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1.
J Nanosci Nanotechnol ; 21(2): 1054-1060, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33183443

RESUMO

This article explores the role of lysin nanocarriers in inducing apoptosis of human hepatocellular carcinoma cells and the possible molecular mechanisms. Cytotoxicity tests were performed in human fibroblast cell line MRC-5. Anti-cancer activity was tested in liver cancer cell lines HepG2 and HCCLM3. The results show that nanocarriers have a targeting effect on cancer cells, have high safety, and are good delivery vehicles for drugs. In this paper, the stability of lycopene and its degradation in aqueous solutions at different temperatures were studied, and the structure and mechanism of degradation products were determined. A new type of mesoporous silica nanocarrier was synthesized as a delivery carrier of lysin and its derivatives, which has a targeting effect on cancer cells and has a slow-release effect. Surface modification can improve circulation time and stability for future resistance in vivo. The cancer experiment laid the foundation. The results showed that the lysin nanocarriers inhibited the proliferation of HepG2 and HCCLM3 human liver cancer cells in a dependent manner. After the lysin nanocarriers acted on HepG2 human hepatocellular carcinoma cells for 48 h, the cell apoptosis rate was significantly increased by flow cytometry analysis. The carrier can significantly increase the levels of reactive oxygen species and malondialdehyde, and reduce the content of reduced glutathione and superoxide dismutase. At the same time, the lysin nanocarrier can down-regulate the expression of Nrf2 and HO-1 proteins, and inhibit the occurrence of Nrf2 Nuclear displacement. The lycopene nanocarrier inhibits the proliferation of HepG2, HCCLM3 human liver cancer cells, induces apoptosis, regulates the oxidative stress response in the cell, and regulates the Nrf2/AREE antioxidant signaling pathway, thereby promoting tumor cell apoptosis.

2.
Medicine (Baltimore) ; 99(50): e23230, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327242

RESUMO

BACKGROUND: Hepatolithiasis commonly occurs in the bile duct proximal to the confluence of the right and left hepatic ducts, regardless of the coexistence of gallstones in gallbladder or the common bile duct. Clinical research proves that minimally invasive surgery is effective in the treatment of hepatolithiasis. Although previous meta-analysis also shows that it could reduce intraoperative bleeding and blood transfusion, and shorten hospital stay time, there are few meta-analyses on its long-term efficacy. We conducted the meta-analysis and systematic review to systematically evaluate the long-term efficacy and advantages of minimally invasive hepatectomy in the treatment of hepatolithiasis. METHODS: Articles of randomized controlled trials will be searched in the PubMed, Medline, Embase, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database, and Wanfang database until September, 2020. Literature extraction and risk of bias assessment will be completed by 2 reviewers independently. Statistical analysis will be conducted in RevMan 5.3. RESULTS: This study will summarize the present evidence by exploring the long-term efficacy and advantages of minimally invasive hepatectomy in the treatment of hepatolithiasis CONCLUSIONS:: The findings of the study will help to determine potential long-term efficacy and advantages of minimally invasive hepatectomy in the treatment of hepatolithiasis. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/H6WRV.


Assuntos
Colelitíase/cirurgia , Hepatectomia , Procedimentos Cirúrgicos Minimamente Invasivos , Hepatectomia/efeitos adversos , Hepatectomia/métodos , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Resultado do Tratamento
3.
Immunol Rev ; 298(1): 254-263, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33037700

RESUMO

Unique Vγ2Vδ2 (Vγ9Vδ2) T cells existing only in human and non-human primates, account for the majority of circulating γδ T cells in human adults. Vγ2Vδ2 T cells are the sole γδ T-cell subpopulation capable of recognizing the microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by selected pathogens during infections. Recent seminal studies in non-human primate models have demonstrated that the unique HMBPP-specific Vγ2Vδ2 T cells are fast-acting, multi-functional, and protective during infections. This article reviews the recent seminal observations of Vγ2Vδ2 T cells in protective mechanisms against tuberculosis and other infections.

