Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Nat Immunol ; 21(11): 1470, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32939095

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Nat Immunol ; 21(5): 546-554, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231300

RESUMO

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Caspase 9/metabolismo , Inibidores de Caspase/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Colorretais/terapia , Ácidos Pentanoicos/uso terapêutico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Caspase 9/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Transdução de Sinais , Regulação para Cima
3.
Immunity ; 47(2): 363-373.e5, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28801234

RESUMO

Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein α (SIRPα) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPα with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPα axis is critical for DC-driven antitumor immunity.


Assuntos
Antígenos de Diferenciação/metabolismo , Neoplasias do Colo/imunologia , DNA Mitocondrial/imunologia , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Receptores Imunológicos/metabolismo , Animais , Anticorpos Bloqueadores/uso terapêutico , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Células Cultivadas , Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Apresentação Cruzada , Modelos Animais de Doenças , Humanos , Interferon Tipo I/metabolismo , Macrófagos/imunologia , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2 , NADPH Oxidases/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Evasão Tumoral
4.
PLoS Pathog ; 14(11): e1007455, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30444918

RESUMO

[This corrects the article DOI: 10.1371/journal.ppat.1007075.].

5.
PLoS Pathog ; 14(5): e1007075, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29782532

RESUMO

Toll-like receptor 3 (TLR3) senses dsRNA intermediates produced during RNA virus replication to activate innate immune signaling pathways through adaptor protein TRIF. Many viruses have evolved strategies to block TLR3-mediated interferon signaling via targeting TRIF. Here we studied how hepatitis C virus (HCV) antagonizes the TLR3-mediated interferon signaling. We found that HCV-encoded NS4B protein inhibited TLR3-mediated interferon signaling by down-regulating TRIF protein level. Mechanism studies indicated that the downregulation of TRIF by NS4B was dependent on caspase8. NS4B transfection or HCV infection can activate caspase8 to promote TRIF degradation, leading to suppression of TLR3-mediated interferon signaling. Knockout of caspase8 can prevent TRIF degradation triggered by NS4B, thereby enhancing the TLR3-mediated interferon signaling activation in response to HCV infection. In conclusion, our work revealed a new mechanism for HCV to evade innate immune response by blocking the TLR3-mediated interferon signaling via NS4B-induced TRIF degradation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Hepacivirus/fisiologia , Interferons/metabolismo , Transdução de Sinais/fisiologia , Receptor 3 Toll-Like/antagonistas & inibidores , Proteínas não Estruturais Virais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistemas CRISPR-Cas , Caspase 8/genética , Caspase 8/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Evasão da Resposta Imune/fisiologia , Imunidade Inata/imunologia , Proteínas de Membrana/fisiologia , Receptor 3 Toll-Like/metabolismo , Transfecção
6.
J Virol ; 92(21)2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30111563

RESUMO

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV can be sensed by host innate immunity to induce expression of interferons (IFNs) and a number of antiviral effectors. In this study, we found HCV infection induced the expression of neuralized E3 ubiquitin protein ligase 3 (NEURL3), a putative E3 ligase, in a manner that requires the involvement of innate immune sensing but is independent of the IFN action. Furthermore, we showed that NEURL3 inhibited HCV infection while it had little effect on other RNA viruses, including Zika virus (ZIKV), dengue virus (DENV), and vesicular stomatitis virus (VSV). Mechanistic studies demonstrated that NEURL3 inhibited HCV assembly by directly binding HCV envelope glycoprotein E1 to interfere with the E1/E2 heterodimerization, an important prerequisite for virion morphogenesis. Finally, we showed that knockout of NEURL3 significantly enhanced HCV infection. In summary, we identified NEURL3 as a novel inducible antiviral host factor that suppresses HCV assembly. Our results not only shed new insight into how host innate immunity acts against HCV but also revealed a new important biological function for NEURL3.IMPORTANCE The exact biological function of NEURL3, a putative E3 ligase, remains largely unknown. In this study, we found that NEURL3 could be upregulated upon HCV infection in a manner dependent on pattern recognition receptor-mediated innate immune response. NEURL3 inhibits HCV assembly by directly binding viral E1 envelope glycoprotein to disrupt its interaction with E2, an action that requires its Neuralized homology repeat (NHR) domain but not the RING domain. Furthermore, we found that NEURL3 has a pangenotypic anti-HCV activity and interacts with E1 of genotypes 2a, 1b, 3a, and 6a but does not inhibit other closely related RNA viruses, such as ZIKV, DENV, and VSV. To our knowledge, our study is the first report to demonstrate that NEURL3 functions as an antiviral host factor. Our results not only shed new insight into how host innate immunity acts against HCV, but also revealed a new important biological function for NEURL3.


