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1.
Medicine (Baltimore) ; 98(39): e17311, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574860

RESUMO

Immune infiltration of nasopharyngeal carcinoma (NPC) is closely associated with the patients' prognosis. However, previous studies have not interpreted the difference of infiltrating immune cells in NPC.We comprehensively analyzed the tumor-infiltrating immune cells present in NPC for the first time, which was based on a scientific deconvolution algorithm (CIBERSORT) and the gene expression data of GSE64634. The fractions of 22 immune cells were assessed to reveal the associations between normal samples and NPC samples.Profiles of immune infiltration vary significantly between normal samples and NPC samples, and the variation could characterize the individual differences. NPC samples contained a higher proportion for M1 macrophages, whereas memory B cells and CD4 memory resting T cells were relatively lower.Our data suggest that the differences in the infiltrating immune cells in NPC and these differences would probably facilitate patient consultation and individualized treatment.


Assuntos
Linfócitos do Interstício Tumoral , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Adulto , Algoritmos , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , China , Correlação de Dados , Feminino , Expressão Gênica , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Prognóstico , Reprodutibilidade dos Testes
2.
Anticancer Res ; 39(9): 4787-4794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519580

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. MATERIALS AND METHODS: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. RESULTS: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. CONCLUSION: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.


Assuntos
Anisóis/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Imuno-Histoquímica , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Carga Tumoral/efeitos dos fármacos
3.
J Agric Food Chem ; 67(32): 9070-9078, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343168

RESUMO

In this study, an immunologically active novel microparticulate mushroom ß-glucan (PRA-1p) was prepared using an alkali-soluble glucan PRA-1 by an emulsification and cross-linking method. PRA-1 was a hyperbranched (1→3),(1→6)-ß-d-glucan with a degree of branching of 0.89, isolated from the sclerotia of Polyporus rhinocerus. PRA-1 had a rod-like conformation, while PRA-1p exhibited a monodisperse and homogeneous spherical conformation with a diameter ranging from 0.3 to 2.0 µm in water. PRA-1p significantly induced nitric oxide and reactive oxygen species production as well as morphological changes of murine macrophages (RAW 264.7 cells) and upregulated their phagocytic activity. Furthermore, PRA-1p treatment markedly enhanced the secretion of cytokines, including cutaneous T cell-attracting chemokine 27, granulocyte-colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, macrophage inflammatory protein 2, regulated on activation, normal T cell expressed and secreted, soluble tumor necrosis factor receptor 1, and tissue inhibitors of metalloproteinases. Activation of RAW 264.7 cells triggered by PRA-1p was associated with activation of inducible nitric oxide synthase, nuclear factor κB, extracellular signal-regulated kinase, and protein kinase B. This work suggests that novel PRA-1p derived from the mushroom sclerotia of P. rhinocerus has potential application as an immunostimulatory agent.


Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polyporus/química , beta-Glucanas/química , beta-Glucanas/farmacologia , Animais , Quimiocina CCL27/genética , Quimiocina CCL27/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Imunológicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polyporus/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , beta-Glucanas/isolamento & purificação
4.
J Agric Food Chem ; 67(32): 8810-8818, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31318199

RESUMO

Citrus grandis (L.) Osbeck is a popular fruit cultivated around the world, and its peels are sometimes used for the treatment of cough, abdominal pain, and indigestion in China. However, the peel is discarded after fruit consumption in most cases, and its chemical constituents and biological activities have not been validated before. The present study focused on evaluation of the chemical and pharmacological profile of coumarins from peels of C. grandis against inflammation. The extracts and phytochemicals from peels of C. grandis were prepared, and anti-inflammatory activities were carried out in vivo and in vitro, including inhibiting xylene-induced ear edema and carrageenan-induced paw edema in mice and the production of inflammatory cytokines (interleukin 1ß, prostaglandin 2, and tumor-necrosis factor α) in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results indicated that methanolic extract, ethyl acetate fraction, and four major coumarins (compounds 7, 8, 13, and 16) inhibited swelling induced by xylene and carrageenan, separately, in vivo. Furthermore, 18 coumarins inhibited inflammatory factor secretion in macrophages primed by LPS, in which compounds 4, 6, 7, 10, 17 showed the most pronounced change, which were comparable to dexamethasone. In summary, peel of C. grandis showed an anti-inflammatory effect and coumarin compounds were responsible for regulating inflammatory mediators and cytokines, which might provide a novel nutritional strategy for inflammatory diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Citrus/química , Cumarínicos/administração & dosagem , Edema/tratamento farmacológico , Frutas/química , Extratos Vegetais/administração & dosagem , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Cumarínicos/química , Cumarínicos/isolamento & purificação , Dinoprostona/imunologia , Edema/genética , Edema/imunologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Resíduos/análise
5.
J Agric Food Chem ; 67(30): 8339-8347, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31291543

RESUMO

The dried seeds of Cuminum cyminum L. have been traditionally used as food and medicine. To explore its chemical composition and anti-inflammatory activity, four new compounds (1-4) along with five known compounds (5-9) were isolated from the seeds in the present study. The chemical structures of the new compounds were identified as follows: methyl 3-((7H-purin-2-yl) amino)-3-(4-isopropylphenyl) propanoate (1), 8-(amino(4-isopropylphenyl)methyl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4-oxo-4H-chromene-6-carboxylic acid (2), (3,4,5-trihydroxy-6-((4-isopropylbenzyl)oxy)tetrahydro-2H-pyran-2-yl)methyl (E)-3-(4-propoxyphenyl)acrylate (3), and (3,4,5-trihydroxy-6-((5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl 3-(4-isopropylphenyl)-2-methoxypropanoate (4). Compound 2, an atypical nitrogen-containing flavonoid, exhibited the most active inhibitory effect on nitride oxide, with IC50 of 5.25 µM in the lipopolysaccharide-stimulated RAW264.7 cell assay. Compound 2 was found to suppress the expression levels of inducible nitric oxide synthase and cyclooxygenase-2. Furthermore, it was revealed that both nuclear factor κB and mitogen-activated protein kinase were involved in the anti-inflammatory process of compound 2.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cuminum/química , Flavonoides/química , Flavonoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7 , Sementes/química
6.
J Microbiol Biotechnol ; 29(7): 1053-1060, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31280523

RESUMO

Thermal drying is a common process used in the food industry for the modification of agricultural products. However, while various studies have investigated the alteration in physiochemical properties and chemical composition after drying, research focusing on the relationship between different dehydration conditions and bioactivity is scarce. In the current study, we prepared dried ginger under nine different conditions by varying the processing time and temperature and compared their immunomodulatory effects. Interestingly, depending on the drying condition, there were significant differences in the immunestimulating activity of the dried ginger samples. Gingers processed at 50°C 1h displayed the strongest activation of macrophages measured by TNF-α and IL-6 levels, whereas, freezedried or 70°C- and 90°C-dried ginger showed little effect. Similar results were recapitulated in primary bone marrow-derived macrophages, further confirming that different dehydration conditions can cause significant differences in the immune-stimulating activity of ginger. Induction of ERK, p38, and JNK signaling was found to be the major underlying molecular mechanism responsible for the immunomodulatory effect of ginger. These results highlight the potential to improve the bioactivity of functional foods by selectively controlling processing conditions.


Assuntos
Dessecação , Gengibre/imunologia , Animais , Sobrevivência Celular , Citocinas/metabolismo , Feminino , Gengibre/química , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Temperatura Ambiente , Fatores de Tempo , Água/análise
7.
J Agric Food Chem ; 67(33): 9382-9389, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361959

RESUMO

Early stage exposure of foodborne substances, such as brightening agent titanium dioxide nanoparticles (TiO2 NPs), can cause long-term effects in adulthood. We aimed to explore the potential adverse effect of long-term dietary intake of TiO2 NPs. After feeding for 2-3 months from weaning, TiO2 NPs-exposed mice showed lower body weight and induced intestinal inflammation. However, this phenomenon was not observed in gut microbiota-removed mice. TiO2 NPs exposure rarely affected the diversity of microbial communities, but significantly decreased the abundance of several probiotic taxa including Bifidobacterium and Lactobacillus. Additionally, TiO2 NPs aggravated DSS-induced chronic colitis and immune response in vivo, and reduced the population of CD4+T cells, regulatory T cells, and macrophages in mesenteric lymph nodes. Therefore, dietary TiO2 NPs could interfere with the balance of immune system and dynamic of gut microbiome, which may result in low-grade intestinal inflammation and aggravated immunological response to external stimulus, thus introducing potential health risk.


Assuntos
Intestinos/efeitos dos fármacos , Intestinos/imunologia , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Titânio/metabolismo , Titânio/toxicidade , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fatores de Tempo
8.
J Agric Food Chem ; 67(28): 7855-7868, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31274310

RESUMO

Bee pollen (BP) collected from different floras possesses various potential bioactivities, but the mechanism-related research on anti-inflammatory effects is limited. Here, three types of BP originating from Camellia sinensis L. (BP-Cs), Nelumbo nucifera Gaertn. (BP-Nn), and Brassica campestris L. (BP-Bc) were assessed using molecular and metabolomics methods to determine their anti-inflammatory effects. The differences in polyphenolic abundance of three types of BP extracts were determined by HPLC-DAD/Q-TOF-MS. In vitro anti-inflammatory effects of three BP extracts were evaluated in a lipopolysaccharide (LPS)-induced RAW 264.7 cells model. BP-Cs extract with the most abundant polyphenols was found to be the most effective in reducing inflammation by downregulating inflammatory-related genes expression and blocking the activation of MAPK and NF-κB signaling pathways. Polyphenol-rich BP-Cs was further evaluated for their in vivo anti-inflammatory effect in a LPS-induced acute lung injury mouse model. An UPLC-Q-TOF/MS-based metabolomics approach was applied to analyze metabolite changes in mouse serum. Weshowed that the pretreated BP-Cs extract alleviated inflammation and regulated glycerophospholipid metabolism significantly. Our findings provide a foundation for developing and justifying BP as a potential anti-inflammatory ingredient in functional foods or nutraceutical formulations.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Extratos Vegetais/administração & dosagem , Pólen/química , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/imunologia , Animais , Anti-Inflamatórios/química , Abelhas , Brassica/química , Camellia sinensis/química , Cromatografia Líquida de Alta Pressão , Humanos , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos ICR , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Nelumbo/química , Extratos Vegetais/química , Polifenóis/administração & dosagem , Polifenóis/química , Células RAW 264.7
9.
Cancer Sci ; 110(9): 2711-2721, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294893

RESUMO

The percentage of programmed death ligand 1 (PD-L1) positivity in cancer cells, named as the tumor proportion score, is considered to be a predictive biomarker for anti-PD-1/PD-L1 therapy in lung cancer. PD-L1 is expressed on not only cancer cells but also on immune cells, including macrophages. Although previous studies related to PD-L1/2 expression in cancer tissues have been generally based on single immunohistochemistry (IHC), in the present study, we attempted to evaluate accurate PD-L1/2 expression in cancer cells in lung adenocarcinoma cells using double IHC to also evaluate macrophages. Of the 231 patients, PD-L1 expression was negative in 169 patients (73.2%), 1%-49% positive in 47 patients (20.3%), and ≥50% positive in 15 patients (6.5%). Interestingly, PD-L1 positivity was decreased when using double IHC compared with the estimation by single IHC. High PD-L1 expression was associated with high-grade cancer cells and in higher stage cancer. PD-L2 was negative in 109 patients (47.2%), 1%-49% positive in 50 patients (21.6%), and ≥50% positive in 72 patients (31.2%). The number of PD-L2-positive patients was increased in cases that had an epidermal growth factor receptor (EGFR) mutation and in lower stage cancer. Thirty-five patients (15.2%) were positive for both PD-L1 and PD-L2, whereas 81 patients (35.1%) were negative for both PD-L1 and PD-L2. Log-rank analysis showed that progression-free survival and overall survival were significantly the longest in the PD-L1-negative and PD-L2-positive groups (P < .0001 and P = .0120). We observed lower PD-L1 or PD-L2 expression in lung adenocarcinoma than previously reported. Double IHC for macrophages may help clinicians to evaluate PD-L1 or PD-L2 expression specifically in cancer cells.


Assuntos
Adenocarcinoma de Pulmão/patologia , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Neoplasias Pulmonares/patologia , Proteína 2 Ligante de Morte Celular Programada 1/análise , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imuno-Histoquímica/métodos , Pulmão/citologia , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Resultado do Tratamento
10.
Life Sci ; 233: 116696, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351969

RESUMO

AIMS: To explore the mechanism of how LSD1 regulates autophagy and the correlation between LSD1 and Ox-LDL-induced inflammation. MAIN METHODS: RAW264.7 cells were used during the whole study. Firstly, the effect of Ox-LDL-stimulation on LSD1 expression was detected. Through loss-of-function assay, the associations between LSD1 interference and SESN2 expression, autophagy, NLRP3 inflammasome and inflammatory cytokines were explored. Finally, the function of LSD1 exerted on activation of PI3K/Akt/mTOR signal pathway was detected using western blotting assay. KEY FINDINGS: The expression of LSD1 was significantly elevated in Ox-LDL-treated RAW264.7 cells. Inhibition of LSD1 promoted autophagy, inhibited inflammation and activated NLRP3 inflammasome. SESN2 was elevated by LSD1 inhibition, and thus activate the PI3K/Akt/mTOR signal pathway. What' more, Knockdown of SESN2 or deactivate the PI3K/Akt/mTOR signal pathway partly reversed the effect of LSD1 inhibition on autophagy. SIGNIFICANCE: Our present study drew the finding that the knockdown of LSD1 meliorated Ox-LDL-stimulated NLRP3 activation and inflammation through promoting autophagy via SESN2-mediated PI3K/Akt/mTOR pathway.


Assuntos
Autofagia , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/metabolismo , Inflamação/patologia , Lipoproteínas LDL/efeitos adversos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Nucleares/metabolismo , Animais , Células Cultivadas , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/genética , Inflamação/etiologia , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
11.
Nat Commun ; 10(1): 2410, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160587

RESUMO

Medulloblastoma, which is the most common malignant paediatric brain tumour, has a 70% survival rate, but standard treatments often lead to devastating life-long side effects and recurrence is fatal. One of the emerging strategies in the search for treatments is to determine the roles of tumour microenvironment cells in the growth and maintenance of tumours. The most attractive target is tumour-associated macrophages (TAMs), which are abundantly present in the Sonic Hedgehog (SHH) subgroup of medulloblastoma. Here, we report an unexpected beneficial role of TAMs in SHH medulloblastoma. In human patients, decreased macrophage number is correlated with significantly poorer outcome. We confirm macrophage anti-tumoural behaviour in both ex vivo and in vivo murine models of SHH medulloblastoma. Taken together, our findings suggest that macrophages play a positive role by impairing tumour growth in medulloblastoma, in contrast to the pro-tumoural role played by TAMs in glioblastoma, another common brain tumour.


Assuntos
Neoplasias Cerebelares/imunologia , Macrófagos/imunologia , Meduloblastoma/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/metabolismo , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Humanos , Macrófagos/metabolismo , Meduloblastoma/genética , Meduloblastoma/metabolismo , Camundongos , Microglia/imunologia , Células Mieloides/imunologia , Receptores CCR2/genética , Regulação para Cima
12.
Nat Commun ; 10(1): 2402, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160588

RESUMO

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to  stat1-/- mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.


Assuntos
Plaquetas/metabolismo , Vírus da Dengue/imunologia , Dengue/imunologia , Vesículas Extracelulares/imunologia , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Micropartículas Derivadas de Células/imunologia , Micropartículas Derivadas de Células/metabolismo , Citocinas/imunologia , Dengue/virologia , Exossomos/imunologia , Exossomos/metabolismo , Armadilhas Extracelulares/imunologia , Vesículas Extracelulares/metabolismo , Humanos , Inflamação , Lectinas Tipo C/genética , Camundongos , Camundongos Knockout , Ativação Plaquetária , Receptores de Superfície Celular/genética , Fator de Transcrição STAT1/genética , Taxa de Sobrevida
13.
Nat Commun ; 10(1): 2416, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186412

RESUMO

Cancer response to immunotherapy depends on the infiltration of CD8+ T cells and the presence of tumor-associated macrophages within tumors. Still, little is known about the determinants of these factors. We show that LIF assumes a crucial role in the regulation of CD8+ T cell tumor infiltration, while promoting the presence of protumoral tumor-associated macrophages. We observe that the blockade of LIF in tumors expressing high levels of LIF decreases CD206, CD163 and CCL2 and induces CXCL9 expression in tumor-associated macrophages. The blockade of LIF releases the epigenetic silencing of CXCL9 triggering CD8+ T cell tumor infiltration. The combination of LIF neutralizing antibodies with the inhibition of the PD1 immune checkpoint promotes tumor regression, immunological memory and an increase in overall survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL9/metabolismo , Fator Inibidor de Leucemia/imunologia , Macrófagos/imunologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/farmacologia , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CCL2/metabolismo , Epigênese Genética , Humanos , Memória Imunológica , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , Transplante de Neoplasias , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/imunologia
14.
Cancer Immunol Immunother ; 68(7): 1073-1085, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31161238

RESUMO

Cryptotanshinone (CT), a purified compound initially isolated from the dried roots of Salvia militorrhiza. Bunge, exhibits cytotoxic antitumor effects on many tumors. We have shown that CT possesses the dual capacities to concomitantly inhibit the proliferation of lung cancer cells and promote the generation of antitumor immunity. In this study, we investigated whether CT could be used to treat hepatocellular carcinoma (HCC) using a mouse Hepa1-6 model. CT inhibited the proliferation of mouse hepatoma (Hepa1-6) cells in vitro by inducing Hepa1-6 cells apoptosis through the JAK2/STAT3 signaling pathway. In addition, CT activated macrophages and polarized mouse bone marrow-derived macrophages (BMM) toward an M1 phenotype in vitro, which depended on the TLR7/MyD88/NF-κB signaling pathway. Furthermore, CT significantly inhibited the growth of syngeneic Hepa1-6 hepatoma tumors, and, in combination with anti-PD-L1 cured Hepa1-6-bearing mice with the induction of long-term anti-Hepa1-6 specific immunity. Immunoprofiling of treated Hepa1-6-bearing mice revealed that CT-promoted activation of tumor-infiltrating macrophages and dendritic cells, induction of antitumor T cell response, and infiltration of effector/memory CD8 T cells in the tumor tissue. Importantly, the immunotherapeutic effects of CT and anti-PD-L1 depended on the presence of CD8 T cells. Thus, CT and anti-PD-L1 may provide an effective immunotherapeutic regimen for human HCC based on a combination of cytotoxic effects and induction of tumor-specific immunity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Fenantrenos/farmacologia , Receptor 7 Toll-Like/metabolismo , Imunidade Adaptativa/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Ativação Linfocitária , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fenantrenos/uso terapêutico , Salvia miltiorrhiza/química , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/imunologia , Resultado do Tratamento
15.
Nat Commun ; 10(1): 2450, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164648

RESUMO

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8+ T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2-/- mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2-/- macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8+ T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.


Assuntos
Neoplasias da Mama/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/imunologia , Carcinoma/imunologia , Neoplasias Mamárias Animais/imunologia , Células Mieloides/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/imunologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proliferação de Células , Quimiocinas/imunologia , Feminino , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Macrófagos/imunologia , Macrófagos/metabolismo , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células Mieloides/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Evasão Tumoral/genética
16.
Environ Pollut ; 246: 963-971, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31159146

RESUMO

Bisphenol S (BPS) has been widely used as a bisphenol alternative in recent few years. However, with mounting evidence suggesting that the presence of BPS in the environment also poses risks to ecosystems and human health, we decided to use the juvenile common carp (Cyprinus carpio) and its primary macrophages as in vivo and in vitro models to examine if BPS is a safe substitute of BPA. The present study evaluated the immune responses of chronic BPS exposure and their mechanisms of action associated with peroxisome proliferator-activated receptor (PPAR) signaling pathway. Potential oxidative stress and pro-inflammatory effects of BPS exposure were identified in fish liver after 60-day exposure, based on the increased reactive oxygen species (ROS) production, antioxidant capacity, NO production, lipid peroxidation, and induction of inflammatory cytokine expression, as well as acute phase protein levels of C-reactive protein, immunoglobulin M, lysozyme, and complement component 3. Moreover, pparγ, PPAR pathway-associated genes retinoid x receptor α (rxrα) and nuclear factor-κb (nfκb) presented a rough concentration-dependent alteration after BPS exposure. An acute BPS exposure to the isolated primary macrophages from juvenile common carp was performed to help elucidate gene expression patterns of pparγ, rxrα, and nfκb in a typical immune cell model, the results were consistent with what we found in vivo experiments for long-term BPS exposure. Furthermore, with coexposure to BPS and a PPARγ antagonist, the restriction of PPAR signaling pathway significantly inhibited the induction of ROS and the mRNA level of interleukin-1ß, confirming the involvement of PPAR pathway in BPS-induced chronic inflammatory stress in liver.


Assuntos
Poluentes Ambientais/toxicidade , Inflamação/metabolismo , Fígado/efeitos dos fármacos , PPAR gama/metabolismo , Fenóis/toxicidade , Sulfonas/toxicidade , Animais , Carpas/imunologia , Carpas/metabolismo , Inflamação/genética , Fígado/imunologia , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
17.
J Microbiol Biotechnol ; 29(7): 1022-1032, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216608

RESUMO

Probiotics are known to provide the host with immune-modulatory effects and are therefore of remarkable interest for therapeutic and prophylactic applications against various disorders, including inflammatory diseases. Weissella cibaria JW15 (JW15) has been reported to possess probiotic and antioxidant properties. However, the effect of JW15 on inflammatory responses has not yet been reported. Therefore, the objective of the current study was to evaluate the anti-inflammatory potential of JW15 against lipopolysaccharide (LPS) stimulation. The production of pro-inflammatory factors and the cellular signaling pathways following treatment with heat-killed JW15 was examined in LPS-induced RAW 264.7 cells. Treatment with heat-killed JW15 decreased nitric oxide and prostaglandin E2 production via downregulation of the inducible nitric oxide synthase and cyclooxygenase-2. In addition, treatment with heat-killed JW15 suppressed the expression of pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. The anti-inflammatory properties of treating with heat-killed JW15 were associated with mitogen-activated protein kinase signaling pathwaymediated suppression of nuclear factor-κB. These results indicated that JW15 possesses antiinflammatory potential and provide a molecular basis regarding the development of functional probiotic products.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Probióticos/farmacologia , Fator de Transcrição RelA/metabolismo , Weissella/fisiologia , Animais , Sobrevivência Celular , Ciclo-Oxigenase 2/genética , Citocinas/genética , Citocinas/metabolismo , Dinoprostona/metabolismo , Alimentos Fermentados/microbiologia , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
18.
Future Microbiol ; 14: 705-716, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31161794

RESUMO

Aim: Aspergillus fumigatus is one of the most common opportunistic fungi that can cause invasive infection. To profile the kinetic variation of immune cells and cytokines after exposure to A. fumigatus thoroughly, we established a pulmonary A. fumigatus infection model in temporarily immunosuppressed mice. Materials & methods: Systematic and kinetic studies of different immune cells and cytokines were performed. Results: We observed that the granulocytes and macrophages recruited to the site of infection played an important role in the infectious phase. There was a significant increase in the cytokines IFN-γ, IL-6, TNF-α as well as the chemokines CXCL1, MIP-1α, MIP-2 and CCL5 after infection. IL-10 was found to participate in balancing the anti-inflammatory response in the recovery phases. The immune response mediated by T cells was mainly presented by the Th1-type on day 7 after exposure with a high proportion of IFN-γ+ CD4+ T cells and CD4+CD44highCD62Llow effector T cells. Conclusion: These kinetic parameters of the immune response might provide diagnostic clues for A. fumigatus infection.


Assuntos
Aspergilose/imunologia , Aspergillus fumigatus/patogenicidade , Quimiocinas/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Animais , Linfócitos T CD4-Positivos , Quimiocina CCL3/metabolismo , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiocinas/sangue , Citocinas/sangue , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Cinética , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/microbiologia , Linfonodos/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Linfócitos T/imunologia , Células Th1/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Gen Physiol Biophys ; 38(4): 315-324, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31241043

RESUMO

Diosmin is an unsaturated flavonoid glycoside, presents in citrus fruits. The aim of this study is to investigate the molecular mechanism of diosmin with respect to the NF-κB and MAPKs signaling pathways. Firstly, 10, 20, 30, 40 and 50 µM diosmin were treated to lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The anti-inflammatory effects of diosmin was displayed via measuring prostaglandin E2 (PGE2), nitric oxide (NO), interleukines (IL-6, IL-12), tumor necrosis factor α (TNF-α) production, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), IL-6, IL-12, TNF-α mRNA levels, and phosphorylation levels of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκB-α) and mitogen-activated protein kinases (MAPKs); JNK, ERK, and p38 in LPS induced RAW264.7 macrophages. Our study showed that especially high concentrations of diosmin decreased NO, PGE2, IL-6, IL-12, TNF-α production and mRNA levels of these mediators (p < 0.05). The expression of phosphorylated-JNK was significantly suppressed by diosmin at 40 and 50 µM concentrations. Furthermore, diosmin significantly inhibited the expression of phosphorylated-ERK, p38, and p-IκB-α in a dose-dependent manner. Our results suggest that diosmin is a potent anti-inflammatory agent and has potential for development into a therapeutic agent for inflammation-associated disorders.


Assuntos
Diosmina/farmacologia , Mediadores da Inflamação/antagonistas & inibidores , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Macrófagos/enzimologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos
20.
Vet Microbiol ; 233: 124-132, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31176398

RESUMO

Leptospirosis is a zoonosis, caused by pathogenic spirochetes of the genus Leptospira. Although cattle are usually the maintenance hosts of serovar Hardjo, Pomona is the most frequent serovar circulating in Argentina. The understanding of bovine innate immune response and the virulence of this serovar is important for future control measures. This work compares infection of bovine macrophages with the virulent L. interrogans sv Pomona strain AKRFB (P1) and its attenuated counterpart (P19). First, we confirmed attenuation in the hamster model. Mortality and lung hemorrhages occurred after P1 inoculation, while the survival rate was 100% in P19-infected animals. Cells infected with both strains showed statistically upregulated gene expression of pro-inflammatory cytokines, IL-1ß, IL-6 and TNFα. The level of expression of anti-inflammatory cytokine IL-10 was statistically different between strains. Increased expression of IL-10 was observed only in P1-infected cells. For the first time, we describe macrophages extracellular traps induced by infection of bovine macrophages (bMETs) with both, the virulent and attenuated Leptospira interrogans Pomona strains. P1 was found higher internalized when the phagocytosis was inhibited, suggesting a cell entrance of this strain also by an independent-phagocytosis pathway. Furthermore, P1 was higher colocalized with acidic and late endosomal compartments compared with P19. This data emphasizes the importance to deepen in Leptospira bovine macrophages particular invasion mechanisms and, furthermore, underline the value of studying the main hosts.


Assuntos
Imunidade Inata , Leptospira interrogans serovar pomona/patogenicidade , Macrófagos/imunologia , Macrófagos/microbiologia , Animais , Argentina , Bovinos , Células Cultivadas , Cricetinae , Citocinas/genética , Citocinas/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Leptospirose/imunologia , Pulmão/microbiologia , Pulmão/patologia , Sorogrupo , Virulência
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