4.
Sci Rep ; 10(1): 6626, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296079

RESUMO

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

5.
Exp Ther Med ; 19(2): 1203-1212, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32010290

RESUMO

The therapeutic effect of saikosaponin a (SSa) on hyperlipidemic pancreatitis (HP) is not completely understood. The aim of the present study was to investigate the therapeutic effect and the underlying mechanism of SSa using a rat model of HP. Following successful establishment of the HP rat model, different doses of SSa (low dose group, 10 mg/kg or high dose group, 20 mg/kg) were administrated. Histopathological examination, the wet/dry (W/D) ratio and myeloperoxidase (MPO) activity of the pancreatic tissues were assessed. The lipid, amylase (AMY), lipase and proinflammatory cytokine profiles in serum, as well as the expression of peroxisome proliferator-activated receptor (PPAR)-γ and the NF-κB signaling pathway-related proteins in pancreatic tissues were evaluated. The results showed that SSa effectively attenuated pancreatic pathological injury and reduced both the W/D ratio and MPO activity compared to the HP model rats. SSa also improved lipid metabolism by significantly decreasing the serum levels of total cholesterol and triglycerides (P<0.05). Following the administration of SSa, the activity of AMY and lipase, as well as the levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1ß and IL-6 were reduced, particularly in the high dosage group (P<0.05). Furthermore, SSa activated PPAR-γ expression and suppressed the NF-κB signaling pathway in pancreatic tissues. The present study suggested that SSa attenuated HP in rats by increasing lipid metabolism and inhibiting the release of proinflammatory cytokines via the NF-κB inflammatory pathway. The results from the present study indicated that SSa might be a promising therapeutic agent for the treatment of HP.

6.
Angew Chem Int Ed Engl ; 59(8): 3226-3234, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-31756258

RESUMO

Pathogenesis hallmarks for tuberculosis (TB) are the Mycobacterium tuberculosis (Mtb) escape from phagolysosomal destruction and limited drug delivery into infected cells. Several nanomaterials can be entrapped in lysosomes, but the development of functional nanomaterials to promote phagolysosomal Mtb clearance remains a big challenge. Here, we report on the bactericidal effects of selenium nanoparticles (Se NPs) against Mtb and further introduce a novel nanomaterial-assisted anti-TB strategy manipulating Ison@Man-Se NPs for synergistic drug-induced and phagolysosomal destruction of Mtb. Ison@Man-Se NPs preferentially entered macrophages and accumulated in lysosomes releasing Isoniazid. Surprisingly, Ison@Man-Se/Man-Se NPs further promoted the fusion of Mtb into lysosomes for synergistic lysosomal and Isoniazid destruction of Mtb. Concurrently, Ison@Man-Se/Man-Se NPs also induced autophagy sequestration of Mtb, evolving into lysosome-associated autophagosomal Mtb degradation linked to ROS-mitochondrial and PI3K/Akt/mTOR signaling pathways. This novel nanomaterial-assisted anti-TB strategy manipulating antimicrobial immunity and Mtb clearance may potentially serve in more effective therapeutics against TB and drug-resistant TB.

10.
Tuberculosis (Edinb) ; 118: 101861, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31526947

RESUMO

Histone deacetylase inhibitors (HDACi), a novel class of anti-cancer drug, have been recently reported to suppress host immunity and increase susceptibility to infection. Tuberculosis, a leading infectious disease killer caused by Mycobacterium tuberculosis (M.tb), is basically the product of the interaction between bacterial virulence and host resistance. However, the effects of HDACi in host immunity against M.tb is largely unknown. In this study, we found that HDACi including Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) significantly impaired phagocytosis and killing activity of macrophage. In line with these findings, we noted that M.tb induced reactive oxygen species (ROS) production and autophagy are significantly suppressed by TSA. Transcriptome analysis revealed that the suppression of autophagy by TSA might due to its inhibiting autophagy-regulating genes such as CACNA2D3, which regulates intracellular Ca2+ levels. Finally, we confirmed that HDACi including TSA and SAHA significantly exacerbated the histopathological damage and M.tb load in the lung of M.tb infected mice. Taken together, our results indicated that HDACi at least TSA and SAHA significantly impaired macrophage immunity against M.tb and therefore increase susceptibility to TB, our findings raised the concern that the potential side effects of HDACi on latent TB reactivation should be considered in clinic.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Tuberculose/imunologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Carga Bacteriana/efeitos dos fármacos , Células Cultivadas , Contagem de Colônia Microbiana , Suscetibilidade a Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Tuberculose/microbiologia , Vorinostat/farmacologia
12.
Mater Sci Eng C Mater Biol Appl ; 103: 109777, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349400

