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2.
Cancer Cell ; 35(6): 901-915.e4, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185213

RESUMO

Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.

3.
Cell Rep ; 24(8): 2101-2111, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134171

RESUMO

CD47 on tumor cells protects from phagocytosis, while PD-L1 dampens T cell-mediated tumor killing. However, whether and how CD47 and PD-L1 coordinate is poorly understood. We reveal that CD47 and PD-L1 on tumor cells coordinately suppress innate and adaptive sensing to evade immune control. Targeted blockade of both CD47 and PD-L1 on tumor cells with a bispecific anti-PD-L1-SIRPα showed significantly enhanced tumor targeting and therapeutic efficacy versus monotherapy. Mechanistically, systemic delivery of the dual-targeting heterodimer significantly increased DNA sensing, DC cross-presentation, and anti-tumor T cell response. In addition, chemotherapy that increases "eat me" signaling further synergizes with the bispecific reagent for better tumor control. Our data indicate that tumor cells evolve to utilize both innate and adaptive checkpoints to evade anti-tumor immune responses and that tumor cell-specific dual-targeting of both checkpoints represents an improved strategy for tumor immunotherapy.

4.
Front Neurosci ; 12: 320, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867331

RESUMO

Glioblastoma multiforme (GBM) is the most lethal glioma variant in the adult brain and among the deadliest of human cancers. Increasing evidence has shown that metabotropic glutamate receptor subtype 4 (mGluR4) expression may play roles in regulating the growth of neural stem cells as well as several cancer cell lines. Here, we investigated the effects of mGluR4 on the growth and apoptosis of the LN229 GBM cell line. Involvement of Gli-1, one of the key transcription factors in the sonic Hedgehog (SHH) signaling pathway, was further explored. In this study, mGluR4 was activated using selective agonist VU0155041; and gene-targeted siRNAs were used to generate loss of function of mGluR4 and Gli-1 in LN229 cells. The results demonstrated that LN229 cells expressed mGluR4 and the agonist VU0155041 decreased cell viability in a dose- and time-dependent manner. Activation of mGluR4 inhibited cyclin D1 expression, activated pro-caspase-8/9/3, and disrupted the balance of Bcl-2/Bax expression, which indicated cell cycle arrest and apoptosis of LN229 cells, respectively. Furthermore, Gli-1 expression was reduced by mGluR4 activation in LN229 cells, and downregulation of Gli-1 expression by gene-targeted siRNA resulted in both inhibition of cell proliferation and promotion of apoptosis. Moreover, VU0155041 treatment substantially blocked SHH-induced cyclin D1 expression and cell proliferation, while increasing TUNEL-positive cells and the activation of apoptosis-related proteins. We concluded that activation of mGluR4 expressed in LN229 cells could inhibit GBM cell growth by decreasing cell proliferation and promoting apoptosis. Further suppression of intracellular Gli-1 expression might be involved in the action of mGluR4 on cancer cells. Our study suggested a novel role of mGluR4, which might serve as a potential drug target for control of GBM cell growth.

5.
Pak J Pharm Sci ; 31(3(Special)): 1109-1113, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29735459

RESUMO

Infection after gynecologic surgery is very common and frequent. If the control is not good, it will lead to serious consequences. Therefore, it is necessary to use antibiotics in the period of obstetrics and gynecology. This study will explore the use of antimicrobial agents in gynecologic and obstetric surgery, thus standardizing the use of antibiotics in the process of obstetrics and gynecology. Through the analysis of the use of antibacterials, we can see that the highest utilization rate of 5 kinds of antibacterial drugs followed by Cefaclor Sustained Release Tablets (65.7%), metronidazole (32.5%), cefathiamidine (26.8%), enoxacin (22.5%) and cefoperazone tazobactam sodium (11.8%). At the same time, the hospital should improve the consciousness of rational drug use and strengthen the administration of antibacterials in the operative period of obstetrics and gynecology. The application of antibiotics in the operative period of the department of obstetrics and gynecology can improve the current situation of its irrational use. Nursing work must take strict aseptic operation to prevent cross infection. At the same time, we should strengthen the observation of the effect of medication, monitor the body temperature and blood pressure, and identify the side effects of drugs.

