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1.
RNA ; 26(1): 91-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31676570

RESUMO

Coxsackievirus B (CVB) is the major cause of human myocarditis and dilated cardiomyopathy. Toll-like receptor 3 (TLR3) is an intracellular sensor to detect pathogen's dsRNA. TLR3, along with TRAF6, triggers an inflammatory response through NF-κB signaling pathway. In the cells infected with CVB type 3 (CVB3), the abundance of miR-146a was significantly increased. The role of miR-146a in CVB infection is unclear. In this study, TLR3 and TRAF6 were identified as the targets of miR-146a. The elevated miR-146a inhibited NF-κB translocation and subsequently down-regulated proinflammatory cytokine expression in the CVB3-infected cells. Therefore, the NF-κB pathway can be doubly blocked by miR-146a through targeting of TLR3 and TRAF6. MiR-146a may be a negative regulator on inflammatory response and an intrinsic protective factor in CVB infection.

2.
Antiviral Res ; : 104699, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31883926

RESUMO

Viral myocarditis caused by Coxsackievirus B (CVB) infection is a severe inflammatory disease of the myocardium, which may develop to cardiomyopathy and heart failure. No effective specific treatment is available presently. Our previous study demonstrated that suppression of proinflammatory caspase-1 activation effectively inhibited CVB replication. N-acetyl cysteine (NAC) is a widely used antioxidant. In this study, we found that NAC significantly alleviated the myocardial injury caused by CVB type 3 (CVB3) under in vivo condition. Importantly, NAC treatment simultaneously suppressed viral replication and inflammatory response in both myocardium and cell culture. The antiviral and anti-inflammation mechanism of NAC, while independent of its antioxidant property, relies on its inhibition on caspase-1 activation. Moreover, NAC promotes procaspase-1 degradation via ubiquitin proteasome system, which further contributes to caspase-1 down-regulation. NAC also inhibits the activity of viral proteases. Taken together, this study shows that NAC exerts potent anti-CVB and anti-inflammation effect through targeting caspase-1. Given that NAC is a clinically approved medicine, we recommend NAC as a valuable therapeutic agent for viral myocarditis caused by CVB.

3.
Virol Sin ; 34(6): 618-630, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31388922

RESUMO

The roles of lncRNAs in the infection of enteroviruses have been barely demonstrated. In this study, we used coxsackievirus B3 (CVB3), a typical enterovirus, as a model to investigate the expression profiles and functional roles of lncRNAs in enterovirus infection. We profiled lncRNAs and mRNA expression in CVB3-infected HeLa cells by lncRNA-mRNA integrated microarrays. As a result, 700 differentially expressed lncRNAs (431 up-regulated and 269 down-regulated) and 665 differentially expressed mRNAs (299 up-regulated and 366 down-regulated) were identified in CVB3 infection. Then we performed lncRNA-mRNA integrated pathway analysis to identify potential functional impacts of the differentially expressed mRNAs, in which lncRNA-mRNA correlation network was built. According to lncRNA-mRNA correlation, we found that XLOC-001188, an lncRNA down-regulated in CVB3 infection, was negatively correlated with NFAT5 mRNA, an anti-CVB3 gene reported previously. This interaction was supported by qPCR detection following siRNA-mediated knockdown of XLOC-001188, which showed an increase of NFAT5 mRNA and a reduction of CVB3 genomic RNA. In addition, we observed that four most significantly altered lncRNAs, SNHG11, RP11-145F16.2, RP11-1023L17.1 and RP11-1021N1.2 share several common correlated genes critical for CVB3 infection, such as BRE and IRF2BP1. In all, our studies reveal the alteration of lncRNA expression in CVB3 infection and its potential influence on CVB3 replication, providing useful information for future studies of enterovirus infection.