RESUMO

Tuberculosis (TB), caused by M.tuberculosis (Mtb), has become a top killer among infectious diseases. Enhancing the ability of anti-TB drugs to kill intracellular Mtb in host cells remains a big challenge. Here, an innovative nano-system was developed to increase drug delivery and Mtb-killing efficacy in Mtb-infected macrophages. We employed mannose surface decoration to develop mannosylated and PEGylated graphene oxide (GO-PEG-MAN). Such nano-platform exhibited increased uptake by macrophages via mannose receptor-mediated endocytosis in vitro. Interestingly, drug-loaded GO-PEG-MAN was preferentially up-taken by mannose receptor-expressing mucosal CD14+ macrophages isolated from Mtb-infected rhesus macaques than drug-loaded GO-PEG. Consistently, the drug concentration was also significantly higher in macrophages than that in T and B cells expressing no or low mannose receptor, implicating a useful macrophage/mannose receptor-targeted drug-delivery system relevant to the in vivo settings. Concurrently, rifampicin-loaded GO-PEG-MAN (Rif@GO-PEG-MAN) significantly increased rifampicin uptake, inducing long-lasting higher concentration of rifampicin in macrophages. Such innovative Rif@GO-PEG-MAN could readily get into the lysosomes of the Mtb host cells, where rifampicin underwent an accelerated release in acidic lysosomic condition, leading to explosive rifampicin release after cell entry for more effective killing of intracellular Mtb. Most importantly, Rif@GO-PEG-MAN-enhanced intracellular rifampicin delivery and pharmacokinetics significantly increased the efficacy of rifampicin-driven killing of intracellular BCG and Mtb bacilli in infected macrophages both in vitro and ex vivo. Such innovative nanocarrier approach may potentially enhance anti-TB drug efficacy and reduce drug side effects.


Assuntos
Sistemas de Liberação de Medicamentos , Grafite , Macrófagos , Manose , Mycobacterium tuberculosis/metabolismo , Nanopartículas , Rifampina , Tuberculose , Animais , Grafite/química , Grafite/farmacocinética , Grafite/farmacologia , Humanos , Macaca mulatta , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/patologia , Manose/química , Manose/farmacocinética , Manose/farmacologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Rifampina/química , Rifampina/farmacocinética , Rifampina/farmacologia , Células THP-1 , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Tuberculose/patologia
13.
Zhongguo Zhong Yao Za Zhi ; 44(7): 1464-1474, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090306

RESUMO

To predict the targets of active ingredients of Kuihua Hugan Tablets by network pharmacology, and explore the "multi-component-multi-target-multi-pathway" hepatoprotective mechanism of action. First, through traditional Chinese medicine systems pharmacology(TCMSP) and TCM Database@Taiwan Database, main active ingredients of Kuihua Hugan Tablets were screened out based on oral bioavailability(OB), drug-likeness(DL) and effective half-lives(HL). The targets of active ingredients of Kuihua Hugan Tablets were predicted based on the PharmMapper method. Then, the prediction was conducted by screening the target genes associated with chronic hepatitis and early cirrhosis through CooLGeN and GeneCards databases. Target gene functions and signal pathways were analyzed by bioinformatics annotation database Metascape. Cytoscape software was used to construct the Kuihua Hugan Tablets ingredient-target and ingredient-target-pathway network. String database combined with Cytoscape software was used to construct the networks of component-target and component-target-pathway. STRING database was combined with Cytoscape software to draw protein-protein interaction(PPI) network and conduct network topology analysis. Finally, Systems Dock Web Site software was applied in verifying the molecular docking between active ingredients and potential protein targets. A total of 26 compounds and 509 potential targets were screened out from Kuihua Hugan Tablets in the experiment. The results of PPI network analysis indicated that albumin(ALB), insulin-like growth factor 1(IGF1), matrix metalloproteinase-9(MMP9), matrix metalloproteinase-2(MMP2), non-receptor tyrosine kinase proto-oncogene(SRC), estrogen receptor 1(ESR1) and cancer-signal transduction-inflammation-drugs metabolism-related biological processes and metabolic pathways were closely associated with the active ingredients in Kuihua Hugan Tablets. The effects of Kuihua Hugan Tablets in alleviating chronic hepatitis and early cirrhosis indicated the multi-component, multi-target, and multi-pathway characteristics of traditional Chinese medicines, providing new ideas for further research and development of Kuihua Hugan Tablets.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Redes e Vias Metabólicas , Mapeamento de Interação de Proteínas , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Comprimidos
14.
Front Immunol ; 10: 913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080452