Assuntos
Antivirais/farmacologia , Hepatite C/prevenção & controle , Imunidade Inata/imunologia , Infecções por Vírus de RNA/virologia , Ubiquitina-Proteína Ligases/farmacologia , Proteínas do Envelope Viral/antagonistas & inibidores , Vírus da Dengue/efeitos dos fármacos , Células HEK293 , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Infecções por Vírus de RNA/tratamento farmacológico , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Montagem de Vírus , Zika virus/efeitos dos fármacos
7.
Environ Monit Assess ; 189(3): 100, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28185155

RESUMO

Perfluoroalkyl acids (PFAAs) have been observed in various environmental matrices globally in recent years. In this study, the levels, spatial distribution tendencies, and partitioning characteristics of the target 12 PFAAs were investigated in water and sediment from the coastal regions of Shandong peninsula in China, and two sediment core samples were also collected to study the vertical and historical variation of PFAAs. The ranges (means) of total PFAA concentrations were 23.69-148.48 ng/L (76.11 ng/L) in the water and 1.30-11.17 ng/g (5.93 ng/g) in the surface sediment, respectively. Among the target 12 PFAAs, perfluorooctanoic acid (PFOA) was the dominant component in water, followed by perfluorooctane sulfonate (PFOS) and perfluorohexanoic acid (PFHxA). PFOS, perfluoroundecanoic acid, and PFOA were the dominant components in sediment. For their spatial distribution, higher levels of PFAAs were found at the locations close to much developed cities. The PFAA concentrations showed an overall decreasing tendency with depth increase in the two sediment cores, which indicates that the extent of PFAAs pollution is aggravating trend in recent years. Results of the partition coefficient (K d ) show that the compounds with longer carbon chains (C ≥ 7) generally had higher K d values, which suggest that long-chain PFAAs are prone to be adsorbed by sediment. In addition, the Log K d of PFHxA, PFOA, and PFOS were significantly and positively correlated to the salinity of the water. The results of risk assessment suggest appreciable risk of PFAAs to the local ecosystem.


Assuntos
Ácidos Alcanossulfônicos/análise , Caproatos/análise , Caprilatos/análise , Monitoramento Ambiental/métodos , Ácidos Graxos/análise , Fluorocarbonos/análise , Sedimentos Geológicos/química , Poluentes Químicos da Água/análise , Adsorção , China , Cidades , Água
8.
J Virol ; 89(13): 6805-16, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25903345

RESUMO

UNLABELLED: Hepatitis C virus (HCV), a single-stranded positive-sense RNA virus of the Flaviviridae family, causes chronic liver diseases, including hepatitis, cirrhosis, and cancer. HCV infection is critically dependent on host lipid metabolism, which contributes to all stages of the viral life cycle, including virus entry, replication, assembly, and release. 25-Hydroxycholesterol (25HC) plays a critical role in regulating lipid metabolism, modulating immune responses, and suppressing viral pathogens. In this study, we showed that 25HC and its synthesizing enzyme cholesterol 25-hydroxylase (CH25H) efficiently inhibit HCV infection at a postentry stage. CH25H inhibits HCV infection by suppressing the maturation of SREBPs, critical transcription factors for host lipid biosynthesis. Interestingly, CH25H is upregulated upon poly(I · C) treatment or HCV infection in hepatocytes, which triggers type I and III interferon responses, suggesting that the CH25H induction constitutes a part of host innate immune response. To our surprise, in contrast to studies in mice, CH25H is not induced by interferons in human cells and knockdown of STAT-1 has no effect on the induction of CH25H, suggesting CH25H is not an interferon-stimulated gene in humans but rather represents a primary and direct host response to viral infection. Finally, knockdown of CH25H in human hepatocytes significantly increases HCV infection. In summary, our results demonstrate that CH25H constitutes a primary innate response against HCV infection through regulating host lipid metabolism. Manipulation of CH25H expression and function should provide a new strategy for anti-HCV therapeutics. IMPORTANCE: Recent studies have expanded the critical roles of oxysterols in regulating immune response and antagonizing viral pathogens. Here, we showed that one of the oxysterols, 25HC and its synthesizing enzyme CH25H efficiently inhibit HCV infection at a postentry stage via suppressing the maturation of transcription factor SREBPs that regulate lipid biosynthesis. Furthermore, we found that CH25H expression is upregulated upon poly(I·C) stimulation or HCV infection, suggesting CH25H induction constitutes a part of host innate immune response. Interestingly, in contrast to studies in mice showing that ch25h is an interferon-stimulated gene, CH25H cannot be induced by interferons in human cells but rather represents a primary and direct host response to viral infection. Our studies demonstrate that the induction of CH25H represents an important host innate response against virus infection and highlight the role of lipid effectors in host antiviral strategy.