6.
Int J Mol Med ; 42(2): 1096-1105, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29767257

RESUMO

Worldwide, neovascular age­related macular degeneration (nAMD) is one of the most common causes of blindness in the elderly. In particular, degeneration of retinal pigment epithelial (RPE) cells represents the main pathological process in the development of nAMD, and oxidative stress serves a major role. The present study aimed to investigate the association between bone morphogenetic protein 6 (BMP­6) and nAMD. BMP­6 concentration was significantly reduced in patients with wet nAMD compared with in the control group. Furthermore, the present study investigated the protective effects of BMP­6 on RPE cells following oxidative stress­induced injury. Cell Counting Kit­8 assay and terminal deoxynucleotidyl transferase dUTP nick­end labeling staining demonstrated that BMP­6 increased RPE cell viability, which was decreased following treatment with hydrogen peroxide (H2O2), and reduced H2O2­induced apoptosis. In addition, western blotting revealed that BMP­6 reversed the decrease in pro­caspase­3 levels and the dysregulation of the B­cell lymphoma 2 (Bcl­2)/Bcl­2­associated X protein (Bax) balance caused by H2O2. In addition, alterations in c­Jun N­terminal protein kinase (JNK) and p38 mitogen­activated protein kinase (MAPK) expression were examined, and pretreatment with BMP­6 was demonstrated to reduce H2O2­induced activation of JNK and p38 MAPK. Conversely, the effects of BMP­6 were attenuated by its inhibitor noggin. In conclusion, the present study demonstrated that BMP­6 may protect RPE cells from oxidative stress injury to a certain extent, which may be associated with alterations in the MAPK signaling pathway. However, the specific mechanism of action underlying this effect requires further investigation. Overall, the present study laid a foundation for exploring novel nAMD treatment methods.


Assuntos
Proteína Morfogenética Óssea 6/metabolismo , Sistema de Sinalização das MAP Quinases , Estresse Oxidativo , Epitélio Pigmentado da Retina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linhagem Celular , Sobrevivência Celular , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Pessoa de Meia-Idade , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/patologia
7.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 35(4): 368-372, 2017 Aug 01.
Artigo em Chinês | MEDLINE | ID: mdl-28853501

RESUMO

Objective To explore the impact of nicotine on proliferation and osteogenic capability of periodontal ligament stem cells (PDLSCs), and the role of Toll-like receptor 4 (TLR4) in nicotine, suppressing the osteogenic capability of PDLSCs. Methods PDLSCs were cultured in vitro, and the flow cytometer was used to identify the surface antigen markers of PDLSCs. WST-1 was used to detect the proliferation ability of PDLSCs, which were stimulated by different concentrations of nicotine. Alizarin red staining was used to observe the formation of mineralized nodules after PDLSCs stimulation with different concentrations of nicotine. Real-time polymerase chain reaction (RT-PCR) and Western blot were used to detect the change in osteogenic potential of PDLSCs stimulated by nicotine, after TAK-242, and with the inhibitor of TLR4. Results PDLSCs expressed mesenchymal stem cell-associated markers CD90 and CD105. When the concentration of nicotine was 10⁻4 mol·L⁻¹, the PDLSC proliferation could be suppressed after 3 d compared with the control group (P<0.05). The amount of mineralized nodules reduced after osteogenic differentiation at 21 d by alizarin red staining. RT-PCR and Western blot showed the expression levels of alkaline phosphatase (ALP), and osteocalcin (OCN), and the Runt-related transcription factor-2 (Runx-2) were lower than in the control group when nicotine suppressed the PDLSCs (P<0.05). This effect was attenuated after TAK-242 was added. Conclusion Nicotine suppresses the proliferation and osteogenic capability of PDLSCs, which may be regulated by TLR4.


Assuntos
Estimulantes Ganglionares/farmacologia , Nicotina/farmacologia , Osteogênese , Ligamento Periodontal , Receptor 4 Toll-Like/metabolismo , Fosfatase Alcalina , Diferenciação Celular , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core , Humanos , Células-Tronco Mesenquimais , Osteocalcina , Reação em Cadeia da Polimerase em Tempo Real , Células-Tronco , Sulfonamidas
8.
Cancer Immunol Res ; 5(7): 560-570, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28533311