RESUMO

While IL-12 plays a key role in differentiation of protective CD4+ Th1 response, little is known about mechanisms whereby IL-12 differentiates other T-cell populations. Published studies suggest that predominant Vγ2Vδ2 T cells in humans/nonhuman primates (NHP) are a fast-acting T-cell subset, with capacities to rapidly expand and produce Th1 and cytotoxic cytokines in response to phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by Mycobacterium tuberculosis (Mtb) or others. However, whether IL-12 signaling pathway mediates fast-acting and Th1 or anti-microbial features of Vγ2Vδ2 T cells remains poorly defined. Here, we show that IL-12, but not other IL-12 family members IL-27/IL-35, apparently expanded HMBPP-activated Vγ2Vδ2 T cells. Although IL-12 and IL-2 similarly expanded HMBPP-activated Vγ2Vδ2 T-cell clones, the IL-12-induced expansion did not require endogenous IL-2 or IL-2 co-signaling during HMBPP + IL-12 co-treatment. IL-12-induced expansion of Vγ2Vδ2 T cells required the PI3K/AKT and STAT4 activation pathways and endogenous TNF-α signaling but did not involve p38/MAPK or IFN-γ signals. IL-12-expanded Vγ2Vδ2 T cells exhibited central/effector memory phenotypes and differentiated into polyfunctional effector cell subtypes which expressed TBX21/T-bet, antimicrobial cytokines IFN-γ, TNF-α, GM-CSF, and cytotoxic granule molecules. Furthermore, the IL-12-expanded Vγ2Vδ2 T cells inhibited the growth of intracellular mycobacteria in IFN-γ- or TNF-α-dependent fashion. Our findings support the concept that IL-12 drives early development of fast-acting Vγ2Vδ2 T effector cells in antimicrobial immune responses.


Assuntos
Interleucina-12/imunologia , Linfócitos Intraepiteliais/imunologia , Mycobacterium tuberculosis/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th1/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Humanos , Ativação Linfocitária/efeitos dos fármacos , Organofosfatos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT4/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismo
15.
Proc Natl Acad Sci U S A ; 116(13): 6371-6378, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850538

RESUMO

Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection against Mycobacterium tuberculosis (Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuated Listeria monocytogenes (Lm ΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an Lm ΔgcpE strain, which did not produce HMBPP. Lm ΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+ and CD8+ T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.


Assuntos
Imunização , Ativação Linfocitária/efeitos dos fármacos , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Feminino , Memória Imunológica/imunologia , Interferon gama/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/imunologia , Pulmão/imunologia , Pulmão/patologia , Macaca mulatta/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Mycobacterium tuberculosis/efeitos dos fármacos , Organofosfatos , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Tuberculose/patologia , Vacinas contra a Tuberculose/farmacologia , Vacinas Atenuadas/imunologia
16.
Emerg Microbes Infect ; 7(1): 207, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30538219

