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1.
Infect Immun ; 88(2)2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31611280

RESUMO

The pulmonary immune response protects healthy individuals against Pneumocystis pneumonia (PcP). However, the immune response also drives immunopathogenesis in patients who develop severe PcP, and it is generally accepted that optimal treatment requires combination strategies that promote fungal killing and also provide effective immunomodulation. The anti-inflammatory drug sulfasalazine programs macrophages for enhanced Pneumocystis phagocytosis and also suppresses PcP-related immunopathogenesis. Anti-Pneumocystis antibody opsonizes Pneumocystis organisms for greater phagocytosis and may also mask antigens that drive immunopathogenesis. Thus, we hypothesized that combining antibody and sulfasalazine would have the dual benefit of enhancing fungal clearance while dampening immunopathogenesis and allow the rescue of severe PcP. To model a clinically relevant treatment scenario in mice, therapeutic interventions were withheld until clear symptoms of pneumonia were evident. When administered individually, both passive antibody and sulfasalazine improved pulmonary function and enhanced Pneumocystis clearance to similar degrees. However, combination treatment with antibody and sulfasalazine produced a more rapid improvement, with recovery of body weight, a dramatic improvement in pulmonary function, reduced lung inflammation, and the rapid clearance of the Pneumocystis organisms. Accelerated fungal clearance in the combination treatment group was associated with a significant increase in macrophage phagocytosis of Pneumocystis Both passive antibody and sulfasalazine resulted in the suppression of Th1 cytokines and a marked increase in lung macrophages displaying an alternatively activated phenotype, which were enhanced by combination treatment. Our data support the concept that passive antibody and sulfasalazine could be an effective and specific adjunctive therapy for PcP, with the potential to accelerate fungal clearance while attenuating PcP-associated immunopathogenesis.


Assuntos
Anticorpos/imunologia , Fungos/efeitos dos fármacos , Fungos/imunologia , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/imunologia , Sulfassalazina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Citocinas/imunologia , Feminino , Fatores Imunológicos/imunologia , Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Imunoterapia/métodos , Inflamação/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Camundongos , Camundongos SCID , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia
2.
J Surg Res ; 246: 213-223, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31606511

RESUMO

BACKGROUND: For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown. MATERIALS AND METHODS: Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD [medium dose]), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses. RESULTS: The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher. CONCLUSIONS: In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.


Assuntos
Diabetes Mellitus Experimental/complicações , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Quercetina/administração & dosagem , Pele/lesões , Cicatrização/efeitos dos fármacos , Administração Cutânea , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/imunologia , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Ratos , Pele/imunologia , Pele/patologia , Estreptozocina/toxicidade , Resultado do Tratamento , Cicatrização/imunologia
3.
Toxicol Lett ; 321: 54-60, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31862508

RESUMO

Ricin toxin (RT) is a natural plant-derived protein toxin from the seed of castor beans that belongs to a family of type II ribosome-inactivating proteins (RIPs). In addition to its main toxic mechanism of inhibiting the synthesis of cellular proteins, RT can induce the production of inflammatory cytokines and cause inflammatory injury. Macrophages play a crucial role in innate immunity and the adaptive immune response as the first line of host defense against bacterial infections and various types of invading pathogens. Upon activation, macrophages release types of cytokines to remove pathogens. However, the effect of RT on the immune response and its mechanism are not well characterized. In the current study, we investigated the activation of the TLR4-mediated signaling pathway by low-dose RT treatment and its interaction with signaling molecules in the transduction pathway. We found that low-dose RT can activate MyD88- and TRIF-dependent signaling pathways, revealing a possible mechanism by which low-dose RT-activates TLR4-mediated signaling pathways. We also confirmed that the TLR4-induced activation of the inflammatory signaling pathways was produced via its binding to RT. This study may help to identify the most important target molecules and clarify the mechanism of inflammatory injury of ricin.