RESUMO

Anti-hCD20 is a therapeutic mAb that is clinically used to treat B-cell lymphoma. Some lymphomas are resistant to anti-hCD20; others relapse after treatment with anti-hCD20. Using a syngeneic immunocompetent mouse model, we observed that targeting lymphoma with interferon-α (IFNα) abolished resistance of B-cell lymphoma to anti-CD20 while limiting interferon (IFN)-associated systemic toxicity in the host. Control of tumors by a fusion of anti-CD20 and IFNα (anti-CD20-IFNα) depended on existing tumor-infiltrating CD8+ T cells. Although lymphomas were resistant to IFN-directed killing, IFN-exposed tumor cells became the dominant antigen-presenting cells (APC) for the reactivation of tumor-infiltrating CD8+ T cells that then controlled those lymphomas. Anti-CD20-IFNα also abolished checkpoint blockade resistance in advanced B-cell lymphoma. Our findings indicate that anti-CD20-IFNα eradicates B-cell lymphoma by employing tumor cells as APCs to reactivate tumor-infiltrating CD8+ T cells and synergizing with anti-PD-L1 treatment. Cancer Immunol Res; 5(7); 560-70. ©2017 AACR.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos CD20/imunologia , Interferon-alfa/imunologia , Linfoma de Células B/tratamento farmacológico , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Antígenos CD20/genética , Antígenos CD20/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno B7-H1/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Interferon-alfa/genética , Interferon-alfa/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Camundongos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Rituximab/administração & dosagem , Rituximab/imunologia
9.
Clin Cancer Res ; 23(1): 193-203, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-27354469

RESUMO

PURPOSE: The inhibition of tumor growth by anti-CD20 antibody (Ab) treatment is mediated by Ab- and complement-dependent cytotoxicity in xenograft tumor models. In addition, anti-CD20 therapy for B-cell lymphoma can result in intrinsic and extrinsic tumor resistance to further Ab treatment. However, adaptive immune response-related resistance has not been well studied in anti-CD20-mediated tumor control, and adaptive immunity has long been underestimated. The purpose of this study was to explore whether T cells are involved in mediating the effects of anti-CD20 therapy and what factors contribute to adaptive immune response-related resistance. EXPERIMENTAL DESIGN: Using a syngeneic mouse B-cell lymphoma model, we investigated the role of CD8+ T cells in anti-CD20-mediated tumor regression. Furthermore, we revealed how the tumor-specific T-cell response was initiated by anti-CD20. Finally, we studied adaptive immune response-related resistance in advanced B-cell lymphoma. RESULTS: CD8+ T cells played an essential role in anti-CD20-mediated tumor regression. Mechanistically, anti-CD20 therapy promoted dendritic cell (DC)-mediated cross-presentation. Importantly, macrophages were also necessary for the increase in the tumor-specific CTL response after anti-CD20 treatment, via the production of type I IFN to activate DC function. Furthermore, adaptive resistance is gradually developed through the CTLA-4 pathway in Treg cells in larger lymphomas. Further blockade of CTLA-4 can synergize with anti-CD20 treatment in antitumor activities. CONCLUSIONS: The therapeutic function of anti-CD20 depends on tumor-specific CD8+ T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response-related resistance in advanced B-cell lymphoma. Clin Cancer Res; 23(1); 193-203. ©2016 AACR.


Assuntos
Antígenos CD20/metabolismo , Antineoplásicos Imunológicos/farmacologia , Biomarcadores Tumorais , Antígeno CTLA-4/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Rituximab/farmacologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Linhagem Celular Tumoral , Apresentação Cruzada , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Pharmacol Sci ; 130(1): 15-23, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26810570

RESUMO

We investigated the ameliorative effects and potential mechanisms of tannic acid (TA) in carbon tetrachloride (CCl4)-intoxicated mice and hepatic stellate cells (HSCs). Liver fibrosis was observed in CCl4 (800 ml/kg)-induced mice, and high viability was observed in CCl4 (10 mM)-intoxicated HSCs. Pre-treatment of mice with TA (25 or 50 g/kg/day) significantly ameliorated hepatic morphology and coefficient values and reduced the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), the concentrations of malondialdehyde (MDA) and serum levels of endothelin-1 (ET-1). In addition, TA increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and endothelial nitric oxide synthase (eNOS) and the serum level of NO. Moreover, TA reduced the expression of angiotensin II receptor-1 (ATR-1), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), caspase-3, c-fos, c-jun, the ratio of Bax/bcl-2, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TA increased matrix metal proteinase-9 (MMP-9), matrix metalloproteinase-1 (MMP-1). Furthermore, TA (0.01 µM, 0.1 µM or 1 µM) decreased the TIMP-1/MMP-1 ratio and reduced the viability of HSCs. These results indicated that TA exerts significant liver-protective effects in mice with CCl4-induced liver fibrosis. The potential mechanism may rely on the inhibition of collagen accumulation, oxidative stress, inflammation and apoptosis.