RESUMO

Tuberculosis (TB) has become the most deadly infectious diseases due to epidemics of HIV/AIDS and multidrug-resistant/extensively drug-resistant TB (MDR-/XDR-TB). Although person-to-person transmission contributes to MDR-TB, it remains unknown whether infection with MDR strains resembles infection with drug-sensitive (DS) TB strains, manipulating limited or broad immune responses. To address these questions, macaques were infected with MDR strain V791 and a drug-sensitive Erdman strain of TB. MDR bacilli burdens in the airway were significantly higher than those of the Erdman control after pulmonary exposure. This productive MDR strain infection upregulated the expression of caspase 3 in macrophages/monocytes and induced appreciable innate-like effector responses of CD3-negative lymphocytes and Ag-specific γδ T-cell subsets. Concurrently, MDR strain infection induced broad immune responses of T-cell subpopulations producing Th1, Th17, Th22, and CTL cytokines. Furthermore, MDR bacilli, like the Erdman strain, were capable of inducing typical TB disease characterized by weight loss, lymphocytopenia, and severe TB lesions. For the first time, our results suggest that MDR-TB infection acts like DS to induce high bacterial burdens in the airway (transmission advantage), innate/adaptive immune responses, and disease processes. Because nonhuman primates are biologically closer to humans than other species, our data may provide useful information for predicting the effects of primary MDR strain infection after person-to-person transmission. The findings also support the hypothesis that a vaccine or host-directed adjunctive modality that is effective for drug-sensitive TB is likely to also impact MDR-TB.


Assuntos
Imunidade Adaptativa , Carga Bacteriana/imunologia , Imunidade Inata , Pulmão/imunologia , Tuberculose Resistente a Múltiplos Medicamentos/imunologia , Animais , Caspase 3 , Citocinas/imunologia , Farmacorresistência Bacteriana Múltipla , Pulmão/microbiologia , Macaca , Macrófagos/imunologia , Macrófagos/microbiologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Tuberculose Pulmonar/imunologia
17.
BMC Infect Dis ; 18(1): 453, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180814

RESUMO

BACKGROUND: It is not fully explained why some active tuberculosis patients show negative interferon-γ release assays (IGRAs). In this study, we tried to explore associations of IGRAs with the characteristics of peripheral Vγ2Vδ2 T cells and their functions of producing cytokines. METHODS: 32 pulmonary tuberculosis patients were enrolled and divided into two groups according to their IGRAs results: 16 with IGRA-negative as test group and 16 with IGRA-positive as control group. Chest X-rays and T-SPOT.TB tests were performed and the severity of the lung lesions was scored. The amount of Vγ2Vδ2T cell and their expression levels of the apoptosis-related membrane surface molecule Fas and FasL in peripheral blood were analyzed by flow cytometry, and the function of secreting cytokines (IFN-γ, TNF-α and IL-17A) of Vγ2Vδ2 T cell were determined by intracellular cytokine staining. RESULTS: The IGRA-negative TB patients had more lesion severity scores and displayed reduced peripheral blood Vγ2Vδ2 T cell counts (p = 0.009) as well as higher Fas and FasL expression in peripheral blood Vγ2Vδ2 T cells (p = 0.043, 0.026). A high lesion severity score was correlated with a decreased Vδ2+ T cell number and increased Vγ2Vδ2 T cells Fas/FasL expression leve in the peripheral blood (p = 0.00, P < 0.01). The function of secreting cytokines was slightly impaired in IGRA-negative TB patients (p = 0.402). There is no significant differences in expression levels of Fas and FasL in CD4+ T cells (p = 0.224, 0.287) or CD8+ T cells (p = 0.184, 0.067) between test and control groups. CONCLUSION: Compared with IGRA-positive TB patients, the IGRA-negative TB patients had more lesion severity scores, the number of Vγ2Vδ2 T cells decreased and the function of secreting cytokines impaired. In addition, we suggest that increased expression of Fas/FasL triggers Vγ2Vδ2 T cell apoptosis.


Assuntos
Testes de Liberação de Interferon-gama , Linfócitos Intraepiteliais/metabolismo , Tuberculose Pulmonar/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Citocinas/metabolismo , Proteína Ligante Fas/sangue , Feminino , Humanos , Linfócitos Intraepiteliais/citologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/metabolismo , Índice de Gravidade de Doença , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Adulto Jovem , Receptor fas/sangue
18.
Clin Immunol ; 193: 1-9, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753126