Assuntos
Inflamação/induzido quimicamente , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Ricina/toxicidade , Receptor 4 Toll-Like/agonistas , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Substâncias para a Guerra Química , Citocinas/metabolismo , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais , Células THP-1 , Receptor 4 Toll-Like/metabolismo
4.
Life Sci ; 237: 116915, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610207

RESUMO

AIMS: The objective of the study was to determine whether ß-caryophyllene (BCP) exerts a neuroprotective effect in cerebral ischemia-reperfusion (I/R) injury by inhibiting microglial activation and modulating their polarization via the TLR4 pathway. MAIN METHODS: Wild-type (WT) and TLR4 knockout (KO) C57BL/6J mice were subjected to cerebral I/R injury and neurologic dysfunction, cerebral infarct volume, brain edema, microglia activation and polarization, and TLR4 expression were determined. In vitro, primary microglia were stimulated with LPS and IFN-γ or IL-4 to induce polarization of microglia toward M1 or M2 phenotypes. KEY FINDINGS: BCP reduced cerebral infarct volume, brain edema, and neurologic deficits in WT mice after I/R. The optimal dose of BCP, 72 mg/kg body weight, inhibited microglial activation and reduced the secretion of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 by microglia of WT mice. BCP inhibited the level of TLR4 in WT mice, and partially reduced neurologic deficits, infarct volume, and brain edema in TLR4 KO mice. Importantly, BCP reduced the number of activated M1-type microglia and increased the number of M2-type microglia in the ipsilateral cortex of both WT and TLR4 KO mice. In vitro, BCP decreased the secretion of proinflammatory cytokines induced by LPS plus IFN-γ, downregulated the level of TLR4 protein, and polarized microglia towards the M2 phenotype. SIGNIFICANCES: The decrease in TLR4 activity mediated, at least in part, the anti-inflammatory effects of BCP and its ability to shift microglia polarization from the M1 to M2 phenotype.


Assuntos
Isquemia Encefálica/prevenção & controle , Macrófagos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Sesquiterpenos/farmacologia , Acidente Vascular Cerebral/prevenção & controle , Receptor 4 Toll-Like/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
5.
Carbohydr Polym ; 226: 115295, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31582086

RESUMO

Tumor-associated macrophages (TAMs) with an M2-like phenotype have been linked to the proliferation, invasion and metastasis of tumor cells. Resetting tumor-associated macrophages represents an attractive target for an effective cancer immunotherapy. WCCP-N-b, a novel linear 3-O-methylated galactan, isolated from Cantharellus cibarius, can convert tumor-promoting M2-like macrophages to tumor-inhibiting M1-like phenotype. On a cellular mechanistic level, WCCP-N-b inhibited M2-like macrophages polarization through suppression of STAT6 activation. Furthermore, WCCP-N-b increased the phosphorylation of mitogen-activated protein kinases (MAPKs) and degradation of IκB-α through targeting Toll-like receptor 2 (TLR2). The activation of MAPKs and degradation of IκB-α were responsible for converting M2-like macrophages to M1-like macrophages. Importantly, cell culture supernatants of WCCP-N-b-treated M2-like macrophages could inhibit the cell viability of B16F1 and B16F10. Our findings provide a potential natural and harmless polysaccharide for macrophage-based tumor immunotherapy.


Assuntos
Antineoplásicos/farmacologia , Galactanos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Basidiomycota/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Células RAW 264.7 , Fator de Transcrição STAT6/metabolismo , Receptor 2 Toll-Like/metabolismo
6.
Int J Nanomedicine ; 14: 7309-7322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571855

RESUMO

Introduction: The only treatment for aseptic loosening is the replacement of the prosthesis through revision surgery. A preventive approach, achieved through anti-inflammatory drugs released from the device, has shown to be a viable strategy; however, the performance of these devices is not yet satisfactory thus further improvements are necessary. Methods: We used titanium nanoparticles as a model for implant surfaces and developed a coating containing dexamethasone (DEX) using layer-by-layer deposition. Results: The amount of deposited drug depended on the number of layers and the release was sustained for months. The efficiency of the released DEX in reducing inflammation markers (tumor necrosis factor alpha and IL-6) produced by human monocytes and macrophages was similar to the pure drug at the same concentration without negative impacts on the viability and morphology of these cells. Conclusion: These coatings were not inferior to medical grade titanium (the standard material used in uncemented devices) regarding their ability to sustain osteoblasts and fibroblasts growth.