Assuntos
Tetracloreto de Carbono/toxicidade , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Taninos/farmacologia , Taninos/uso terapêutico , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Tetracloreto de Carbono/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Humanos , Inflamação , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
11.
Int Immunopharmacol ; 31: 248-56, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26773772

RESUMO

BACKGROUND: Programmed cell death ligand-1 (PD-L1) with its receptor PD-1 pathway is overactivated in many tumors. Inhibiting the interaction of PD-L1 and PD-1 is an attractive strategy to restore tumor-specific T cell immunity for tumor therapy. METHODS: A fully human anti-PD-L1 monoclonal antibody (mAb) B60-55 was identified by yeast surface display. The affinity, specificity, activity, and efficacy of mAb B60-55 were investigated in vitro or in vivo. RESULTS: mAb B60-55 (purity >99%) could bind to PD-L1 that is expressed on HEK293 cells with a dissociation constant of 0.2 nM, and specifically bind to human or cynomolgus macaque PD-L1 without a cross-reaction with murine PD-L1. Moreover, mAb B60-55 is an antagonistic antibody, which can block PD-L1 binding to its receptors, including PD-1 (PDCD1) and B7.1 (CD80). In vitro assays demonstrated the ability of mAb B60-55 to enhance T cell responses and cytokine production in the mixed lymphocyte reaction. In vivo studies showed that administration of mAb B60-55 exhibited a potent antitumor activity toward tumor cell carcinoma xenograft, with a mean half-life of 177.9h in cynomolgus monkeys. CONCLUSION: mAb B60-55 is a potential candidate for clinical development in cancer treatment.


Assuntos
Anticorpos Bloqueadores/imunologia , Anticorpos Monoclonais/imunologia , Antineoplásicos/imunologia , Antígeno B7-H1/imunologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Bloqueadores/isolamento & purificação , Anticorpos Monoclonais/isolamento & purificação , Antineoplásicos/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Reações Cruzadas , Citocinas/metabolismo , Feminino , Células HEK293 , Humanos , Teste de Cultura Mista de Linfócitos , Macaca fascicularis , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oncol Lett ; 7(5): 1385-1390, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24765142

RESUMO

The aim of the present study was to investigate the sonication effects of 21-kHz ultrasound (US) with microbubbles (MBs) on the subcutaneous prostate tumors of nude mice. In total, 15 tumor-bearing nude mice were divided into three groups: The control group, the low-frequency US group and the US+MB group. The MBs used were from US contrast agent SonoVue. The parameters of the US were as follows: 21 kHz, 26 mW/cm2 and a 40% duty cycle (2 sec on, 3 sec off) for 3 min, once every other day for 2 weeks. Color Doppler flow imaging, hematoxylin and eosin (HE) staining, immunoblotting and transmission electron microscopy (TEM) were used to evaluate the results. Following 2 weeks of treatment, the blood flow signal disappeared in the US+MB group only, and the tumor size was smaller when compared with the control and US groups. For the immunoblotting, the intensity of cyclooxygenase-2 and vascular endothelial growth factor in the US+MB group was lower compared with the other two groups. Tumor necrosis was present and the nucleus disappeared upon HE staining in the US+MB group. Upon TEM analysis, increased cytoplasmic vacuolation and dilatation of the perinuclear cisternae of the tumor cells were found in the US+MB group. In the control and US groups, the tumors had intact vascular endothelia and vessel lumens. However, lumen occlusion of the vessels was observed in the US+MB group. In conclusion, 21-kHz low-intensity US with MBs may result in vessel occlusion and growth inhibitory effects in the subcutaneous tumors of nude mice.