4.
Front Microbiol ; 10: 1633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379784

RESUMO

Manipulating cell cycle is one of the common strategies used by viruses to generate favorable cellular environment to facilitate viral replication. Coxsackievirus B (CVB) is one of the major viral pathogens of human myocarditis and cardiomyopathy. Because of its small genome, CVB depends on cellular machineries for productive replication. However, how the structural and non-structural components of CVB would manipulate cell cycle is not clearly understood. In this study, we demonstrated that the capsid protein VP1 of CVB type 3 (CVB3) induced cell cycle arrest at G1 phase. G1 arrest was the result of the decrease level of cyclin E and the accumulation of p27Kip1. Study on the gene expression profile of the cells expressing VP1 showed that the expression of both heat shock protein 70-1 (Hsp70-1) and Hsp70-2 was significantly up-regulated. Knockdown of Hsp70 resulted in the increased level of cyclin E and the reduction of p27Kip1. We further demonstrated that the phosphorylation of the heat shock factor 1, which directly promotes the expression of Hsp70, was also increased in the cell expressing VP1. Moreover, we show that CVB3 infection also induced G1 arrest, likely due to dysregulating Hsp70, cyclin E, and p27, while knockdown of Hsp70 dramatically inhibited viral replication. Cell cycle arrest at G1 phase facilitated CVB3 infection, since viral replication in the cells synchronized at G1 phase dramatically increased. Taken together, this study demonstrates that the VP1 of CVB3 induces cell cycle arrest at G1 phase through up-regulating Hsp70. Our findings suggest that the capsid protein VP1 of CVB is capable of manipulating cellular activities during viral infection.

5.
OMICS ; 23(12): 649-659, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31313980

RESUMO

Cardiovascular disease is a common complex trait that calls for next-generation biomarkers for precision diagnostics and therapeutics. The most common type of post-translational protein modification involves glycosylation. Glycans participate in key intercellular and intracellular functions, such as protein quality control, cell adhesion, cell-cell recognition, signal transduction, cell proliferation, and cell differentiation. In this context, immunoglobulin G (IgG) N-glycans affect the anti-inflammatory and proinflammatory responses of IgG, and are associated with cardiometabolic risk factors such as aging, central obesity, dyslipidemia, and hyperglycemia. Yet, the role of such glycomic biomarkers requires evaluation in diverse world populations. We report here original observations on association of IgG N-glycan biosignatures with 15 cardiometabolic risk factors in a community-based cross-sectional study conducted in 701 Chinese Han participants. After controlling for age and sex, we found that the 16, 21, and 18 IgG N-glycan traits were significantly different in participants with and without metabolic syndrome, hypertriglyceridemic waist phenotype, or abdominal obesity, respectively. The canonical correlation analysis showed that IgG N-glycan profiles were significantly associated with cardiometabolic risk factors (r = 0.469, p < 0.001). Classification models based on IgG N-glycan traits were able to differentiate participants with (1) metabolic syndrome, (2) hypertriglyceridemic waist phenotype, or (3) abdominal obesity from controls, with an area under receiver operating characteristic curves (AUC) of 0.632 (95% confidence interval [CI], 0.574-0.691, p < 0.001), 0.659 (95% CI, 0.587-0.730, p < 0.001), and 0.610 (95% CI, 0.565-0.656, p < 0.001), respectively. These new data suggest that IgG N-glycans may play an important role in cardiometabolic disease pathogenesis by regulating the proinflammatory or anti-inflammatory responses of IgG. Looking into the future, IgG N-glycan biosignatures warrant further research in other world population samples with a view to applications in clinical cardiology and public health practice.

6.
Viruses ; 11(4)2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022927

RESUMO

As the only widely used live lentiviral vaccine, the equine infectious anima virus (EIAV) attenuated vaccine was developed by in vitro passaging of a virulent strain for 121 generations. In our previous study, we observed that the attenuated vaccine was gradually selected under increased environmental pressure at the population level (termed a quasispecies). To further elucidate the potential correlation between viral quasispecies evolution and pathogenesis, a systematic study was performed by sequencing env using several methods. Some key mutations were identified within Env, and we observed that increased percentages of these mutations were accompanied by an increased passage number and attenuated virulence. Phylogenetic analysis revealed that env mutations related to the loss of virulence might have occurred evolutionarily. Among these mutations, deletion of amino acid 236 in the V4 region of Env resulted in the loss of one N-glycosylation site that was crucial for virulence. Notably, the 236-deleted sequence represented a "vaccine-specific" mutation that was also found in wild EIAVLN40 strains based on single genome amplification (SGA) analysis. Therefore, our results suggest that the EIAV attenuated vaccine may originate from a branch of quasispecies of EIAVLN40. Generally, the presented results may increase our understanding of the attenuation mechanism of the EIAV vaccine and provide more information about the evolution of other lentiviruses.