Assuntos
Anti-Inflamatórios/farmacologia , Cimentos para Ossos/farmacologia , Materiais Revestidos Biocompatíveis/farmacologia , Liberação Controlada de Fármacos , Nanopartículas/química , Falha de Prótese , Linhagem Celular , Forma Celular/efeitos dos fármacos , Dexametasona/farmacologia , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Monócitos/efeitos dos fármacos , Nanopartículas/ultraestrutura , Osteoblastos/efeitos dos fármacos , Osteoblastos/patologia , Tamanho da Partícula , Termogravimetria
7.
Exp Oncol ; 41(3): 248-253, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31569929

RESUMO

Macrophages are important effectors of innate immunity and the key component of the tumor microenvironment strongly influencing cancer disease outcome and efficiency of cancer therapy. Moreover, recent data have shown that monocytes as macrophage precursors can impact on tumor ability to progression. It's well known that although tumor-associated macrophages consist of diverse populations, in general, they have tumor-supporting activity. To change tumor-supporting state of tumor-associated macrophages toward tumor-inhibiting mode is one of prospective aims of modern cancer immunotherapy. Cytostatics seems to be possible tools to achieve this aim, because recently it has been shown that chemo- and radiotherapy possess immunomodulatory effects. Most of the findings are related to lymphocytes - T-lymphocytes and NK-cells, but not to monocyte/macrophage lineage. In the review, we have analyzed how cytostatic drugs influence the properties of monocyte/macrophage lineage cells to prospect using of chemotherapy to enhance their antitumor activity.


Assuntos
Antineoplásicos/farmacologia , Citostáticos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Citostáticos/uso terapêutico , Humanos , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
8.
Food Chem Toxicol ; 134: 110816, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518602

RESUMO

Our previous study has demonstrated that Pseudostellaria heterophylla protein hydrolysate (PPH) has immunomodulatory activity on murine spleen lymphocytes. The aim of this study was to investigate the excitation of PPH in RAW264.7 macrophage cells and the protective effect in cyclophosphamide (CTX)-treated mice. The results showed PPH of 50 µg/mL could stimulate macrophages resulting in significant promotions of nitric oxide (NO) production, endocytosis and reactive oxygen species formation. Meanwhile, enzyme-linked immunosorbent assay (ELISA) revealed that the levels of tumor necrosis factor-α and interleukin-10 were significantly upregulated by PPH. Furthermore, 50 mg/kg per day PPH restored the T lymphocyte proliferation and natural killer cell activity, and increased NO production and pinocytosis of peritoneal macrophages in CTX-treated mice. These findings indicate PPH plays a crucial role in RAW264.7 macrophage cells activation and in the protection against immunosuppression in CTX-treated mice and could be used as a potential immunostimulant agent.


Assuntos
Caryophyllaceae/química , Ciclofosfamida/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Hidrolisados de Proteína/farmacologia , Animais , Citocinas/metabolismo , Suplementos Nutricionais , Alimento Funcional , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Peso Molecular , Hidrolisados de Proteína/química , Células RAW 264.7 , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
9.
World Neurosurg ; 132: e99-e108, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518751

RESUMO

BACKGROUND: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated. METHODS: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI. RESULTS: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment. CONCLUSIONS: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.