Assuntos
Hepacivirus/imunologia , Hidroxicolesteróis/metabolismo , Imunidade Inata , Fatores Imunológicos/metabolismo , Esteroide Hidroxilases/metabolismo , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Técnicas de Silenciamento de Genes , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Hepatócitos/imunologia , Hepatócitos/virologia , Humanos
9.
J Hepatol ; 62(4): 771-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25463548

RESUMO

BACKGROUND & AIMS: Hepatitis C virus (HCV) is a human pathogen that can evade host immunity to cause persistent infection, leading to liver cirrhosis and hepatocellular carcinoma. The transfected 3'UTR of HCV genomic RNA can be recognized by host protein RIG-I to activate interferon production in hepatocytes. However, it is difficult to demonstrate the RIG-I mediated sensing of HCV genomic RNA in the context of HCV infection because HCV-encoded NS3-4A protease can inactivate MAVS, a critical adaptor protein in interferon signaling. Our aim was to identify the viral sensor that triggers interferon response in hepatocytes during HCV infection. METHODS: We generated a hepatic cell line that stably expressed mutant MAVS resistant to the NS3-4A cleavage. This cell line allowed us to investigate the interferon signaling pathway in the context of HCV infection. By using the knockdown and knockout technology together with biochemical approaches, we were able to identify the actual viral sensor in hepatocytes during HCV infection. RESULTS: We showed that HCV infection induced robust interferon response in the cells expressing MAVS resistant to the NS3-4A cleavage. Unexpectedly, the interaction between HCV's 3'UTR and RIG-I seemed to play a minor role in this activation, while another helicase MDA5 played a more important role in sensing HCV infection to trigger interferon response. CONCLUSIONS: Our data demonstrate that MDA5 recognizes HCV to initiate host innate immune response during HCV infection. This study provides insight into how host senses HCV to initiate innate immunity during HCV infection.


Assuntos
RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Hepacivirus/genética , Hepatite C Crônica , Hepatócitos , Interferons/metabolismo , Proteínas não Estruturais Virais/metabolismo , Regiões 3' não Traduzidas/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular , Proteína DEAD-box 58 , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Fatores Reguladores de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Imunológicos , Serina Endopeptidases/metabolismo , Transdução de Sinais
10.
Environ Monit Assess ; 187(10): 611, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26341502

RESUMO

In this study, the distribution and partitioning of nine perfluorinated compounds (PFCs) in the water and sediment of Nansi Lake were systematically investigated. The total concentration of PFCs was in the range of 38.4-91.4 ng/L in the water and 0.47-1.81 ng/g in the sediment. The concentration of perfluorooctanoic acid (PFOA) was the highest in all the homologues in the water and was in the range of 34.9-84.6 ng/L. However, perfluorooctane sulfonate (PFOS), PFOA, and perfluoroundecanoic acid (PFUnDA) were the predominant PFCs in the sediment, and their levels were similar. The levels of PFOA, PFHpA, PFOS, PFNA, and the total PFCs in the water were relatively higher in the upper region than those in the lower region of Nansi Lake. In the sediment, the levels of PFOA, PFOS, and PFUnDA showed the similar distribution tendency. Industrial wastewater discharged from the cities around Nansi Lake was the main sources of PFCs. The partitioning coefficients (K d ) of PFOA, PFNA, PFDA, and PFOS were in the range of 0.29-0.87, 1.43-2.18, 2.08-3.15, and 2.20-2.80, respectively. Therefore, the log K d of PFDA and PFOS was apparently high as compared to two other compounds. The organic matter content of the sediment had no effect on the partitioning of PFCs between sediment and water in Nansi Lake.