Assuntos
Evolução Molecular , Genoma Viral , Vírus da Anemia Infecciosa Equina/genética , Vírus da Anemia Infecciosa Equina/patogenicidade , Quase-Espécies , Proteínas do Envelope Viral , Animais , Anemia Infecciosa Equina/prevenção & controle , Cavalos , Mutação , Filogenia , Análise de Sequência , Deleção de Sequência , Vacinas Atenuadas , Vacinas Virais , Virulência/genética
7.
Antiviral Res ; 166: 1-10, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30904424

RESUMO

Coxsackievirus group B (CVB) is considered as one of the most common pathogens of human viral myocarditis. CVB-induced myocarditis is mainly characterized by the persistence of the virus infection and immune-mediated inflammatory injury. Costimulatory signals are crucial for the activation of adaptive immunity. Our data reveal that the CVB type 3 (CVB3) infection altered the expression profile of costimulatory molecules in host cells. CVB3 infection caused the decrease of PD-1 ligand expression, partially due to the cleavage of AU-rich element binding protein AUF1 by the viral protease 3Cpro, leading to the exacerbated inflammatory injury of the myocardium. Moreover, systemic PD-L1 treatment, which augmented the apoptosis of proliferating lymphocytes, alleviated myocardial inflammatory injury. Our findings suggest that PD1-pathway can be a potential immunologic therapeutic target for CVB-induced myocarditis.

8.
Virol Sin ; 33(4): 314-322, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29959686

RESUMO

Stress granules (SGs) are intracellular granules formed when cellular translation is blocked and have been reported to be involved in a variety of viral infections. Our previous studies revealed that SGs are involved in the coxsackievirus B (CVB) infection process, but the role of SGs in CVB infection has not been fully explored. In this study, we found that CVB type 3 (CVB3) could induce SG formation in the early phase of infection. Results showed that levels of CVB3 RNA and protein were significantly inhibited during the early stage of CVB3 infection by the elevated formation of SGs, while viral RNA and protein synthesis were significantly promoted when SG formation was blocked. Our findings suggest that SG formation is one of the early antiviral mechanisms for host cells against CVB infection.


Assuntos
Antivirais/metabolismo , Infecções por Coxsackievirus/virologia , Grânulos Citoplasmáticos/metabolismo , Enterovirus Humano B/fisiologia , Proteínas do Capsídeo/biossíntese , DNA Helicases/genética , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Técnicas de Silenciamento de Genes , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Fosforilação , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , RNA Viral/biossíntese , Estresse Fisiológico , Antígeno-1 Intracelular de Células T/genética , Antígeno-1 Intracelular de Células T/metabolismo , Replicação Viral
9.
Nat Commun ; 9(1): 2268, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891946

RESUMO

Most eukaryotic genes express alternative polyadenylation (APA) isoforms with different 3'UTR lengths, production of which is influenced by cellular conditions. Here, we show that arsenic stress elicits global shortening of 3'UTRs through preferential usage of proximal polyadenylation sites during stress and enhanced degradation of long 3'UTR isoforms during recovery. We demonstrate that RNA-binding protein TIA1 preferentially interacts with alternative 3'UTR sequences through U-rich motifs, correlating with stress granule association and mRNA decay of long 3'UTR isoforms. By contrast, genes with shortened 3'UTRs due to stress-induced APA can evade mRNA clearance and maintain transcript abundance post stress. Furthermore, we show that stress causes distinct 3'UTR size changes in proliferating and differentiated cells, highlighting its context-specific impacts on the 3'UTR landscape. Together, our data reveal a global, 3'UTR-based mRNA stability control in stressed cells and indicate that APA can function as an adaptive mechanism to preserve mRNAs in response to stress.


Assuntos
Regiões 3' não Traduzidas , Poliadenilação , Estabilidade de RNA , Animais , Arsenitos , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Humanos , Camundongos , Células NIH 3T3 , Poliadenilação/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Compostos de Sódio , Estresse Fisiológico , Antígeno-1 Intracelular de Células T/metabolismo
10.
Oncotarget ; 9(19): 14815-14827, 2018 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-29599909

RESUMO

Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3' untranslated region (3'UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3'UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.