13.
Hepatology ; 59(4): 1331-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24677193

RESUMO

UNLABELLED: It is well established that interleukin (IL)-22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly up-regulated in hepatitis B virus (HBV)-infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver-infiltrating IL-22(+) cells were largely increased in HBV-infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells and, preferentially, by T-helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T-cell-mediated chronic liver inflammation and fibrosis, blockade of IL-22 attenuated hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C-X-C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs. CONCLUSIONS: IL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV-infected patients and HBV Tg mice.


Assuntos
Hepatite B/fisiopatologia , Interleucinas/fisiologia , Cirrose Hepática/fisiopatologia , Transdução de Sinais/fisiologia , Células Th17/patologia , Adulto , Idoso , Animais , Estudos de Casos e Controles , Contagem de Células , Quimiocina CCL20/metabolismo , Quimiotaxia/efeitos dos fármacos , Doença Crônica , Comorbidade , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/patologia , Hepatite B/epidemiologia , Hepatite B/patologia , Humanos , Técnicas In Vitro , Interleucinas/farmacologia , Cirrose Hepática/epidemiologia , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade
14.
PLoS Pathog ; 10(3): e1004032, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24651854

RESUMO

The mechanisms of chronic HBV infection and immunopathogenesis are poorly understood due to a lack of a robust small animal model. Here we report the development of a humanized mouse model with both human immune system and human liver cells by reconstituting the immunodeficient A2/NSG (NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice with human HLA-A2 transgene) with human hematopoietic stem cells and liver progenitor cells (A2/NSG-hu HSC/Hep mice). The A2/NSG-hu HSC/Hep mouse supported HBV infection and approximately 75% of HBV infected mice established persistent infection for at least 4 months. We detected human immune responses, albeit impaired in the liver, chronic liver inflammation and liver fibrosis in infected animals. An HBV neutralizing antibody efficiently inhibited HBV infection and associated liver diseases in humanized mice. In addition, we found that the HBV mediated liver disease was associated with high level of infiltrated human macrophages with M2-like activation phenotype. Importantly, similar M2-like macrophage accumulation was confirmed in chronic hepatitis B patients with liver diseases. Furthermore, gene expression analysis showed that induction of M2-like macrophage in the liver is associated with accelerated liver fibrosis and necrosis in patients with acute HBV-induced liver failure. Lastly, we demonstrate that HBV promotes M2-like activation in both M1 and M2 macrophages in cell culture studies. Our study demonstrates that the A2/NSG-hu HSC/Hep mouse model is valuable in studying HBV infection, human immune responses and associated liver diseases. Furthermore, results from this study suggest a critical role for macrophage polarization in hepatitis B virus-induced immune impairment and liver pathology.


Assuntos
Modelos Animais de Doenças , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Cirrose Hepática/patologia , Macrófagos/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Células-Tronco Hematopoéticas/citologia , Vírus da Hepatite B , Hepatócitos/citologia , Hepatócitos/transplante , Humanos , Imuno-Histoquímica , Cirrose Hepática/etiologia , Camundongos , Camundongos Endogâmicos NOD , Células-Tronco/citologia , Transplante Heterólogo
15.
Artigo em Chinês | MEDLINE | ID: mdl-25764758

RESUMO

OBJECTIVE: To study the influence of PD173074 on proliferation and apoptosis of nasopharyngeal carcinoma. METHOD: With immunoblotting and RT-PCR, FGFR1 expression was detected in CNE, PONE1 and C666-1 cell lines. With MTT assay,the time-effect and dose-effect correlation between PD173074 and inhibition of CNE proliferation was evaluated. After PD173074 stimulation, the phosphorylation level of FGFR1 and AKT was detected with immunoblotting assay. Furthermore, influence of PD173074 on the activation of Caspase3 and Caspase9 was detected to study the underlying mechanism of why PD173074 could inhibit CNE proliferation. RESULT: FGFR1 has the highest expression in CNE cell line. Under incubation of 10 nmol/L PD173074 stimulation for 36 hours to 72 hours, the phosphorylation of FGFR1 and AKT was impaired significantly, which further reduced the proliferation of CNE. Moreover, PD173074 can activate the intrinsic apoptotic pathway by stimulating Caspase9,which activated Caspase3 and induced the apoptosis. CONCLUSION: PD173074 could inhibit proliferation of nasopharyngeal carcinoma cell through reducing the phosphorylation of FGFR1 and AKT. Additionally, PD173074 can induce CNE apoptosis by activating intrinsic apoptotic pathway via cleaving Caspase9 and Caspase3.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Nasofaríngeas/patologia , Pirimidinas/farmacologia , Carcinoma , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamento farmacológico
16.
J Transl Med ; 10: 176, 2012 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-22929614