Assuntos
Ácidos Alcanossulfônicos/análise , Caprilatos/análise , Monitoramento Ambiental/métodos , Fluorocarbonos/análise , Sedimentos Geológicos/química , Lagos/química , Poluentes Químicos da Água/análise , China , Cidades , Águas Residuárias/química
11.
J Biol Chem ; 288(49): 35093-103, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24129573

RESUMO

Although lysine methylation is classically known to regulate histone function, its role in modulating antiviral restriction factor activity remains uncharacterized. Interferon-induced transmembrane protein 3 (IFITM3) was found monomethylated on its lysine 88 residue (IFITM3-K88me1) to reduce its antiviral activity, mediated by the lysine methyltransferase SET7. Vesicular stomatitis virus and influenza A virus infection increased IFITM3-K88me1 levels by promoting the interaction between IFITM3 and SET7, suggesting that this pathway could be hijacked to support infection; conversely, IFN-α reduced IFITM3-K88me1 levels. These findings may have important implications in the design of therapeutics targeting protein methylation against infectious diseases.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Chlorocebus aethiops , Técnicas de Silenciamento de Genes , Células HEK293 , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/genética , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza A/patogenicidade , Interferon Tipo I/metabolismo , Lisina/química , Proteínas de Membrana/genética , Metilação , Dados de Sequência Molecular , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Células Vero , Vesiculovirus/imunologia , Vesiculovirus/patogenicidade , Viroses/imunologia , Viroses/metabolismo , Viroses/prevenção & controle
12.
Environ Monit Assess ; 186(12): 8845-56, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25240496

RESUMO

The contamination levels and ecological risks of heavy metals in the sediments of the Nansi Lake were investigated. The contents of Cd, Cr, Cu, Pb, Zn, Ni, and Co in the surface sediments collected at 20 sites ranged from 0.08 to 1.12, 58.92 to 135.62, 38.09 to 78.65, 24.51 to 53.95, 110.51 to 235.36, 11.30 to 65.40, and 4.12 to 20.14 mg/kg, respectively. The results of partitioning analysis revealed that the proportions of soluble and exchangeable fraction were less than 1 %, the proportions of carbonate, amorphous oxides, organic matter, and crystalline oxides fraction were less than 10 %, and 10.52 % of Cd was associated with carbonate. The average proportions in the residual fraction ranged from 48.62 % for Cu to 73.76 % for Ni, indicating low mobility and bioavailability. The geoaccumulation index (I geo), relative enrichment factor (REF), sediment pollution index (SPI), and potential effect concentration quotient (PECQ) values of the heavy metals in the sediments were not in agreement with each another. The average REF values of Cd and Zn were higher than those of other metals. However, the average PECQ values were higher for Cr and Ni than those of other metals, indicating that these two metals would cause higher adverse biological effects. Therefore, it is suggested that future management and pollution control might focus on Cd, Zn, Cr, and Ni in the sediments of the Nansi Lake.


Assuntos
Sedimentos Geológicos/química , Metais Pesados/análise , Poluentes Químicos da Água/análise , China , Ecologia , Monitoramento Ambiental , Lagos/química , Medição de Risco
13.
Vaccines (Basel) ; 12(5)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38793728

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), remains a formidable global health challenge, affecting a substantial portion of the world's population. The current tuberculosis vaccine, bacille Calmette-Guérin (BCG), offers limited protection against pulmonary tuberculosis in adults, underscoring the critical need for innovative vaccination strategies. Cytokines are pivotal in modulating immune responses and have been explored as potential adjuvants to enhance vaccine efficacy. The strategic inclusion of cytokines as adjuvants in tuberculosis vaccines holds significant promise for augmenting vaccine-induced immune responses and strengthening protection against M. tuberculosis. This review delves into promising cytokines, such as Type I interferons (IFNs), Type II IFN, interleukins such as IL-2, IL-7, IL-15, IL-12, and IL-21, alongside the use of a granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant, which has shown effectiveness in boosting immune responses and enhancing vaccine efficacy in tuberculosis models.

