RESUMO
The discovery of the 'two birds, one stone' electrochemical nitrate reduction reaction (NO3RR) allows for the removal of harmful NO3-pollutants as well as the production of economically beneficial ammonia (NH3). However, current understanding of the catalytic mechanism of NO3RR is not enough, and this research is still challenging. To determine the mechanism needed to create efficient electrocatalysts, we thoroughly examined the catalytic activity of molybdenum-based diatomic catalysts (DACs) anchored on two-dimensional carbon-rich conjugated frameworks (2D CCFs) for NO3RR. Among the 23 candidate materials, after a four-step screening method and detailed mechanism studies, we discovered that NO3RR can efficiently generate NH3by following the N-end pathway on the MoTi-Pc, MoMn-Pc, and MoNb-Pc, with limiting potential of -0.33 V, -0.13 V, and -0.38 V, respectively. The activity of NO3RR can be attributed to the synergistic effect of the TM1-TM2dimer d orbital coupling to the anti-bonding orbital of NO3-. Additionally, high hybridization between the Mo-4d, TM-3d(4d), and NO3--2p orbitals on the MoTMs-Pc DACs can speed up the flow of electrons from the Mo-TM dual-site to NO3-. The research presented here paves the way for the reasonable design of effective NO3RR catalysts and offers a theoretical basis for experimental research.
RESUMO
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole ß-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Monócitos/imunologia , Neutrófilos/imunologia , beta-Glucanas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Apresentadoras de Antígenos/imunologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Western Blotting , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Diferenciação Celular/imunologia , Separação Celular , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Lectinas Tipo C/metabolismo , Neoplasias Pulmonares/imunologia , Teste de Cultura Mista de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Monócitos/citologia , Células Mieloides/citologia , Células Mieloides/imunologia , Neutrófilos/citologia , Reação em Cadeia da Polimerase em Tempo Real , Leveduras , beta-Glucanas/imunologiaRESUMO
Human ficolin-2 (FCN-2) and mouse ficolin-A (FCN-A, a ficolin-2-like molecule in mouse) are activators of the lectin complement pathway, present in normal plasma and usually associated with infectious diseases, but little is known about the role of FCN-A/2 in inflammatory bowel disease (IBD). In our present study, we found that patients with IBD exhibited much higher serum FCN-2 levels than healthy controls. In the dextran sulphate sodium-induced acute colitis mouse model, FCN-A knockout mice showed much milder disease symptoms with less histological damage, lower expression levels of pro-inflammatory cytokines [interleukin-6 (IL-6), IL-1ß and tumour necrosis factor-α (TNF-α)], chemokines (CXCL1/2/10 and CCL4) and higher levels of the anti-inflammatory cytokine IL-10 compared with wild-type mice. We demonstrated that FCN-A/2 exacerbated the inflammatory pathogenesis of IBD by stimulating M1 polarization through the TLR4/MyD88/MAPK/NF-κB signalling pathway in macrophages. Hence, our data suggest that FCN-A/2 may be used as a novel therapeutic target for IBD.
Assuntos
Diferenciação Celular , Colite/imunologia , Inflamação/imunologia , Lectinas/metabolismo , Macrófagos/imunologia , Animais , Células Cultivadas , Lectina de Ligação a Manose da Via do Complemento/genética , Citocinas/metabolismo , Humanos , Lectinas/genética , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo , FicolinasRESUMO
Tumor-associated macrophages (TAM) with an alternatively activated phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. In this study, we demonstrate that particulate yeast-derived ß-glucan, a natural polysaccharide compound, converts polarized alternatively activated macrophages or immunosuppressive TAM into a classically activated phenotype with potent immunostimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, Krebs cycle, and glutamine utilization. In addition, particulate ß-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1-induced spleen tyrosine kinase-Card9-Erk pathway. Further in vivo studies show that oral particulate ß-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate ß-glucan-treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared with those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate ß-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed light on the action mode of ß-glucan treatment in cancer.