RESUMO

BACKGROUND: In China, high prevalence of HBV and HCV parallels with the growing epidemic of syphilis and HIV in the general population poses a great threat to blood safety. This study investigated the prevalence of serologic markers for transfusion transmissible infections (TTIs) among four Chinese blood centers. METHODS: We examined whole blood donations collected from January 2000 through December 2010 at four Chinese blood centers. Post-donation testing of TTIs (HIV, HBV, HCV and syphilis) were conducted using two different enzyme-linked immunosorbent assay kits for each seromarker. The prevalence of serologic markers for TTIs (%) was calculated and additional analysis was conducted to examine donor characteristics associated with positive TTIs serology. RESULTS: Of the 4,366,283 donations, 60% were from first-time donors and 40% were from repeated donors. The overall prevalence of HIV, HBsAg, HCV and syphilis was 0.08%, 0.86%, 0.51% and 0.47%, respectively. The prevalence profile of TTIs varied among different blood centers and appeared at relatively high levels. Overall, the prevalence of HBsAg and HCV demonstrated a decline trend among four blood centers, while the prevalence of HIV and syphilis displayed three different trends: constantly steady, continually increasing and declining among different centers. CONCLUSIONS: This study reflects the risk of TTIs has been greatly reduced in China, but blood transfusion remains an ongoing risk factor for the spread of blood-borne infections, and further work and improvements are needed to strengthen both safety and availability of blood in China.


Assuntos
Doadores de Sangue , Patógenos Transmitidos pelo Sangue/isolamento & purificação , Doenças Transmissíveis/transmissão , Reação Transfusional , Adolescente , Adulto , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
17.
Clin Physiol Funct Imaging ; 31(4): 315-9, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21672140

RESUMO

BACKGROUND: Radiofrequency (RF) data technology is a newly developed method to evaluate vascular disease, especially subclinical atherosclerotic change. Data regarding predictors of intima-media thickness (IMT) and vascular elasticity of the common carotid artery (CCA) in subjects with isolated systolic hypertension (ISH) using ultrasound RF-data technology are scarce. AIMS: We evaluated the change in IMT and vascular elasticity of the CCA in patients with ISH at an early phase using US RF-data technology. METHODS: Thirty-nine patients with ISH and 41 age-matched control subjects were the study population. The common carotid arterial systolic diameter (Ds), diastolic diameter (Dd), IMT, carotid distensibility (CD), local pulse wave velocity (PWVß) and stiffness (ß) were compared between the two groups, as were correlations between pulse pressure (PP) and parameters of vascular stiffness. RESULTS: Common carotid arterial Ds, Dd, IMT, PWVß and ß increased whereas CD decreased more significantly in the ISH group than in age-matched controls. The level of PP in the ISH group had significant positive correlations with PWVß (r = 0·298, P<0·05) and ß (r = 0·291, P<0·05), whereas significant correlations with CD were not observed. CONCLUSIONS: US RF-data technology could be used to accurately and quantitatively evaluate increased IMT and decreased arterial elasticity of the CCA in patients with ISH compared with normal subjects.


Assuntos
Artéria Carótida Primitiva/fisiopatologia , Técnicas de Imagem por Elasticidade/métodos , Hipertensão/fisiopatologia , Túnica Íntima/fisiopatologia , Túnica Média/fisiopatologia , Idoso , Artéria Carótida Primitiva/diagnóstico por imagem , Módulo de Elasticidade , Humanos , Hipertensão/diagnóstico por imagem , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Resistência Vascular
18.
Clin Cancer Res ; 16(16): 4105-12, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20682706