14.
Biomater Adv ; 159: 213835, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38531259

RESUMO

Additive manufacturing (AM) technology has paved the way for manufacturing personalised stents. However, there is a notable gap in comprehensive microstructure analyses and in vitro evaluations of the AM CoCr stents using advanced methodologies. To address this gap, this study focuses on investigating the microstructure and in vitro performance of personalised CoCr stents manufactured through micro-laser powder bed fusion (µ-LPBF). The evaluation process begins with the measurements of dimensions and surface roughness, followed by in-depth microstructural analyses. To improve surface roughness and reduce excessive strut size, the µ-LPBF stents undergo electrochemical polishing. Importantly, in vitro stent deployments are carried out in artificial arteries manufactured based on actual patients' data. Compared to the commercial MULTI-LINK VISION CoCr stent, the µ-LPBF personalised stents have rough surface finish (average roughness: 1.55 µm for µ-LPBF vs. 1.09 µm for commercial) and compromised grain microstructures (elongated for µ-LPBF vs. equiaxed for commercial). However, the personalised stents demonstrate better performances in in vitro tests. Notably, compared to the commercial stent in the two studied cases, they deliver larger lumen gains (up to 11.24 %) and reduced recoils (up to 4 times). This study validates the merit of the lesion-specific designs and the feasibility of using AM technology for stent fabrication.


Assuntos
Artérias , Stents , Humanos , Leitos , Comércio , Grão Comestível
15.
Clin Cancer Res ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691100

RESUMO

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

16.
J Hepatol ; 59(1): 52-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23542348

RESUMO

BACKGROUND & AIMS: Hepatitis C virus (HCV) is a major human viral pathogen that causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. In most cases, acute HCV infection becomes persistent, at least in part due to viral evasion of host innate immune response. Although HCV genomic RNA contains pathogen-associated molecular pattern (PAMP) that is able to induce host interferon responses, HCV can shut down the responses by using the viral NS3/4A protease to cleave MAVS/VISA and TRIF, two key adaptor molecules essential for the interferon signaling activation. The aim of this study was to explore a novel NS3/4A-independent mechanism HCV utilizes to evade host innate immune responses. METHODS: We used the interferon promoter-reporter system to screen HCV encoded proteins for their activities to suppress the interferon signaling and to determine the molecular targets of viral proteins. Co-immunoprecipitation, confocal microscopy, and siRNA-based gene silencing were used to investigate the molecular mechanism. RESULTS: We found that, in addition to NS3/4A, NS4B can suppress double-stranded RNA or RNA virus induced interferon activation. NS4B interacts with STING/MITA, an important molecule that mediates the HCV PAMP induced interferon signaling. Mechanistic studies indicated that NS4B disrupts the interactions between STING/MITA and TBK1. CONCLUSIONS: In conclusion, we reported an additional mechanism for HCV evasion of host interferon responses in which viral NS4B protein targets STING/MITA to suppress the interferon signaling. Our results present important evidence for the control of interferon response by HCV, and shed more light on the molecular mechanisms underlying the persistence of HCV infection.


Assuntos
Hepacivirus/imunologia , Hepacivirus/patogenicidade , Proteínas de Membrana/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas não Estruturais Virais/imunologia , Linhagem Celular , Células HEK293 , Hepacivirus/enzimologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/imunologia , Interferons/biossíntese , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , NF-kappa B/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Transdução de Sinais/imunologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
17.
Environ Pollut ; 316(Pt 1): 120460, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273687

RESUMO

Per- and polyfluorolkyl substances (PFAS) were measured in the water and fish from 20 coastal tourist resorts in China, to investigate their sources, seasonal differences, and bioconcentration. An oxidative method with hydroxyl radicals was used to extract potential perfluoroalkyl acid (PFAA) precursors in the water of resorts. The results indicated that the total concentrations of target chemicals (i.e., ΣPFAS) in the original water were 59.4-138, 32.7-77.2, and 14.6-29.9 ng L-1 in December, April, and August, respectively. C4-C10 perfluorocarboxlate (PFCA) and perfluorooctane sulfonate (PFOS) accounted for 67%-92% of the ΣPFAS contents in all water samples. The PFAS concentrations in the muscles and liver of fish were 16.0-162 ng g-1 ww and 186-1240 ng g-1 ww, respectively. The dominant compounds were perfluorobutanoate acid (PFBA) and PFOS in the water, and perfluorooctanoic acid (PFOA) and PFOS in fish tissues. High bioconcentration were observed for PFCA (C ≥ 8) and perfluorosulfonate (PFSA, C ≥ 6). After oxidative conversion, the water exhibited a noticeable increase in the ΣPFAS value. Precursors that generated C4-C9 PFCA were more prevalent than precursors that generated other PFCA upon oxidation. The concentration of C8-based precursor was higher than that of C6-based precursor in wet and dry seasons. This study is the first to apply an oxidative method to investigate PFAS pollution in the water of coastal tourist resorts. The results verified that PFAA precursors exist in the water of coastal tourist resorts, and more attention should be given to the existence of PFAA precursors and the safety of water in coastal tourist resorts.


Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Poluentes Químicos da Água , Animais , Fluorocarbonos/análise , Monitoramento Ambiental , Poluentes Químicos da Água/análise , Ácidos Carboxílicos/química , Ácidos Alcanossulfônicos/análise , Água , Peixes
18.
J Colloid Interface Sci ; 640: 750-760, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-36898181

RESUMO

HYPOTHESIS: Despite that the development of Cu2SnS3 (CTS) catalyst has attracted increasing interests, few study has reported to investigate its heterogeneous catalytic degradation of organic pollutants in a Fenton-like process. Furthermore, the influence of Sn components towards Cu (II)/Cu (I) redox cycling in CTS catalytic systems remains a fascinating research. EXPERIMENTS: In this work, a series of CTS catalysts with controlled crystalline phases were prepared via a microwave-assisted pathway and applied in the H2O2 activation for phenol degradation. The efficiency of phenol degradation in CTS-1/H2O2 system (CTS-1: the molar ratio of Sn (copper acetate) and Cu (tin dichloride) is determined to be Sn:Cu = 1:1) was systematically investigated by controlling various reaction parameters including H2O2 dosage, initial pH and reaction temperature. We discovered that Cu2SnS3 exhibited superior catalytic activity to the contrast monometallic Cu or Sn sulfides and Cu (I) acted as the dominant active sites. The higher Cu (I) proportions conduce to the higher catalytic activities of CTS catalysts. Quenching experiments and electron paramagnetic resonance (EPR) further proved that the activation of H2O2 by CTS catalyst produces reactive oxygen species (ROS) and subsequently leads to degradation of the contaminants. A reasonable mechanism of enhanced H2O2 activation in Fenton-like reaction of CTS/H2O2 system was proposed for phenol degradation by investigating the roles of copper, tin and sulfur species. FINDINGS: The developed CTS acted as a promising catalyst in Fenton-like oxidation progress for phenol degradation. Importantly, the copper and tin species contribute to a synergetic effect for the promotion of Cu (II)/Cu (I) redox cycle, which thus enhanced the activation of H2O2. Our work may offer new insight on the facilitation of Cu (II)/Cu (I) redox cycle in Cu-based Fenton-like catalytic systems.

19.
Cell Rep Med ; 3(3): 100554, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35492873

RESUMO

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Receptor de Morte Celular Programada 1/genética , Proteínas Serina-Treonina Quinases/genética , Receptor Tirosina Quinase Axl
20.
Nat Commun ; 12(1): 5866, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620867

RESUMO

Type I interferon is promising in treating different kinds of tumors, but has been limited by its toxicity, lack of tumor targeting, and very short half-life. To target tumors, reduce systemic toxicity, and increase half-life, here we engineer a masked type I IFN-Fc (ProIFN) with its natural receptor connected by a cleavable linker that can be targeted by tumor-associated proteases. ProIFN has a prolonged serum half-life and shows an improved tumor-targeting effect. Interestingly, ProIFN-treated mice show enhanced DC cross-priming and significant increased CD8+ infiltration and effector function in the tumor microenvironment. ProIFN is able to improve checkpoint blockade efficacy in established tumors, as well as radiation efficacy for both primary and metastatic tumors. ProIFN exhibits superior long-term pharmacokinetics with minimal toxicity in monkeys. Therefore, this study demonstrates an effective tumor-activating IFN that can increase targeted immunity against primary tumor or metastasis and reduce periphery toxicity to the host.


Assuntos
Antineoplásicos/imunologia , Imunidade , Interferon Tipo I/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Haplorrinos , Imunoterapia , Cinética , Camundongos , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA