inflammation and T-cell differentiation. Microarray and qPCR analyses were used to enumerate candidate factors to investigate the starting point of immunological modification immediately after stress exposure. Furthermore, we focused on interleukin-1ß (IL-1ß), which initiates these immune modifications, and performed experiments using its receptor blocker interleukin-1 receptor antagonist (IL-1RA). RESULTS: Stress exposure during immune tolerance induction increased eosinophil and neutrophil airway infiltration. This inflammation was associated with decreased T regulatory cell levels and increased Th2 and Th17 levels in bronchial lymph node cells. Microarray and qPCR analyses showed that the initiation of Th17 differentiation might be triggered by stress exposure during tolerance induction. IL-1RA administration during stress exposure suppressed neutrophilic and eosinophilic airway inflammation via Th17 reduction and Treg increase. CONCLUSIONS: Our results show that psychological stress causes both eosinophilic and neutrophilic inflammatory responses due to the breakdown of immune tolerance. Furthermore, stress-induced inflammation can be abolished using IL-1RA.


Assuntos
Asma , Proteína Antagonista do Receptor de Interleucina 1 , Animais , Feminino , Camundongos , Modelos Animais de Doenças , Tolerância Imunológica , Imunidade , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos BALB C , Neutrófilos , Ovalbumina , Estresse Psicológico/complicações , Células Th17 , Células Th2
8.
Int J Colorectal Dis ; 38(1): 85, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36977940

RESUMO

PURPOSE: This study aimed to compare the reduction in rectocele size after laparoscopic ventral rectopexy (LVR) with that after transanal repair (TAR). METHODS: Forty-six patients with rectocele who underwent LVR and 45 patients with rectocele who received TAR between February 2012 and December 2022 were included. This was a retrospective analysis of prospectively collected data. All patients had clinical evidence of a symptomatic rectocele. Bowel function was evaluated using the constipation scoring system (CSS) and fecal incontinence severity index (FISI). Substantial symptom improvement was defined as at least a 50% reduction in the CSS or FISI scores. Evacuation proctography was performed before surgery and 6 months postoperatively. RESULTS: Constipation was substantially improved in 40-70% of the LVR patients and 70-90% of the TAR patients over 5 years. Fecal incontinence was markedly improved in 60-90% of the LVR patients across 5 years and in 75% of the TAR patients at 1 year. Postoperative proctography showed a reduction in rectocele size in the LVR patients (30 [20-59] mm preoperatively vs. 11 [0-44] mm postoperatively, P < 0.0001) and TAR patients (33 [20-55] mm preoperatively vs. 8 [0-27] mm postoperatively, P < 0.0001). The reduction rate of rectocele size in the LVR patients was significantly lower than that in the TAR patients (63 [3-100] % vs. 79 [45-100] %, P = 0.047). CONCLUSION: The reduction in rectocele size was lower in the patients who underwent LVR than in those who received TAR.


Assuntos
Incontinência Fecal , Laparoscopia , Humanos , Retocele/complicações , Retocele/diagnóstico por imagem , Retocele/cirurgia , Incontinência Fecal/etiologia , Incontinência Fecal/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Constipação Intestinal/etiologia , Constipação Intestinal/cirurgia
9.
Proc Natl Acad Sci U S A ; 117(50): 32078-32085, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33257564

RESUMO

Human sapoviruses (HuSaVs) cause acute gastroenteritis similar to human noroviruses. Although HuSaVs were discovered four decades ago, no HuSaV has been grown in vitro, which has significantly impeded the understanding of viral biology and the development of antiviral strategies. In this study, we identified two susceptible human cell lines, that originated from testis and duodenum, that support HuSaV replication and found that replication requires bile acids. HuSaVs replicated more efficiently in the duodenum cell line, and viral RNA levels increased up to ∼6 log10-fold. We also detected double-stranded RNA, viral nonstructural and structural proteins in the cell cultures, and intact HuSaV particles. We confirmed the infectivity of progeny viruses released into the cell culture supernatants by passaging. These results indicate the successful growth of HuSaVs in vitro. Additionally, we determined the minimum infectious dose and tested the sensitivities of HuSaV GI.1 and GII.3 to heat and ultraviolet treatments. This system is inexpensive, scalable, and reproducible in different laboratories, and can be used to investigate mechanisms of HuSaV replication and to evaluate antivirals and/or disinfection methods for HuSaVs.


Assuntos
Ácidos e Sais Biliares/metabolismo , Meios de Cultura/metabolismo , Sapovirus/fisiologia , Cultura de Vírus/métodos , Replicação Viral , Infecções por Caliciviridae/terapia , Infecções por Caliciviridae/virologia , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Células Epiteliais , Fezes/virologia , Gastroenterite/terapia , Gastroenterite/virologia , Humanos , Sapovirus/isolamento & purificação
10.
Br J Cancer ; 127(3): 462-473, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35449452

RESUMO

BACKGROUND: Serum starvation and hypoxia (SSH) mimics a stress condition in tumours. We have shown that intercellular adhesion molecule-1 (ICAM-1) protein is synergistically expressed in ovarian clear cell carcinoma (CCC) cells under SSH in response to an insufficient supply of fatty acids (FAs). This ICAM-1 expression is responsible for resistance against the lethal condition, thereby promoting tumour growth. However, the underlying mechanisms that link SSH-driven ICAM1 gene expression to impaired FA supply and its clinical relevance are unclear. METHODS: The underlying mechanisms of how FA deficiency induces ICAM-1 expression in cooperation with hypoxia were analysed in vitro and in vivo. Clinical significance of CCC cell-derived ICAM-1 and the mechanism associated with the transcriptional synergism were also investigated. RESULTS: ICAM-1 expression was mediated through lipophagy-driven lipid droplet degradation, followed by impaired FA-lipid droplet flow. Lipophagy induced ICAM1 expression through stabilisation of NFκB binding to the promoter region via Sam68 and hTERT. Analyses of clinical specimens revealed that expression of ICAM-1 and LC3B, an autophagy marker associated with lipophagy, significantly correlated with poor prognoses of CCC. CONCLUSIONS: The lipophagy-ICAM-1 pathway induced under a tumour-like stress conditions contributes to CCC progression and is a potential therapeutic target for this aggressive cancer type.


Assuntos
Adenocarcinoma de Células Claras , Molécula 1 de Adesão Intercelular , Neoplasias Ovarianas , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Autofagia/genética , Ácidos Graxos/metabolismo , Feminino , Humanos , Hipóxia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Prognóstico
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