RESUMO

The PPV23 immunizes healthy elderly and other high-risk populations against pneumococcal disease. Immune mechanisms whereby these populations differently mount antibody(Ab) and cellular responses to PPV23 vaccination remain unknown. Here, healthy elderly, those elderly with prior tuberculosis-cured history (TB-cured), and HIV-infected humans were vaccinated with PPV23, and assessed for opsonophagocytic Ab responses and potential cellular mechanisms. PPV23 vaccination elicited hierarchical responses of opsonophagocytic Ab. PPV23-elicited Ab titers were highest in healthy elderly, significantly lower in TB-cured elderly and lowest in HIV-infected subjects. Mechanistically, high PPV23-elicited Ab titers in healthy elderly were associated with increases in CD19 + CD69+ cells and CD19 + CD138 + plasma cells. Surprisingly, TB-cured elderly failed to show PPV23-induced increases in these cells. While HIV-infected subjects showed a depressed CD19 + CD69+ cellular response, PPV23 vaccination uncovered HIV-related over-reactive increases in CD19 + CD138 + cells. For the first time, we demonstrate that PPV23-elicted opsonophagocytic Ab titers correlate with different cellular responses in healthy, TB-cured and HIV statuses.


Assuntos
Infecções por HIV/imunologia , HIV-1/fisiologia , Plasmócitos/imunologia , Infecções Pneumocócicas/imunologia , Vacinas Pneumocócicas/imunologia , Tuberculose/imunologia , Adulto , Idoso , Formação de Anticorpos , Antígenos CD/metabolismo , Antígenos CD19/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Imunidade Celular , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Fagocitose , Sindecana-1 , Vacinação
19.
Exp Ther Med ; 15(3): 3034-3039, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29599838

RESUMO

The emergence of drug-resistant tuberculosis (TB) and HIV-TB co-infection fuels an urgent need to develop novel therapeutic approaches, including therapeutic vaccines. Therapeutic vaccines have been proven to be a good strategy by inducing antigen specific immune responses against TB infection. In the present study, a recombinant plasmid based on lentiviral vector expressing fusion antigen Ag85B-Rv3425 (A3), and was constructed the immunogenicity and treatment effects in TB mice were assessed. The results showed that A3 delivered by the plasmid could be expressed appropriately in vivo and induced higher production of tumor necrosis factor-α and interleukin-2 compared with A3 recombinant protein in mice. Moreover, the recombinant plasmid expressing A3 confered resistance to acute TB infection in mice, characterized by a reduction in the bacterial load in the lungs and spleen, as well as attenuated TB lesions in lung tissues. These results implicated that the recombinant plasmid based on lentiviral vector expressing A3 is a potent and promising therapeutic agent to treat acute TB infection.

20.
J Immunol ; 200(7): 2405-2417, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29453279

RESUMO

The ability of Mycobacterium tuberculosis to block host antimicrobial responses in infected cells provides a key mechanism for disease pathogenesis. The immune system has evolved to overcome this blockade to restrict the infection, but it is not clear whether two key innate cytokines (IL-12/IL-18) involved in host defense can enhance antimycobacterial mechanisms. In this study, we demonstrated that the combination of IL-12 and IL-18 triggered an antimicrobial response against mycobacteria in infected macrophages (THP-1 and human primary monocyte-derived macrophages) and pulmonary epithelial A549 cells. The inhibition of intracellular bacterial growth required p38-MAPK and STAT4 pathways, the vitamin D receptor, the vitamin D receptor-derived antimicrobial peptide cathelicidin, and autophagy, but not caspase-mediated apoptosis. Finally, the ability of IL-12+IL-18 to activate an innate antimicrobial response in human primary macrophages was dependent on the autonomous production of IFN-γ and the CAMP/autophagy pathway. Together, these data suggest that IL-12+IL-18 cosignaling can trigger the antimicrobial protein cathelicidin and autophagy, resulting in inhibition of intracellular mycobacteria in macrophages and lung epithelial cells.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Imunidade Inata/imunologia , Interferon gama/imunologia , Subunidade p35 da Interleucina-12/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Tuberculose/imunologia , Células A549 , Autofagia/imunologia , Linhagem Celular Tumoral , Células Epiteliais/imunologia , Humanos , Mycobacterium tuberculosis/imunologia , Receptores de Calcitriol/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/imunologia , Fator de Transcrição STAT4/metabolismo , Células THP-1 , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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