Assuntos
Anticolesterolemiantes/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Fármacos Neuroprotetores/uso terapêutico , Sinvastatina/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Colesterol/sangue , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/sangue
10.
Biochemistry (Mosc) ; 84(7): 729-745, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509725

RESUMO

Despite the progress of modern medicine, oncological diseases are still among the most common causes of death of adult populations in developed countries. The current therapeutic approaches are imperfect, and the high mortality of oncological patients under treatment, the lack of personalized strategies, and severe side effects arising as a result of treatment force seeking new approaches to therapy of malignant tumors. During the last decade, cancer immunotherapy, an approach that relies on activation of the host antitumor immune response, has been actively developing. Cancer immunotherapy is the most promising trend in contemporary fundamental and practical oncology, and restoration of the pathologically altered tumor microenvironment is one of its key tasks, in particular, the reprogramming of tumor macrophages from the immunosuppressive M2-phenotype into the proinflammatory M1-phenotype is pivotal for eliciting antitumor response. This review describes the current knowledge about macrophage classification, mechanisms of their polarization, their role in formation of the tumor microenvironment, and strategies for changing the functional activity of M2-macrophages, as well as problems of targeted delivery of immunostimulatory signals to tumor macrophages using nanoparticles.


Assuntos
Imunoterapia , Macrófagos/metabolismo , Nanopartículas/metabolismo , Neoplasias/terapia , Animais , Polaridade Celular/fisiologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Microscopia Intravital , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/química , Macrófagos/classificação , Camundongos , Nanopartículas/química , Fenótipo , Coroa de Proteína/imunologia , Microambiente Tumoral/imunologia
11.
Molecules ; 24(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533249

RESUMO

Bellevalia saviczii is a medicinal plant used as anti-rheumatic and anti-inflammatory herbal remedy in Iraqi-Kurdistan. The aim of this study was to evaluate the anti-inflammatory activity of its extract and the isolated homoisoflavonoid (Dracol) by studying the Ca2+-dependent NF-kB pathway. Nuclear translocation of p65 NF-kB subunit, as parameter of NF-kB activation, was visualized in human leukemic monocytes by immunofluorescence and Western blot analyses, after cell treatment with B. saviczii root extract or Dracol followed by Lipopolysaccharide stimulation. In parallel, Ca2+ signals responsible for NF-kB activation and levels of inflammatory cytokines were investigated. LPS-induced p65 translocation was evident in monocytes and both treatments, in particular that with Dracol, were able to counteract this activation. Intracellular Ca2+ oscillations were halted and the cytokine release reduced. These results confirm the traditional anti-inflammatory efficacy of B. saviczii and identify one of the molecules in the extract which appears to be responsible of this action.


Assuntos
Anti-Inflamatórios/farmacologia , Asparagales/química , Sinalização do Cálcio/efeitos dos fármacos , Isoflavonas/farmacologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Citocinas/metabolismo , Humanos , Isoflavonas/química , Isoflavonas/isolamento & purificação , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais
12.
Mater Sci Eng C Mater Biol Appl ; 104: 109948, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499957

RESUMO

Macrophages play an important role in foreign body reaction (FBR), and exhibit a detrimental or beneficial function in tissue repair while polarized into different phenotypes. The objective of this work is to evaluate the effect of three-dimensional (3D) porous polyetheretherketone (PEEK) on macrophage polarization through sulfonating PEEK and establishing a mouse air pouch model. The in vivo results show that the sulfonated PEEK induced higher levels of anti-inflammatory cytokine together with lower levels of pro-inflammatory cytokine. In addition, it was found that a relatively mild infiltration of inflammatory cells was caused and there were more M2 macrophages and less M1 ones when compared with PEEK. It indicates that 3D porous PEEK induces a shift to M2 macrophages and has large potential in regenerative medicine application.