11.
Sci Rep ; 8(1): 2887, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29440739

RESUMO

Enterovirus 71 (EV71) is the primary causative pathogen of hand, foot, and mouth disease (HFMD), affecting children with severe neurological complications. Pyroptosis is a programmed cell death characterized by cell lysis and inflammatory response. Although proinflammatory response has been implicated to play important roles in EV71-caused diseases, the involvement of pyroptosis in the pathogenesis of EV71 is poorly defined. We show that EV71 infection induced caspase-1 activation. Responding to the activation of caspase-1, the expression and secretion of both IL-1ß and IL-18 were increased in EV71-infected cells. The treatment of caspase-1 inhibitor markedly improved the systemic response of the EV71-infected mice. Importantly, caspase-1 inhibitor suppressed EV71 replication in mouse brains. Similarly, pyroptosis was activated by the infection of coxsackievirus B3 (CVB3), an important member of the Enterovirus genus. Caspase-1 activation and the increased expression of IL-18 and NLRP3 were demonstrated in HeLa cells infected with CVB3. Caspase-1 inhibitor also alleviated the overall conditions of virus-infected mice with markedly decreased replication of CVB3 and reduced expression of caspase-1. These results indicate that pyroptosis is involved in the pathogenesis of both EV71 and CVB3 infections, and the treatment of caspase-1 inhibitor is beneficial to the host response during enterovirus infection.


Assuntos
Enterovirus Humano A/fisiologia , Enterovirus Humano B/fisiologia , Piroptose , Replicação Viral , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/virologia , Caspase 1/metabolismo , Ativação Enzimática , Regulação da Expressão Gênica , Células HeLa , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
12.
Exp Biol Med (Maywood) ; 242(4): 429-435, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27798120

RESUMO

Colorectal cancer is the most common malignancy of the gastrointestinal tract. Surgical treatment combined with radiotherapy is the main treatment course for colorectal cancer; nevertheless, radio-resistance is commonly encountered during the treatment course and seriously influences the therapeutic efficacy. We tested the hypothesis that the CXCL12/CXCR4 axis is closely related to radiotherapy sensitivity in colorectal cancer cells. Here, we found that the decrease in cell viability and the increase in cell death induced by radiotherapy were attenuated by CXCL12 treatment, and the inhibition of CXCR4 promoted colorectal cancer cells to be more sensitive to radiotherapy. We also examined the critical roles of CXCL12/CXCR4 in cell survival and found that radiotherapy induced Bax expression and facilitated the activity of caspase-3 and caspase-9, which were reversed by CXCL12 treatment. Cell apoptosis was enhanced by the inhibition of CXCR4 under radiotherapy conditions. Furthermore, treatment with CXCL12 resulted in an increased expression of survivin, and the inhibitory roles of CXCL12 in radiotherapy-induced apoptosis were mitigated by survivin knockdown. These results indicate that CXCL12/CXCR4 protects colorectal cancer cells against radiotherapy via survivin, implying an important underlying mechanism of resistance to radiotherapy during colorectal cancer therapy.


Assuntos
Quimiocina CXCL12/farmacologia , Neoplasias Colorretais/radioterapia , Proteínas Inibidoras de Apoptose/genética , Tolerância a Radiação/genética , Receptores CXCR4/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiocina CXCL12/metabolismo , Células HCT116 , Humanos , Proteínas Inibidoras de Apoptose/biossíntese , Proteínas Inibidoras de Apoptose/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Tolerância a Radiação/fisiologia , Receptores CXCR4/metabolismo , Survivina , Proteína X Associada a bcl-2/biossíntese
14.
Exp Cell Res ; 349(2): 255-263, 2016 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-27793649

RESUMO

Coxsackievirus group B (CVB) is one of the common pathogens that cause myocarditis and cardiomyopathy. Evidence has shown that CVB replication in cardiomyocytes is responsible for the damage and loss of cardiac muscle and the dysfunction of the heart. However, it remains largely undefined how CVB would directly impact cardiac fibroblasts, the most abundant cells in human heart. In this study, cardiac fibroblasts were isolated from Balb/c mice and infected with CVB type 3 (CVB3). Increased double-membraned, autophagosome-like vesicles in the CVB3-infected cardiac fibroblasts were observed with electron microscope. Punctate distribution of LC3 and increased level of LC3-II were also detected in the infected cardiac fibroblasts. Furthermore, we observed that the expression of pro-inflammatory cytokines, IL-6 and TNF-α, was increased in the CVB3-infected cardiac fibroblasts, while suppressed autophagy by 3-MA and Atg7-siRNA inhibited cytokine expression. Consistent with the in vitro findings, increased formation of autophagosomes was observed in the cardiac fibroblasts of Balb/c mice infected with CVB3. In conclusion, our data demonstrated that cardiac fibroblasts respond to CVB3 infection with the formation of autophagosomes and the release of the pro-inflammatory cytokines. These results suggest that the autophagic response of cardiac fibroblasts may play a role in the pathogenesis of myocarditis caused by CVB3 infection.


Assuntos
Autofagossomos/virologia , Enterovirus Humano B , Fibroblastos/virologia , Miocardite/virologia , Miócitos Cardíacos/virologia , Animais , Autofagia/fisiologia , Enterovirus Humano B/fisiologia , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/patologia , Fagossomos/virologia , Replicação Viral/genética
15.
Oncotarget ; 7(48): 79605-79616, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27793004

RESUMO

Lin28A and Lin28B are highly conserved RNA binding proteins with similar structure and functions. Recent studies demonstrated that both of them act as oncogenes and promote cancer progression. However, few researches compared the expression and functions of both oncogenes in human malignant tumors at same time. Additionally, although the expression and role of Lin28B in colon cancer is frequently reported, the expression and functions of Lin28A in colon cancer are largely unknown. In this study, we have systematically evaluated the expressional pattern, mutation status and correlation of both Lin28A and Lin28B in colon cancer tissues for the first time, and compared the roles of Lin28A and Lin28B in the proliferation, migration, invasion and apoptosis of colon cancer cells in vitro. We have showed that they are co-expressed and have functional similarities, however, the molecular mechanisms underlying their similar functions may not be identical. This study contributes to clarify the similarities and differences of Lin28A and Lin28B in colon cancer progression.


Assuntos
Neoplasias do Colo/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose , Movimento Celular , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Progressão da Doença , Relação Dose-Resposta a Droga , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Transfecção
16.
Exp Ther Med ; 12(4): 2220-2226, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27698715

RESUMO

Coxsackievirus B3 (CVB3) is a common causative agent in the development of inflammatory cardiomyopathy. However, whether the expression of peripheral blood microRNAs (miRNAs) is altered in this process is unknown. The present study investigated changes to miRNA expression in the peripheral blood of CVB3-infected mice. Utilizing miRNA microarray technology, differential miRNA expression was examined between normal and CVB3-infected mice. The present results suggest that specific miRNAs were differentially expressed in the peripheral blood of mice infected with CVB3, varying with infection duration. Using miRNA microarray analysis, a total of 96 and 89 differentially expressed miRNAs were identified in the peripheral blood of mice infected with CVB3 for 3 and 6 days, respectively. Quantitative polymerase chain reaction was used to validate differentially expressed miRNAs, revealing a consistency of these results with the miRNA microarray analysis results. The biological functions of the differentially expressed miRNAs were then predicted by bioinformatics analysis. The potential biological roles of differentially expressed miRNAs included hypertrophic cardiomyopathy, dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. These results may provide important insights into the mechanisms responsible for the progression of CVB3 infection.

17.
Viruses ; 8(5)2016 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-27187444

RESUMO

Coxsackievirus B (CVB) belongs to Enterovirus genus within the Picornaviridae family, and it is one of the most common causative pathogens of viral myocarditis in young adults. The pathogenesis of myocarditis caused by CVB has not been completely elucidated. In CVB infection, autophagy is manipulated to facilitate viral replication. Here we report that protein 2B, one of the non-structural proteins of CVB3, possesses autophagy-inducing capability. The autophagy-inducing motif of protein 2B was identified by the generation of truncated 2B and site-directed mutagenesis. The expression of 2B alone was sufficient to induce the formation of autophagosomes in HeLa cells, while truncated 2B containing the two hydrophobic regions of the protein also induced autophagy. In addition, we demonstrated that a single amino acid substitution (56V→A) in the stem loop in between the two hydrophobic regions of protein 2B abolished the formation of autophagosomes. Moreover, we found that 2B and truncated 2B with autophagy-inducting capability were co-localized with LC3-II. This study indicates that protein 2B relies on its transmembrane hydrophobic regions to induce the formation of autophagosomes, while 56 valine residue in the stem loop of protein 2B might exert critical structural influence on its two hydrophobic regions. These results may provide new insight for understanding the molecular mechanism of autophagy triggered by CVB infection.


Assuntos
Autofagia , Enterovirus Humano B/patogenicidade , Proteínas Virais/metabolismo , Fatores de Virulência/metabolismo , Motivos de Aminoácidos , Análise Mutacional de DNA , Células HeLa , Humanos , Proteínas Virais/genética , Fatores de Virulência/genética
18.
Oncotarget ; 7(22): 32433-48, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27074572

RESUMO

There is growing evidence of dysregulated long non-coding RNAs (lncRNAs) serving as potential biomarkers for cancer prognosis. However, systematic efforts of searching for an expression-based lncRNA signature for prognosis prediction in ovarian cancer (OvCa) have not been made yet. Here, we performed comprehensive analysis for lncRNA expression profiles and clinical data of 544 OvCa patients from The Cancer Genome Atlas (TCGA), and identified an eight-lncRNA signature with ability to classify patients of the training cohort into high-risk group showing poor outcome and low-risk group showing significantly improved outcome, which was further validated in the validation cohort and entire TCGA cohort. Multivariate Cox regression analysis and stratified analysis demonstrated that the prognostic value of this signature was independent of other clinicopathological factors. Associating the outcome prediction with BRCA1 and/or BRCA2 mutation revealed a superior prognosis performance both in BRCA1/2-mutated and BRCA1/2 wild-type tumors. Finally, a significantly correlation was found between the lncRNA signature and the complete response rate of chemotherapy, suggesting that this eight-lncRNA signature may be a measure to predict chemotherapy response and identify platinum-resistant patients who might benefit from other more efficacious therapies. With further prospective validation, this eight-lncRNA signature may have important implications for outcome prediction and therapy decisions.


Assuntos
Neoplasias Ovarianas/genética , RNA Longo não Codificante/biossíntese , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , RNA Longo não Codificante/metabolismo , Resultado do Tratamento
19.
Exp Mol Pathol ; 100(2): 294-302, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26896649

RESUMO

While investigating the inhibitory effect of S-allylmercaptocysteine (SAMC), a garlic derivative, on ovarian cancer, we subjected three ovarian cancer cell lines, HO8910, HO8910PM, and SKOV3, to SAMC treatment. In vivo and in vitro experiments showed that only HO8910 and SKOV3 cells were highly sensitive to SAMC, whereas HO8910PM cells were resistant to SAMC. Subsequently, we examined the apoptosis-related genes in the three cell lines. We found that survivin gene was highly expressed in HO8910PM cells. Down regulation of survivin gene in HO8910PM cells with small interference RNA (siRNA), resulted in increased sensitivity to SAMC together with a decrease in invasiveness of tumor cells. We therefore concluded that the S-allylmercaptocysteine suppresses both the proliferation and distant metastasis of epithelial ovarian cancer cells, insensitivity of HO8910PM cells to SAMC was closely related to the high level of survivin expression and that combination of SAMC treatment together with survivin knockdown might be a potential strategy for treatment of certain variants of ovarian cancers.


Assuntos
Cisteína/análogos & derivados , Regulação Neoplásica da Expressão Gênica , Proteínas Inibidoras de Apoptose/genética , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Caderinas/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisteína/farmacologia , Feminino , Alho/química , Humanos , Integrina beta1/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Survivina , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Biol Macromol ; 85: 102-10, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26718869

RESUMO

Chitosan quaternary ammonium salt displays good antioxidant and antibacterial characteristics and it shows appreciable solubility in water. When added to the traditional denture material to form a resin base, it could promote good oral health by improving the oral environment. In this study, chitosan quaternary ammonium salt was added to the denture material following two different methods. After three months of immersion in artificial saliva, the specimens were tested for tensile strength and were scanned by electron microscope. The murine fibroblast cytotoxicity and antibacterial properties were also tested. The result showed no significant differences in the tensile strength and in the proliferation of murine L929 fibroblast cells. The two structures of chitosan quaternary ammonium salt-modified denture material had different degrees of corrosion resistance and antimicrobial properties. These results indicate that chitosan quaternary ammonium salt-modified resin denture base material has the potential to become a new generation oral denture composite material.


Assuntos
Quitosana/química , Bases de Dentadura , Compostos de Amônio Quaternário/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Linhagem Celular , Sobrevivência Celular , Fibroblastos , Teste de Materiais , Camundongos , Testes de Sensibilidade Microbiana , Resinas Sintéticas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Streptococcus/efeitos dos fármacos , Propriedades de Superfície
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