RESUMO

PURPOSE: To assess the relation of Foxp3(+) regulatory T cells (Treg) in tumor draining lymph nodes (TDLNs) with tumor progression and immune suppression in colorectal cancer (CRC). EXPERIMENTAL DESIGN: Flow cytometry was used to analyze the densities of Tregs in lymphocytes of TDLNs, peripheral blood, and tumors from 34 patients with CRC. The frequency of Tregs was compared and evaluated for the association with disease stage. The effect of Tregs on the function of CD8(+) T cells was investigated by IFN-gamma production. RESULTS: The density of Foxp3(+) Tregs in TDLNs was dramatically higher than that in peripheral blood lymphocytes, but significantly lower than that in tumor-infiltrating lymphocytes. Importantly, the frequency of Foxp3(+) Tregs in TDLNs, rather than that in tumors and peripheral blood, was positively correlated with disease stage. In addition, the functions of CD8(+) T cells were impaired in TDLNs compared with peripheral blood lymphocytes and were restored after Treg depletion. CONCLUSIONS: Foxp3(+) Tregs in TDLNs are more correlated with disease progression and potentially influence CD8(+) T-cell functions. This study suggests that the frequency of Tregs in TDLNs may provide a valuable prognostic tool in the treatment of CRC.


Assuntos
Neoplasias Colorretais/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Separação Celular , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias
19.
Environ Sci Technol ; 43(11): 4044-8, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19569328

RESUMO

Perfluorinated compounds (PFCs), such as perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA), have been identified widely in human. Monitoring of geographical distribution of PFCs in human blood can provide the information to better characterize the exposure source and pathway of these compounds. In this study, 13 PFCs were detected in 138 whole blood samples collected in 2008 from seven cities (Liaoning province, China) including Fuxin, Jinzhou, Shenyang, Anshan, Yingkou, Huludao, and Dalian. The highest geometric mean (GM) concentration of total PFCs was found in samples from Fuxin (17.27 ng/mL) followed by Shenyang (12.70 ng/mL) and Anshan (12.63 ng/mL). The composition profile of PFCs was varied in blood samples from seven cities. In Fuxin and Jinzhou, the percentage proportion of PFOA was significantly higher than that of perfluorohexanesulfonate (PFHxS) by about two times. By contrast, in Shenyang, Anshan, and Yingkou, the percentage proportion of PFHxS was about three times higher than that of PFOA. In Huludao and Dalian, the profile of PFCs in blood was very similar with comparable proportions of PFOA and PFHxS. The results suggested different human exposure sources and pathways of PFCs in Liaoning province, China.


Assuntos
Exposição Ambiental , Monitoramento Ambiental , Poluentes Ambientais/sangue , Hidrocarbonetos Fluorados/sangue , Adulto , Distribuição por Idade , China , Feminino , Humanos , Masculino
20.
Eur J Pharmacol ; 545(2-3): 161-6, 2006 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-16859676

RESUMO

Chlorzoxazone has been reported to activate the intermediate-conductance, Ca(2+)-activated K(+) channels in aortic endothelial cells and to relax the artery. The aim of the present study was to characterize the chlorzoxazone-induced relaxation of rat thoracic artery. Chlorzoxazone did not affect the tension of the thoracic artery rings at rest, but relaxed the precontraction induced by 1 muM noradrenaline in an endothelium independent manner. Preincubation with chlorzoxazone also antagonized the contraction induced by 1 microM noradrenaline or 25 mM KCl. The chlorzoxazone-induced relaxation of the thoracic artery pre-contracted by noradrenaline was suppressed by 5 mM tetraethylammonium, 75 mM ethanol and 2 microM paxilline, but not by 2 microM clotrimazole. Chlorzoxazone relaxed the 4-aminopyridine-induced contraction. The pattern of chlorzoxazone-induced relaxation was different from that of verapamil, the L-type Ca(2+) channel blocker. The inhibition of the noradrenaline-induced contraction by chlorzoxazone was attenuated when chlorzoxazone treatment was prolonged to 4 h. No difference in the contraction-relaxation was found between the artery rings from normal rats and those from rats that received 100 mg/kg chlorzoxazone for 7 days. We conclude that chlorzoxazone abolishes the contraction of rat thoracic artery induced by noradrenaline and that the effect of chlorzoxazone is endothelium independent and also not mediated by intermediate-conductance, Ca(2+)-activated K(+) channels.


Assuntos
Aorta Torácica/efeitos dos fármacos , Clorzoxazona/farmacologia , Relaxantes Musculares Centrais/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Aorta Torácica/fisiologia , Clorzoxazona/sangue , Relação Dose-Resposta a Droga , Etanol/farmacologia , Técnicas In Vitro , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/efeitos dos fármacos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/fisiologia , Masculino , Norepinefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Verapamil/farmacologia
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