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1.
Adv Clin Exp Med ; 28(8): 1101-1110, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31403266

RESUMO

BACKGROUND: Inhibition of the protein C system (PCS) might be one of the mechanisms of ulcerative colitis (UC). OBJECTIVES: The aim of the study was to explore the role of IgG plasma cells in changes in the PCS in UC. MATERIAL AND METHODS: Dextran sulfate sodium (DSS) was chosen to induce mouse UC. Inflammation was assessed using hematoxylin & eosin (H&E) staining and immunofluorescence. The profiling of colonic plasma cells and macrophages from colitis mice was analyzed with flow cytometry. After stimulation of macrophages with IgG type immune complex (IgG-IC), western blot was used to determine tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) protein levels. After co-incubation of colonic mucosa microvascular endothelial cells (MVECs) with TNF-α or IL-6, mitogen-activated protein kinase (MAPK) expression was detected. RESULTS: The DSS-colitis mice showed higher inflammatory indexes (p < 0.05 or p < 0.01), accompanied by greater infiltration of CD38+IgG+ plasma cells (p < 0.01), CD14+CD64+ macrophages (p < 0.01) and IgG-IC than healthy mice. Enhancement of TNF-α and IL-6 protein expression was demonstrated in this subset of macrophages when stimulated by IgG-IC (p < 0.01). After MVECs were incubated with TNF-α or IL-6, the expression of ß-arrestin1, pP38 MAPK and pJNK MAPK exhibited an increase (p < 0.05 or p < 0.01), but downregulation of endothelial protein C receptor (EPCR) expression was observed (p < 0.05 or p < 0.01); this inhibition of EPCR expression was reversed by SB203580, SP600125 or U0126 (p < 0.05 or p < 0.01). In addition, changes in activated protein C (APC) presented results similar to those for EPCR expression (p < 0.05 or p < 0.01). CONCLUSIONS: These results reveal that the PCS is inhibited during UC processing. There is a possibility that the interaction between IgG plasma cells and CD14+CD64+ macrophages, as well as further secretion of cytokines from CD14+CD64+ macrophages by the formation and stimulation of IgG-IC, subsequently influence MVECs through the ß-arrestin-MAPK pathway. Enhancement of PCS activity may represent a novel approach for treating UC.


Assuntos
Colite Ulcerativa , Ativação de Macrófagos , Proteína C , Animais , Colite Ulcerativa/imunologia , Colo , Células Endoteliais , Imunoglobulina G/fisiologia , Receptores de Lipopolissacarídeos , Camundongos , Plasmócitos , Proteína C/fisiologia , Receptores de IgG
2.
J Agric Food Chem ; 67(36): 10069-10078, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31422663

RESUMO

Macrophage polarization has been implicated in the pathogenesis of obesity and type 2 diabetes, which are recognized as chronic proinflammatory diseases. This study investigated that high level of glucose, similar to lipopolysaccharide (LPS), activated macrophages toward M1 phenotypes and 1-20 µM asaronic acid (AA) counteracted diabetic macrophage activation. AA reduced the LPS-promoted secretion of proinflammatory interleukin (IL)-6 and monocyte chemoattractant protein-1. The LPS markedly elevated the macrophage induction of the M1 markers of Toll-like receptor 4 (TLR4), CD36, and CD68, which was attenuated by AA. Also, the LPS significantly enhanced the nuclear factor (NF)-κB transactivation, signal transducers, and activators of transcription 1 (STAT1)/STAT3 activation and suppressor of cytokine signaling 3 (SOCS3) induction in macrophages. However, AA highly suppressed the aforementioned effects of LPS. Glucose-stimulated macrophages expressed advanced glycation end products (AGEs) and receptor for AGE (RAGE). Administration of 20 µM AA to macrophages partly but significantly attenuated such effects (1.65 ± 0.12 vs 0.95 ± 0.25 times glucose control for AGE; 2.33 ± 0.31 vs 1.40 ± 0.22 times glucose control for RAGE). Furthermore, glucose enhanced the macrophage induction of TLR4 and inducible nitric oxide synthase and IL-6 production, while it demoted the production of anti-inflammatory arginase-1 and IL-10. In contrast, AA reversed the induction of these markers in glucose-loaded macrophages. AA dose-dependently and significantly encumbered NF-κB transactivation, Janus kinase 2 (JAK2) and STAT1/STAT3 activation, and SOCS3 induction upregulated in glucose-supplemented macrophages. These results demonstrated for the first time that AA may limit diabetic macrophage activation toward the M1 phenotype through the inhibition of TLR4-/IL-6-mediated NF-κB/JAK2-STAT signaling entailing AGE-RAGE interaction.