Assuntos
Polissacarídeos Fúngicos/farmacologia , Lectinas Tipo C/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Neoplasias Experimentais/tratamento farmacológico , Saccharomyces cerevisiae/química , beta-Glucanas/farmacologia , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Linhagem Celular Tumoral , Polissacarídeos Fúngicos/química , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , beta-Glucanas/químicaRESUMO
Recently, macrophages were shown to be capable of differentiating toward two phenotypes after antigen stimulation: a classically activated (M1) or an alternatively activated phenotype (M2). To investigate the effect of Salmonella enteric serovar typhimurium (S. typhimurium) on macrophage differentiation, we compared macrophage phenotypes after infection of murine bone marrow-derived macrophages with wild-type S. typhimurium and its isogenic rfc mutant. S. typhimurium C5 induced M1 macrophage polarization and enhanced inducible nitric oxide synthase expression by macrophages; this induction was dependent on Toll-like receptor 4. In contrast, the Δrfc mutant (S. typhimurium C5 rfc::Km(r)) lost this function and induced an M2 response in the macrophages. Here, we propose that S. typhimurium C5 is capable of polarizing macrophages towards the M1 phenotype and that this polarization is dependent on the O antigen encoded by rfc. Our finding indicates that M1 macrophage polarization induced by S. typhimurium may be related to the ability of this intracellular bacterium to survive and replicate within macrophages, which is essential for systemic disease.
Assuntos
Macrófagos/imunologia , Macrófagos/microbiologia , Antígenos O/imunologia , Salmonella typhimurium/imunologia , Animais , Diferenciação Celular/imunologia , Citocinas/imunologia , Deleção de Genes , Hexosiltransferases/genética , Hexosiltransferases/imunologia , Interações Hospedeiro-Patógeno , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Antígenos O/genética , Antígenos O/isolamento & purificação , Fenótipo , Salmonella typhimurium/genética , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologiaRESUMO
The major surface lipoglycan of Mycobacterium tuberculosis (M. tb), mannose-capped lipoarabinomannan (ManLAM), is an immunosuppressive epitope of M. tb. We used systematic evolution of ligands by exponential enrichment (SELEX) to generate an aptamer (ZXL1) that specifically bound to ManLAM from the virulent M. tb strain H37Rv. Aptamer ZXL1 had the highest binding affinity, with an equilibrium dissociation constant (Kd) of 436.3 ± 37.84 nmol/l, and competed with the mannose receptor for binding to ManLAM and M. tb H37Rv. ZXL1 significantly inhibited the ManLAM-induced immunosuppression of CD11c(+) dendritic cells (DCs) and enhanced the M. tb antigen-presenting activity of DCs for naive CD4(+) Th1 cell activation. More importantly, we demonstrated that injection of aptamer ZXL1 significantly reduced the progression of M. tb H37Rv infections and bacterial loads in lungs of mice and rhesus monkeys. These results suggest that the aptamer ZXL1 is a new potential antimycobacterial agent and tuberculosis vaccine immune adjuvant.
Assuntos
Aptâmeros de Nucleotídeos/genética , Lipopolissacarídeos/imunologia , Mycobacterium tuberculosis/genética , Tuberculose/terapia , Animais , Aptâmeros de Nucleotídeos/uso terapêutico , Células Dendríticas/imunologia , Epitopos/genética , Epitopos/imunologia , Humanos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/genética , Ativação Linfocitária/imunologia , Macaca mulatta , Manose/genética , Manose/imunologia , Camundongos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Tuberculose/genética , Tuberculose/patologia , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/uso terapêuticoRESUMO
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Increasing evidence suggests that microRNAs (miRNAs) are associated with HCC tumorigenesis. The present study was designed to define the role of miR-141 in HCC. The expression of miR-141 was significantly decreased in four HCC cell lines. Overexpression of miR-141 suppressed both the growth and the motility of HCC cells. Furthermore, we identified zinc finger E-box binding homeobox 2 (ZEB2) as a target of miR-141 and miR-141 functioned as a tumor suppressor via ZEB2 targeting in HCC. These data provide a novel potential therapeutic target for HCC treatment.
Assuntos
Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Homeodomínio/biossíntese , Neoplasias Hepáticas/patologia , Proteínas Repressoras/biossíntese , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Genes Supressores de Tumor , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
OBJECTIVE: Nasopharyngeal Carcinoma (NPC) is lethal cancer. Typically, relapse and metastasis are the outcomes of most patients. Against this backdrop, this study aimed to investigate the correlation between Circulating Tumor Cell (CTC) profiles and clinicopathological features in patients with NPC. PATIENTS AND METHODS: A total of 119 blood samples from 79 patients were collected from patients with NPC during treatment. CanPatrolTM CTC enrichment and RNA In Situ Hybridization (RNA-ISH) were used to characterize CTCs, including epithelial, Mesenchymal (MCTCs), and epithelial/mesenchymal mixed types according to their surface markers. RESULTS: The number of CTCs and MCTCs in the pre-treatment group was significantly higher than that in the post-treatment group (p < 0.05). The total number of CTCs and MCTCs cell numbers was significant correlation with Tumor-Node-Metastasis (TNM) staging (p < 0.05), Progression-Free Survival (PFS), and Overall Survival (OS). The PFS of patients with > 7 CTCs or > 5 MCTCs per 5 mL blood was significantly shorter PFS than those patients with ≤ 7 CTCs or ≤ 5 MCTCs (p < 0.05). Patients treated with targeted therapy combined with chemoradiotherapy had poorer PFS and OS rates than those treated with chemoradiotherapy (p < 0.05). The Kaplan-Meier survival analysis also demonstrated that patients with changes in CTC > 4 were strongly associated with PFS and OS rates (p < 0.05). CONCLUSION: CTC and MCTC number detection in patients with NPC is a useful biomarker for predicting patient progress. Patients with more than 7 CTCs or 5 MCTCs in 5 mL of blood had shorter PFS and OS rates. CTC and MCTC count changes were also significantly associated with the patient's therapy.