Assuntos
Glucose/imunologia , Janus Quinase 2/imunologia , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Linhagem Celular , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , Perilla/química , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética
3.
Anticancer Res ; 39(8): 4533-4537, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366556

RESUMO

BACKGROUND/AIM: Serum-derived macrophage activating factor, serum-MAF, is known to increase the phagocytic activity of macrophages by enhancing the engulfment efficiency. To elucidate the mechanisms underlying phagocytic activation, morphological changes were observed and analyzed. MATERIALS AND METHODS: Morphological changes in macrophages were observed and quantitatively analyzed using scanning electron microscope (SEM) and confocal microscope. RESULTS: SEM and confocal microscopy images revealed frill-like structures and active actin accumulations, respectively, in serum-MAF treated macrophages. Actin accumulation was induced within 5 min following serum-MAF treatment. CONCLUSION: Serum-MAF induced a rapid rearrangement of cytoskeletal actin and enhanced phagocytic activity. Findings of the current study may contribute to the development of techniques that facilitate activation of the human immune system, which in turn may be beneficial for cancer immunotherapy.


Assuntos
Actinas/química , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-maf/farmacologia , Actinas/ultraestrutura , Humanos , Imunoterapia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Varredura , Proteínas Proto-Oncogênicas c-maf/genética , Células U937 , Proteína de Ligação a Vitamina D/química , Proteína de Ligação a Vitamina D/metabolismo
4.
Toxicol Lett ; 314: 89-97, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31325635

RESUMO

Ethanol is a key factor in the pathogenesis of alcoholic liver disease (ALD), commonly characterized as liver inflammation. Recently, circular (circ)RNAs have emerged as important targets to cure liver diseases. However, there are no studies investigating the role of circ_1639 in reducing inflammatory responses in ALD. In this study, we found that circ_1639 was upregulated in Kupffer cells from the livers of alcohol fed mice. We hypothesized that circ_1639 inhibition is a potential novel therapy for treating ALD. To test this hypothesis, RAW 264.7 cells were treated with ethanol and transfected with circ_1639 overexpression or knockdown plasmids. We present western blotting, qRT-PCR, and ELISA data that suggest that circ_1639 is a proinflammatory factor in the liver and is involved in the activation of the NF-κB signaling pathway. Using luciferase reporter assay, we confirmed that microRNA (miR)-122 is a target gene of circ_1639. We also show that TNFRSF13C is a key regulator of RAW 264.7 cell activation, and acts as a downstream target for miR-122. In summary, our results suggest that inhibition of circ_1639 expression may reduce inflammatory responses in ALD.


Assuntos
Mediadores da Inflamação/metabolismo , Hepatopatias Alcoólicas/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , RNA/metabolismo , Animais , Receptor do Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Macrófagos do Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Hepatopatias Alcoólicas/prevenção & controle , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células RAW 264.7 , RNA/genética , Transdução de Sinais
5.
Int J Nanomedicine ; 14: 4145-4155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239673

RESUMO

Background: There is emerging evidence which suggests that cellular ROS including nitric oxide (NO) are important mediators for inflammation and osteoarthritis (OA). Water-soluble polyhydroxylated fullerene C60 (fullerol) nanoparticle has been demonstrated to have an outstanding ability to scavenge ROS. Purpose: The objective of this study is to assess the effects of fullerol on inflammation and OA by in vitro and in vivo studies. Methods: For in vitro experiments, primary mouse peritoneal macrophages and a macrophage cell line RAW264.7 were stimulated to inflammatory phenotypes by lipopolysaccharide (LPS) in the presence of fullerol. For the animal study, OA model was created by intra-articular injection of monoiodoacetate into the knee joints of rats and fullerol was intravenously injected immediately after OA induction. Results: NO production and pro-inflammatory gene expression induced by LPS was significantly diminished by fullerol in both macrophage cell types. Meanwhile, fullerol could remarkably reduce phosphorylation of p38 mitogen-activated protein kinase, and protein level of transcription factors nuclear factor-kappaB and forkhead box transcription factor 1 within the nucleus. The animal study delineated that systematic administration of fullerol prevented OA, inhibiting inflammation of synovial membranes and the damage toward the cartilage chondrocytes in the OA joints. Conclusion: Antioxidative fullerol may have a potential therapeutic application for OA.


Assuntos
Antioxidantes/farmacologia , Fulerenos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Nanopartículas/química , Osteoartrite/patologia , Animais , Células Cultivadas , Feminino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Camundongos , Modelos Biológicos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Osteoartrite/tratamento farmacológico , Células RAW 264.7 , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo
6.
Immunol Med ; 42(1): 45-49, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31204589

RESUMO

A healthy 32-year-old man had a fever and elevated levels of white blood cells (WBC) and C-reactive protein (CRP). In addition, he presented with a skin rash on his forehead, around the neck, and from the anterior chest to the abdomen. His laboratory findings showed elevated levels of hepatic enzyme, CRP, and ferritin; therefore, he was suspected to have adult-onset Still's disease (AOSD) and referred to our department. We ruled out hematological malignancy and established diagnosis of AOSD according to Yamaguchi's criteria and treated with 20 mg/day prednisolone. His clinical condition did not improve, therefore, we increased the dosage of prednisolone to 40 mg/day; however, his rash gradually expanded with papules and plaques. A cervical skin biopsy revealed neutrophil dermatosis and analysis of the MEFV gene revealed a heterozygous variant in exon 2 (E148Q). We found an elevated percentage of CD86+CD14+CD16- classical monocytes in the peripheral blood using flow cytometry. We added oral potassium iodide as a treatment for neutrophil dermatosis. Despite this treatment, his eruption and fever did not subside, therefore, we changed potassium iodide to colchicine, this improved his clinical condition. This case suggests the importance of autoinflammation-related gene abnormalities and macrophage activation in the pathogenesis of neutrophil dermatosis.


Assuntos
Variação Genética , Ativação de Macrófagos , Monócitos/imunologia , Pirina/genética , Síndrome de Sweet/genética , Síndrome de Sweet/imunologia , Administração Oral , Adulto , Colchicina/administração & dosagem , Quimioterapia Combinada , Humanos , Masculino , Iodeto de Potássio/administração & dosagem , Prednisolona/administração & dosagem , Doença de Still de Início Tardio , Síndrome de Sweet/sangue , Síndrome de Sweet/tratamento farmacológico , Resultado do Tratamento
7.
Nat Immunol ; 20(7): 793-801, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213715

RESUMO

Unlike other cells in the body, immune cells have to be able to enter and adapt to life within diverse tissues. Immune cells develop within dedicated immune system organs, such as the bone marrow, thymus and lymphoid tissues, but also inhabit other tissues, wherein they not only provide defense against infection and malignancies but also contribute to homeostatic tissue function. Because different tissues have widely divergent metabolic rates and fuel requirements, this raises interesting questions about the adaptation of immune cells in specific tissues. When immune cells take up residence in different tissues, they develop a transcriptional signature that reflects adaptation to life and function within that tissue. Genes encoding metabolic-pathway proteins are strongly represented within these signatures, reflective of the importance of metabolic adaptation to tissue residence. In this Review, we discuss the available data on the metabolic adaptation of immune cells to life in different tissue sites, within the broader framework of how functional adaptation versus maladaptation in the niche can affect tissue homeostasis.


Assuntos
Adaptação Biológica , Metabolismo Energético , Sistema Imunitário/citologia , Sistema Imunitário/fisiologia , Especificidade de Órgãos/imunologia , Animais , Biomarcadores , Homeostase , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Transdução de Sinais
8.
J Microbiol ; 57(8): 644-654, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124046

RESUMO

Lipopolysaccharide (LPS) is one of the major components in the outer membrane of Gram-negative bacteria. However, its heterogeneity and variability in different bacteria and differentiation conditions make it difficult to extract all of the structural variants. We designed a solution to improve quality and biological activity of LPS extracted from various bacteria with different types of LPS, as compared to conventional methods. We introduced a quality index as a simple measure of LPS purity in terms of a degree of polysaccharide content detected by absorbance at 204 nm. Further experiments using gel electrophoresis, endotoxin test, and macrophage activation test were performed to evaluate the performance and reliability of a proposed 'T-sol' method and the biological effectiveness and character of the LPS products. We presented that the T-sol method had differential effects on extraction of a RAW 264.7 cell-activating LPS, which was effective in the macrophage activation with similar effects in stimulating the production of TNF-alpha. In conclusion, the T-sol method provides a simple way to improve quality and biological activity of LPS with high yield.


Assuntos
Acinetobacter baumannii/química , Escherichia coli/química , Lipopolissacarídeos/isolamento & purificação , Salmonella typhimurium/química , Animais , Linhagem Celular , Guanidinas/química , Lipopolissacarídeos/química , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Fenóis/química , Reprodutibilidade dos Testes , Solventes/química
9.
Nat Commun ; 10(1): 2272, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118418

RESUMO

Switching macrophages from a pro-tumor type to an anti-tumor state is a promising strategy for cancer immunotherapy. Existing agents, many derived from bacterial components, have safety or specificity concerns. Here, we postulate that the structures of the bacterial signals can be mimicked by using non-toxic biomolecules of simple design. Based on bioactivity screening, we devise a glucomannan polysaccharide with acetyl modification at a degree of 1.8 (acGM-1.8), which specifically activates toll-like receptor 2 (TLR2) signaling and consequently induces macrophages into an anti-tumor phenotype. For acGM-1.8, the degree of acetyl modification, glucomannan pattern, and acetylation-induced assembly are three crucial factors for its bioactivity. In mice, intratumoral injection of acGM-1.8 suppresses the growth of two tumor models, and this polysaccharide demonstrates higher safety than four classical TLR agonists. In summary, we report the design of a new, safe, and specific TLR2 agonist that can generate macrophages with strong anti-tumor potential in mice.


Assuntos
Antineoplásicos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Neoplasias/tratamento farmacológico , Receptor 2 Toll-Like/agonistas , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HEK293 , Humanos , Injeções Intralesionais , Macrófagos/metabolismo , Mananas/química , Mananas/farmacologia , Mananas/uso terapêutico , Camundongos , Camundongos Knockout , Neoplasias/imunologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
10.
Exp Parasitol ; 203: 1-7, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128104

RESUMO

Fucose-mannose ligand (FML) is a soluble antigen purified from Leishmania donovani complex and used for diagnosis, prognosis, and vaccine development against visceral leishmaniasis (VL). We aimed to explore the effects of FML on the production of cytokines, chemokines and nitric oxide (NO) by macrophages in vitro. Peritoneal macrophages from BALB/c mice were treated with various concentrations of FML purified from Leishmania infantum in the absence or presence of LPS Peritoneal macrophages. After 48hr, cell culture supernatants were recovered and the levels of TNF-α, IL-10, IL-12p70 and IP-10 measured by Sandwich ELISA and NO concentration by Griess reaction. We found that FML significantly increase NO, IL-12p70 and IP-10 production in both LPS-treated and untreated macrophages and increase IL-10 levels only in LPS-treated macrophages. However, FML could not alert TNF-α levels in both LPS-treated and untreated macrophages. Further analysis revealed that FML can also increase IL-12p70/IL-10 ratio in LPS-treated macrophages. We concluded that FML can polarize macrophages to an appropriate phenotype similar to M1 phenotype against Leishmania donovani complex, although IL10 and TNF results are controversial.


Assuntos
Citocinas/metabolismo , Lectinas/farmacologia , Leishmania infantum/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico/metabolismo , Animais , Quimiocina CXCL10/metabolismo , Feminino , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Leishmania infantum/imunologia , Ativação de Macrófagos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismo
11.
Methods Mol Biol ; 1966: 211-224, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041750

RESUMO

Activation of signal transducer and activator of transcription 6 (STAT6) is a key signaling pathway in macrophage function, and is required for the so-called alternative (M2) activation of macrophages. Interleukin (IL)-4 and IL-13 are important M2 polarizing cytokines that act through STAT6 by inducing its phosphorylation and promoting transcription of STAT6-responsive genes. Inactivation of STAT6 signaling in macrophages has not been fully explored; however, a recent model suggests that inactivation of STAT6 signaling can occur via ubiquitination and proteasomal degradation. In this chapter, we describe a combination of techniques that can be used to study the activation/inactivation of STAT6 signaling in macrophages.


Assuntos
Técnicas Imunológicas/métodos , Ativação de Macrófagos , Macrófagos/metabolismo , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Animais , Linhagem Celular , Interleucina-4/metabolismo , Macrófagos/imunologia , Fosforilação , Processamento de Proteína Pós-Traducional
12.
Eur J Pharmacol ; 854: 307-319, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31039343

RESUMO

Interleukin 33 (IL33) has been found to be cardioprotective on various cardiovascular pathologies. However, it is not clear whether IL33 may inhibit myocardial infarction-related ventricular remodeling through inducing macrophage polarization. The objective of present study is to assess whether IL33 can improve ventricular remodeling after myocardial infarction by inducing macrophage polarization. In this study, the direct influence of IL33 on the polarization of macrophages and its mechanism in vitro were investigated. The potential protective effects of IL33 on acute and chronic myocardial infarction (MI) in vivo as well as its underlying mechanism through macrophage polarization were also determined. We found that IL33 significantly enhanced M2 macrophage and decreased the proportion of M1 macrophage. Importantly, IL33 induced M2 macrophage polarization by activating the JAK/STAT signaling pathway. In vivo, IL33 weaken the inflammatory level and myocardial apoptosis after MI and improved the systolic and diastolic function of the heart. Furthermore, IL33 significantly reduced infarct area and prevented the progression of fibrosis by inducing M2 macrophage polarization. The protective effects of IL33 were suppressed by JAK/STAT signaling pathway inhibitor. Our findings highlighted that IL33 not only reduced the early inflammatory response and inhibited myocardial apoptosis, but also increased the number of M2 macrophage in the infarcted area, significantly reduced infarct area and prevented the progression of fibrosis by activating JAK/STAT pathway. Therefore, IL33 may be a novel cardiac protective cytokine for myocardial infarction.


Assuntos
Interleucina-33/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Células RAW 264.7 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
J Agric Food Chem ; 67(19): 5552-5559, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042377

RESUMO

The present study was designed to investigate the role of the canonical and noncanonical inflammasome, MAPKs and NRF-2/HO-1, signaling pathways involved in the antioxidant and anti-inflammatory activities of oleocanthal in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. Isolated cells were treated with oleocanthal in the presence or absence of LPS (5 µg mL-1) for 18 h. Oleocanthal showed a potent reduction of reactive oxygen species (ROS) (25 µM, 50. 612 ± 0.02; 50 µM, 53. 665 ± 0.09; 100 µM, 52. 839 ± 0.02), nitrites (25 µM, 0.631 ± 0.07; 50 µM, 0.652 ± 0.07; 100 µM, 0.711 ± 0.08), and pro-inflammatory cytokines levels when compared with LPS-DMSO-treated control cells. In terms of enzymes protein expression, oleocanthal was able to downregulate iNOS (25 µM, 0.173 ± 0.02; 50 µM, 0.149 ± 0.01; 100 µM, 0.150 ± 0.01; p < 0.001), COX-2 (25 µM, 0.482 ± 0.08; 50 µM, 0.469 ± 0.05; 100 µM, 0.418 ± 0.06; p < 0.001), and mPGES-1 (25 µM, 0.185 ± 0.11; 50 µM, 0.218 ± 0.13; 100 µM, 0.161 ± 0.15; p < 0.001) as well as p38 (25 µM, 0.366 ± 0.11; 50 µM, 0.403 ± 0.13; 100 µM, 0.362 ± 0.15; p < 0.001), JNK (25 µM, 0.443 ± 0.11; 50 µM, 0.514 ± 0.13; 100 µM, 0.372 ± 0.15; p < 0.001), and ERK (25 µM, 0.294 ± 0.01; 50 µM, 0.323 ± 0.01; 100 µM, 0.274 ± 0.01; p < 0.001) protein phosphorylation, which was accompanied by an upregulation of Nrf-2 (25 µM, 1.57 ± 0.01; 50 µM, 1.54 ± 0.01; 100 µM, 1.63 ± 0.05; p < 0.05) and HO-1(25 µM, 2.12 ± 0,03; 50 µM, 2.24 ± 0.01; 100 µM, 1.92 ± 0.05; p < 0.01) expression in comparison with LPS-DMSO cells. Moreover, oleocanthal inhibited canonical and noncanonical inflammasome signaling pathways. Thus, oleocanthal might be a promising natural agent for future treatment of immune-inflammatory diseases.


Assuntos
Aldeídos/farmacologia , Heme Oxigenase-1/imunologia , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Fator 2 Relacionado a NF-E2/imunologia , Fenóis/farmacologia , Animais , Células Cultivadas , Feminino , Heme Oxigenase-1/genética , Inflamassomos/efeitos dos fármacos , Inflamassomos/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fosforilação , Espécies Reativas de Oxigênio/imunologia
14.
DNA Cell Biol ; 38(7): 597-606, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31095428

RESUMO

Mitochondria are highly dynamic organelles beyond powerhouses of a cell. These components also play important roles in cell homeostasis by regulating cell function and phenotypic modulation. Atherosclerosis is the leading cause of morbidity and mortality in developed and developing countries. Mitochondrial dysfunction has been increasingly associated with the initiation and progression of atherosclerosis by elevating the production of reactive oxygen species and mitochondrial oxidative stress damage, mitochondrial dynamics dysfunction, and energy supply. In this review, we describe the progression of the link between mitochondrial dysfunction and atherosclerosis and its potential regulation mechanisms.


Assuntos
Aterosclerose/metabolismo , Mitocôndrias/metabolismo , Animais , Aterosclerose/patologia , Endotélio Vascular/metabolismo , Humanos , Ativação de Macrófagos , Músculo Liso Vascular/metabolismo , Espécies Reativas de Oxigênio/metabolismo
15.
Food Funct ; 10(4): 2186-2197, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30942219

RESUMO

A new acidic polysaccharide (GPTP-3) with a molecular weight of 2.49 × 106 Da was extracted and purified from Gynostemma pentaphyllum tea. Monosaccharide analysis revealed that GPTP-3 mainly comprised mannose (20.4%), glucuronic acid (17.4%), glucose (33.4%), and galactose (21.4%) (parentheses indicate the molar percentages). Immunostimulating assays indicated that GPTP-3 could markedly promote the secretion of NO, TNF-α, IL-1ß, and IL-6 in murine macrophage RAW264.7. TLR4 was found to be a recognized target of GPTP-3. Moreover, TLR4-related mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt, including ERK, JNK, p38, and Akt, were rapidly activated by GPTP-3 in RAW264.7 cells. Furthermore, GPTP-3 was found to induce the nuclear translocation of NF-κB subunit p65. All these findings suggest that MAPK, PI3K/Akt, and NF-κB pathways are involved in GPTP-3-induced macrophage activations, and GPTP-3 has the potential to be developed as a functional food with immunomodulatory functions.


Assuntos
Gynostemma/química , Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Fatores Imunológicos/química , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Extratos Vegetais/química , Polissacarídeos/química , Células RAW 264.7 , Chás de Ervas/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
Molecules ; 24(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999647

RESUMO

Acute lung injury (ALI) is a severe clinical disease marked by dysregulated inflammation response and has a high rate of morbidity and mortality. Macrophages, which play diverse roles in the inflammatory response, are becoming therapeutic targets in ALI. In this study we investigated the effects of dehydrocostus lactone (DHL), a natural sesquiterpene, on macrophage activation and LPS-induced ALI. The macrophage cell line RAW264.7 and primary lung macrophages were incubated with DHL (0, 3, 5, 10 and 30 µmol/L) for 0.5 h and then challenged with LPS (100 ng/mL) for up to 8 hours. C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) to induce acute lung injury (ALI) and then treated with a range of DHL doses intraperitoneally (5 to 20 mg/kg). The results showed that DHL inhibited LPS-induced production of proinflammatory mediators such as iNOS, NO, and cytokines including TNF-α, IL-6, IL-1ß, and IL-12 p35 by suppressing the activity of NF-κB via p38 MAPK/MK2 and Akt signaling pathway in macrophages. The in vivo results revealed that DHL significantly attenuated LPS-induced pathological injury and reduced cytokines expression in the lung. NF-κB, p38 MAPK/MK2 and Akt signaling molecules were also involved in the anti-inflammatory effect. Collectively, our findings suggested that DHL is a promising agent for alleviating LPS-induced ALI.


Assuntos
Lesão Pulmonar Aguda , Anti-Inflamatórios/farmacologia , Lactonas/farmacologia , Lipopolissacarídeos/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Sesquiterpenos/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Macrófagos/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Int J Mol Sci ; 20(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022963

RESUMO

Tet-eleven translocation 1 (TET1) is a dioxygenase that plays an important role in decreasing the abundance of DNA methylation and changing the expression levels of specific genes related to inflammation. Porphyromonas gingivalis (Pg.) lipopolysaccharide (LPS) can induce periodontal diseases that present with severe bone loss and collagen fiber destruction accompanied by a high number of M1 macrophages. M1-polarized macrophages are pivotal immune cells that promote the progression of the periodontal inflammatory response, but the function of TET1 during M1 macrophage activation is still unknown. Our results showed that the mRNA and protein expression levels of TET1 decreased in THP-1 cells during M1 macrophage differentiation. TET1 knockdown resulted in a significant decrease in the production of proinflammatory markers such as IL-6, TNF-α, CCL2, and HLA-DR in Pg. LPS/IFN-γ- and Escherichia coli (E. coli) LPS/IFN-γ-induced M1 macrophages. Mechanistically, TET1 knockdown downregulated the activity of the NF-κB signaling pathway. After treatment with the NF-κB inhibitor BAY 11-7082, M1 marker expression showed no significant difference between the TET1 knockdown group and the control group. Taken together, these results suggest that TET1 depletion inhibited Pg. LPS/IFN-γ-induced M1 macrophage polarization through the NF-κB pathway in THP-1 cells.


Assuntos
Interferon gama/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Oxigenases de Função Mista/genética , NF-kappa B/imunologia , Porphyromonas gingivalis/imunologia , Proteínas Proto-Oncogênicas/genética , Técnicas de Silenciamento de Genes , Humanos , Inflamação/imunologia , Inflamação/microbiologia , Ativação de Macrófagos , Macrófagos/microbiologia , Oxigenases de Função Mista/imunologia , Proteínas Proto-Oncogênicas/imunologia , Transdução de Sinais , Células THP-1
18.
Int J Mol Sci ; 20(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010119

RESUMO

The present study investigated the effects of activated microglia-derived interleukin-4 (IL-4) and IL-13 on neurodegeneration in prothrombin kringle-2 (pKr-2)-treated rat cortex. pKr-2 was unilaterally injected into the Sprague-Dawley rat cerebral cortex and IL-4 and IL-13 neutralizing antibody was used to block the function of IL-4 and IL-13. Immunohistochemical analysis showed a significant loss of NeuN+ and Nissl+ cells and an increase of OX-42+ cells in the cortex at seven days post pKr-2. The levels of IL-4 and IL-13 expression were upregulated in the activated microglia as early as 12 hours post pKr-2 and sustained up to seven days post pKr-2. Neutralization by IL-4 or IL-13 antibodies (NA) significantly increased neuronal survival in pKr-2-treated rat cortex in vivo by suppressing microglial activation and the production of reactive oxygen species, as analyzed by immunohisotochemistry and hydroethidine histochemistry. These results suggest that IL-4 and IL-13 that were endogenously expressed from reactive microglia may play a critical role on neuronal death by regulating oxidative stress during the neurodegenerative diseases, such as Alzheimer's disease and dementia.


Assuntos
Córtex Cerebral/patologia , Interleucina-13/toxicidade , Interleucina-4/toxicidade , Kringles , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Protrombina/química , Protrombina/toxicidade , Animais , Feminino , Mediadores da Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Modelos Biológicos , Degeneração Neural/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
19.
Eur J Pharm Biopharm ; 139: 253-261, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30981947

RESUMO

Resiquimod (R848), a member of the imidazoquinoline family, is a Toll-like receptor 7/8 agonist with high potency for cancer immunotherapy. However, tolerance induction and adverse effects limit its development as a drug. Encapsulation in a polymer matrix can circumvent these limitations, as shown in our formerly published approach where R848 was loaded into polylactic acid (PLA)-based nanoparticles (NP). Although the results were encouraging, low rates of encapsulation and rapid release of the drug were observed. In this study, we present a new strategy using mixed NP from modified linear PLA in order to improve the encapsulation and modulate the release profile of R848. Modified PLA polymers were designed and synthesized by microwave-assisted ring opening polymerization of d,l-lactide, using polyethylene glycol as initiator to increase the hydrophilic properties of the polymer or linear saturated aliphatic chains (C8 or C20) to increase the affinity with hydrophobic R848. NP were prepared by solvent evaporation method, leading to particles of 205-288 nm loaded with either R848 or DiO as a tracking agent. The release profile showed longer retention of R848 at both neutral and acidic pH for NP from grafted polymers. Upon exposure to phagocytic immune cells, NP were actively taken up by the cells and no impact on cell viability was observed, independently of the constitutive polymer. All R848-loaded NP activated macrophages to secrete interleukin-6, demonstrating that the drug cargo was immunologically active. Importantly, macrophage activation by NP-delivered R848 was slower than with free R848, in accordance with the in vitro release profiles. Thus, NP prepared from modified PLA polymers showed no signs of toxicity to immune cells and efficiently delivered their immunoactive cargo in a delayed manner. This delivery strategy may enhance the efficacy and safety of small-molecule immunostimulants.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Portadores de Fármacos/química , Imidazóis/administração & dosagem , Neoplasias/tratamento farmacológico , Poliésteres/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Imunoterapia/métodos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias/imunologia , Tamanho da Partícula , Cultura Primária de Células
20.
Molecules ; 24(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934890

RESUMO

Catalpa ovata (Bignoniaceae) is widely distributed throughout Korea, China, and Japan. This study investigated the anti-inflammatory effects of catalpalactone isolated from C. ovata in lipopolysaccharide (LPS)-induced RAW264.7 cells. Catalpalactone significantly inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in LPS-induced RAW264.7 cells. The levels of cytokines such as interleukin-6 and tumor necrosis factor-α were reduced under catalpalactone exposure in LPS-induced RAW264.7 cells. Additionally, catalpalactone suppressed signal transducer and activator of transcription 1 (STAT-1) protein expression and interferon-ß (IFN-ß) production. Treatment with catalpalactone prevented interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB) activation. Taken together, these results suggest that the anti-inflammatory effects of catalpalactone are associated with the suppression of NO production and iNOS expression through the inhibition of IRF3, NF-κB, and IFN-ß/STAT-1 activation.


Assuntos
Anti-Inflamatórios/farmacologia , Bignoniaceae/química , Lactonas/farmacologia , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Lactonas/química , Lactonas/isolamento & purificação , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Células RAW 264.7
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