Assuntos
Neoplasias Nasofaríngeas , Células Neoplásicas Circulantes , Humanos , Prognóstico , Carcinoma Nasofaríngeo , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Recidiva Local de Neoplasia , RNA , Biomarcadores TumoraisRESUMO
Multidrug-resistant Mycobacterium tuberculosis is resistant to two first-line antituberculosis drugs, isoniazid and rifampin, resulting in the relapse of tuberculosis. M. tuberculosis grows very slowly, and thus traditional examination methods take time to test its drug resistance and cannot meet clinical needs. The use of a DNA probe makes it possible to test rifampin resistance. We developed an asymmetrical split-assembly DNA peroxidase assay to detect drug-resistant mutation of rifampin-resistant M. tuberculosis in the rpoB gene rapidly and visibly. A new strategy was also designed to eliminate the adverse effects caused by the complicated secondary structure of the target DNA and to improve the efficiency of the probes. This detection system consists of five group detections, covers rifampin-resistant determination region of the rpoB gene, and tests 40 kinds of mutations, including the most common mutations at codons 531 and 526. Every group detection or individual mutant allele detection can distinguish corresponding mutant DNA sequences from the wild-type DNA sequences.
Assuntos
Proteínas de Bactérias/genética , DNA Catalítico , Farmacorresistência Bacteriana , Mutação de Sentido Incorreto , Mycobacterium tuberculosis/efeitos dos fármacos , Rifampina/farmacologia , DNA Catalítico/metabolismo , RNA Polimerases Dirigidas por DNA , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Peroxidase/metabolismo , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
Novel pH-activatable fluorescent probes with various pK(a) values have been developed utilizing 4-nitro-benzo[1,2,5]oxadiazole derivatives (NBD) as fluorophores and piperazine moieties as proton receptors. Under acidic conditions, probe FoPz displayed significant fluorescent enhancement of about 30 fold with a pK(a) value of 5.70 and it responds rapidly and sensitively to intracellular pH distributions and cellular pH fluctuations.
Assuntos
Corantes Fluorescentes/química , Microscopia Confocal , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Oxidiazóis/química , PrótonsRESUMO
c-Myc (Myc) is a well-known transcription factor that regulates many essential cellular processes. Myc has been implicated in regulating anti-mycobacterial responses. However, its precise mechanism in modulating mycobacterial immunity remains elusive. Here, we found that a secreted Rv1579c (early secreted target with molecular weight 12 kDa, named EST12) protein, encoded by virulent Mycobacterium tuberculosis (M.tb) H37Rv region of deletion (RD)3, induces early expression and late degradation of Myc protein. Interestingly, EST12-induced Myc was further processed by K48 ubiquitin proteasome degradation in E3 ubiquitin ligase FBW7 dependent manner. EST12 protein activates JNK-AP1-Myc signaling pathway, promotes Myc binding to the promoters of IL-6, TNF-α and iNOS, then induces the expression of pro-inflammatory cytokines (IL-6 and TNF-α)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) to increase mycobacterial clearance in a RACK1 dependent manner, and these effects are impaired by both Myc and JNK inhibitors. Macrophages infected with EST12-deficiency strain (H37RvΔEST12) displayed less production of iNOS, IL-6 and TNF-α. In conclusion, EST12 regulates Myc expression and enhances anti-mycobacterial inflammatory response via RACK1-JNK-AP1-Myc immune pathway. Our finding provides new insights into M.tb-induced immunity through Myc.
Assuntos
Proteínas de Bactérias , Mycobacterium tuberculosis , Proteínas Proto-Oncogênicas c-myc , Tuberculose , Humanos , Proteínas de Bactérias/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , MAP Quinase Quinase 4/metabolismo , Mycobacterium tuberculosis/fisiologia , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores de Quinase C Ativada/metabolismo , Transdução de Sinais , Tuberculose/genética , Tuberculose/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Small peptides that inhibit the hepatitis C virus (HCV) at the stage of viral entry have the potential to serve as attractive antiviral drugs. Ribosome display is a cell-free system for in vitro selection of peptides from large random peptide libraries. Thus, we utilized a ribosome display library technique for affinity selection of HCV envelope protein E2-binding peptide ligands. Through 13 rounds of selection, the ribosome display system generated high-affinity 12-mer peptides, and the selected peptide PE2D (MARHRNWPLVMV) demonstrated the highest specificity and affinity to the HCV E2 protein. Furthermore, amino acids 489 to 508 (YPPRPCGIVPAKSVCGPVYC) of E2 were identified as crucial for binding to PE2D. The selected peptides, especially PE2D, not only dramatically blocked E2 protein binding to hepatocytes but also dramatically inhibited HCV cell culture (HCVcc) entry into hepatocytes. HCVcc and HCV particles from HCV patient serum samples could also be specifically captured using PE2D. Our study demonstrates that the newly selected peptide ligand PE2D holds great promise for developing a new molecular probe, a therapeutic drug specifically for HCV, or an early-diagnostic reagent for HCV surface envelope antigen E2.
Assuntos
Antivirais/metabolismo , Hepacivirus/metabolismo , Sondas Moleculares/metabolismo , Biblioteca de Peptídeos , Peptídeos/metabolismo , Proteínas do Envelope Viral/metabolismo , Antivirais/farmacologia , Proteínas de Transporte , Linhagem Celular Tumoral , Hepacivirus/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Ligantes , Peptídeos/farmacologia , Ribossomos/metabolismoRESUMO
Salmonella are important intracellular pathogens in humans and other animal hosts. IL-24 is a novel tumour suppressor and can mediate induction of Th1-type cytokines from PBMC. However, the immunological consequences of this cytokine during intracellular pathogen infection in vivo remain unclear. In the present study, we used a virulent S. typhimurium C5 infected mouse model of typhoid fever to demonstrate that administration of exogenous IL-24 had a protective effect against the bacteria. The IL-24 glycosylation site mutant, in contrast, showed a decreased protective effect. Furthermore, the protective effect of IL-24 was abrogated in IFN-gamma KO mice. More importantly, we demonstrated that IL-24 predominately stimulated neutrophils to produce IFN-gamma and IL-12, subsequently activating CD8+ T cells both in vivo and in vitro. In addition, IL-24 could induce neutrophils to produce NO. These data indicate that the neutrophils activated by IL-24 may play important roles in host defence against Salmonella infection in vivo. Our findings support the development of a novel cytokine immunotherapy against Salmonella.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Interleucinas/metabolismo , Salmonelose Animal/metabolismo , Animais , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucinas/genética , Interleucinas/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Salmonelose Animal/microbiologia , Salmonelose Animal/prevenção & controle , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/crescimento & desenvolvimento , Células Th1/metabolismo , Transfecção , Febre Tifoide/imunologia , Febre Tifoide/metabolismoRESUMO
Macrophages have been linked to tumor initiation, progression, metastasis, and treatment resistance. However, the transcriptional regulation of macrophages driving the protumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conserved noncoding sequence of the Csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating the TCA cycle and UDP-GlcNAc biosynthesis, thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAMs) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates their immunosuppressive activity. The natural compound ß-glucan downregulates c-Maf expression on macrophages, leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunidade Celular , Neoplasias Pulmonares/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , Neoplasias Experimentais/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Proteínas Proto-Oncogênicas c-maf/genética , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
In an attempt to combine the HIV-inhibitory capacity of different 2',3'-dideoxynucleoside (ddN) analogs, we have designed and synthesized several dimers of [AZT]-[AZT] and [AZT]-[d4T]. In addition, we also synthesized the dimers of 1-(1H-benzimidazol-1-yl)-1-deoxy-beta-D-ribofuranose. The in vitro anti-HIV activity of these compounds on a pseudotype virus, pNL4-3.Luc.R-E-, in the 293T cells has been determined. Among these compounds, 2,2'-(propane-1,3-diyl)bis[1-(beta-D-ribofuranosyl)-1H-benzimidazole] showed the highest anti-HIV activity with similar effect as AZT.
Assuntos
Fármacos Anti-HIV/síntese química , Benzimidazóis/química , Benzimidazóis/síntese química , Didesoxinucleosídeos/química , Nucleosídeos/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular , Didesoxinucleosídeos/síntese química , Didesoxinucleosídeos/farmacologia , Dimerização , Proteína do Núcleo p24 do HIV/metabolismo , Humanos , Nucleosídeos/química , Nucleosídeos/farmacologia , Zidovudina/químicaRESUMO
The entire human population is at risk of infectious diseases worldwide. Thus far, the diagnosis and treatment of human infectious diseases at the molecular and nanoscale levels have been extremely challenging tasks because of the lack of effective probes to identify and recognize biomarkers of pathogens. Oligonucleotide aptamers are a class of small nucleic acid ligands that are composed of single-stranded DNA (ssDNA) or RNA and act as affinity probes or molecular recognition elements for a variety of targets. These aptamers have an exciting potential for diagnose and/or treatment of specific diseases. In this review, we highlight areas where aptamers have been developed as diagnostic and therapeutic agents for both bacterial and viral infectious diseases as well as aptamer-based detection.
Assuntos
Aptâmeros de Nucleotídeos/farmacologia , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/terapia , Anticorpos , HumanosRESUMO
There is a need to develop protective vaccines against tuberculosis (TB). Recently, we identified an immunodominant T-cell antigen, Rv2645, from the region of deletion 13 (RD13) of M. tuberculosis (M. tb) H37Rv, which is absent in Bacille Calmette-Guérin (BCG). Here, a recombinant BCG expressing Rv2645, namely, BCG::Rv2645, was constructed. Compared to BCG, we found that BCG::Rv2645 improved the antigen presentation capacity of dendritic cells (DCs) and elicited much stronger Th1 and Th17 responses, higher CD44highCD62low effector memory CD4+ T cells (TEM), and fewer T regulated cells (Treg) and regulatory B10 in mice. Importantly, BCG::Rv2645 exhibited enhanced protective efficacy against virulent M. tb H37Rv challenge in both mice and rhesus monkeys, showing less severe pathology and reduced pathogens. Further, transcriptomic analysis and reverse transcription-quantitative real time PCR revealed that the mRNA levels of ISGylation (Isg)-related genes such as interferon-stimulated gene 15 (Isg15), and Th1- and Th17-related genes such as interferon-γ (IFN-γ) and interleukin-17A (IL-17A) were significantly up-regulated in splenocytes and macrophages after stimulation with Rv2645. This study shows that BCG::Rv2645 is a promising TB vaccine candidate with enhanced protective immunity. The enhanced Th1/Th17 immune responses and up-regulation of ISGylation-related genes induced by Rv2645 may be major factors contributing to the protective immunity of BCG::Rv2645.
Assuntos
Vacina BCG/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium bovis/imunologia , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tuberculose/prevenção & controle , Animais , Vacina BCG/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/genética , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Genes , Leucócitos Mononucleares/imunologia , Macaca mulatta , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Mycobacterium bovis/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
Abstract Objective: Nasopharyngeal Carcinoma (NPC) is lethal cancer. Typically, relapse and metastasis are the outcomes of most patients. Against this backdrop, this study aimed to investigate the correlation between Circulating Tumor Cell (CTC) profiles and clinicopathological features in patients with NPC. Patients and methods: A total of 119 blood samples from 79 patients were collected from patients with NPC during treatment. CanPatrol™ CTC enrichment and RNA In Situ Hybridization (RNA-ISH) were used to characterize CTCs, including epithelial, Mesenchymal (MCTCs), and epithelial/mesenchymal mixed types according to their surface markers. Results: The number of CTCs and MCTCs in the pre-treatment group was significantly higher than that in the post-treatment group (p < 0.05). The total number of CTCs and MCTCs cell numbers was significant correlation with Tumor-Node-Metastasis (TNM) staging (p < 0.05), Progression-Free Survival (PFS), and Overall Survival (OS). The PFS of patients with > 7 CTCs or > 5 MCTCs per 5 mL blood was significantly shorter PFS than those patients with ≤ 7 CTCs or ≤ 5 MCTCs (p < 0.05). Patients treated with targeted therapy combined with chemoradiother-apy had poorer PFS and OS rates than those treated with chemoradiotherapy (p < 0.05). The Kaplan-Meier survival analysis also demonstrated that patients with changes in CTC > 4 were strongly associated with PFS and OS rates (p < 0.05). Conclusion: CTC and MCTC number detection in patients with NPC is a useful biomarker for predicting patient progress. Patients with more than 7 CTCs or 5 MCTCs in 5 mL of blood had shorter PFS and OS rates. CTC and MCTC count changes were also significantly associated with the patient's therapy.