Assuntos
Cetonas/administração & dosagem , Cetonas/química , Macrófagos/efeitos dos fármacos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Citocinas/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Porosidade
13.
Am J Chin Med ; 47(6): 1289-1305, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488032

RESUMO

The roots of Aucklandia lappa have been used in traditional medicine in Asia to treat inflammation and diseases associated with pain, including endometriosis. The aim of this study was to investigate the anti-endometriotic effect of dehydrocostus lactone, an active compound in A. lappa roots, using human endometriotic cells and macrophages stimulated by these cells. Dehydrocostus lactone induced apoptotic cell death in 12Z human endometriotic cells. Dehydrocostus lactone stimulated the activation of caspase-3, -8, and -9, while caspase inhibitors significantly reversed the dehydrocostus lactone-induced cell death in 12Z cells. In addition, dehydrocostus lactone decreased the production of PGE2 and neurotrophins (BDNF, NGF, NT3, and NT4/5), which are regarded as endometriosis-associated pain factors in human endometriotic cells. Moreover, dehydrocostus lactone inhibited the expression of M2 markers (CD206, and Trem-2), IL-10, VEGF, and MMP-2/-9 in endometriosis-associated macrophages (EAMs). Furthermore, dehydrocostus lactone inhibited the Akt and NFκB pathways in both endometriotic cells and EAMs. Taken together, our findings suggest that dehydrocostus lactone, an active compound of A, lappa, has anti-endometriotic activities via induction of apoptosis and downregulation of pain factors in endometriotic cells and inhibition of the alternative activation of EAMs.


Assuntos
Apoptose/efeitos dos fármacos , Endometriose/tratamento farmacológico , Endometriose/imunologia , Endométrio/citologia , Lactonas/farmacologia , Lactonas/uso terapêutico , Ativação de Macrófagos/efeitos dos fármacos , Fitoterapia , Raízes de Plantas/química , Saussurea/química , Sesquiterpenos/farmacologia , Sesquiterpenos/uso terapêutico , Caspases/metabolismo , Linhagem Celular , Dinoprostona/metabolismo , Feminino , Humanos , Interleucina-10/metabolismo , Lactonas/isolamento & purificação , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Medicina Tradicional , Fatores de Crescimento Neural/metabolismo , Receptores de Superfície Celular/metabolismo , Sesquiterpenos/isolamento & purificação , Estimulação Química
14.
Nutrients ; 11(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412595

RESUMO

Sofrito is a mix of tomato, onion, garlic, and olive oil, which contains phenolic compounds and carotenoids. Consumption of tomato-based sofrito has been related to a lower risk of cardiovascular events, but the mechanisms behind such beneficial effects remain unclear. This study aimed to analyze the effects of representative sofrito compounds such as naringenin, hydroxytyrosol, lycopene, and ß-carotene on mechanisms involved in the pathogenesis of atherosclerosis. We demonstrated that both phenolic compounds and both carotenoids studied were able to inhibit low density lipoproteins (LDL) oxidation, as well as oxidative stress and eicosanoid production induced by oxidized LDL (oxLDL) in macrophage cultures. These effects were not the consequences of disturbing oxLDL uptake by macrophages. Finally, we observed an additive effect of these sofrito compounds, as well as the activity of a main naringenin metabolite, naringenin 7-O-ß-d-glucuronide on LDL oxidation and oxidative stress.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Ácido Araquidônico/metabolismo , Culinária , Frutas , Lycopersicon esculentum , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Frutas/química , Temperatura Alta , Humanos , Lycopersicon esculentum/química , Macrófagos/metabolismo , Extratos Vegetais/isolamento & purificação , Transdução de Sinais , Células THP-1
15.
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
16.
Hum Immunol ; 80(10): 890-896, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447056

RESUMO

The functional phenotype of macrophages (Mφ) is determined by both differentiation factors and polarization stimuli. In mouse Mφ could be easily divided into the distinct Mφ subtypes. However, the identification of human M1 and M2 cells is much more difficult due to the lack of M1- or M2-specific markers. We assumed that the Mφ capacity to induce T cell proliferation in mixed leukocyte culture, or allostimulatory activity, may be a marker of Mφ functional phenotype. We compared the allostimulatory activity of Mφ differentiated with GM-CSF or M-CSF and polarized into M1, M2a, M2c subtypes using appropriate stimuli. GM-CSF-differentiated M1 Mφ showed pronounced allostimulatory activity whereas the polarization into M2a and M2c of GM-CSF-differentiated Mφ was associated with decreased allostimulatory activity. M-CSF-differentiated M1 Mφ demonstrated the moderate increasing of allostimulatory activity but its level has never reached that of GM-CSF-activated M1. The level of allostimulatory activity of M2a and M2c M-CSF-induced Mφ was comparable to that of GM-CSF-induced M2a and M2c Mφ. Thus, low allostimulatory activity is a common property of human M2a and M2c macrophages regardless of the differentiating factor and a polarizing stimulus and can be used to distinguish between M1 and M2 phenotypes.


Assuntos
Polaridade Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/imunologia , Fenótipo , Adulto , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células , Células Cultivadas , Dexametasona/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Voluntários Saudáveis , Humanos , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/classificação , Masculino , Pessoa de Meia-Idade , Curva ROC , Proteínas Recombinantes , Adulto Jovem
17.
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
18.
Ren Fail ; 41(1): 733-741, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31424299

RESUMO

Aim: Supplemental oxygen is often used to treat neonates with respiratory disorders. Human and animal studies have demonstrated that neonatal hyperoxia increases oxidative stress and induces damage and collagen deposition in kidney during the perinatal period. Cathelicidin LL-37 is one important group of human antimicrobial peptides which exhibits antioxidant activity and its overexpression resists hyperoxia-induced oxidative stress. This study was designed to evaluate the protective effects of cathelicidin in hyperoxia-induced kidney injury in newborn rats. Methods: Sprague-Dawley rat pups were reared in either room air (RA) or hyperoxia (85% O2) and were randomly treated with low-dose (4 mg/kg) and high-dose (8 mg/kg) cathelicidin in normal saline (NS) administered intraperitoneally on postnatal days 1-6. The following six groups were obtained: RA + NS, RA + low-dose cathelicidin, RA + high-dose cathelicidin, O2 + NS, O2 + low-dose cathelicidin, and O2 + high-dose cathelicidin. Kidneys were taken for Western blot and histological analyses on postnatal day 7. Results: The hyperoxia-reared rats exhibited significantly lower body weights and anti-inflammatory M2 macrophages, but the kidney injury scores, oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells, pro-inflammatory M1 macrophages, collagen deposition, and NF-κB expression were higher than did the RA-reared rats. Conclusions: Cathelicidin treatment attenuated kidney injury as evidenced by lower kidney injury scores, 8-OHdG-positive cells, collagen deposition, and reversion of hyperoxia-induced M1/M2 macrophage polarization. The role of Cathelicidin in ameliorates kidney injury of the hyperoxia newborn rats was accompanied by decreased NF-κB expression, which probably through the modulating NF-κB activity in the kidney.


Assuntos
Peptídeos Catiônicos Antimicrobianos/administração & dosagem , Hiperóxia/complicações , Nefropatias/prevenção & controle , Oxigenoterapia/efeitos adversos , Oxigênio/efeitos adversos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Rim/patologia , Nefropatias/etiologia , Nefropatias/patologia , Ativação de Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/administração & dosagem , Oxigenoterapia/métodos , Gravidez , Ratos , Ratos Sprague-Dawley , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Transdução de Sinais/efeitos dos fármacos
19.
Mol Cell Biochem ; 462(1-2): 11-23, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446616

RESUMO

BRCA-1 is a nuclear protein involved in DNA repair, transcriptional regulation, and cell cycle control. Its involvement in other cellular processes has been described. Here, we aimed to investigate the role of BRCA-1 in macrophages M(LPS), M(IL-4), and tumor cell-induced differentiation. We used siRNAs to knockdown BRCA-1 in RAW 264.7 macrophages exposed to LPS, IL-4, and C6 glioma cells conditioned medium (CMC6), and evaluated macrophage differentiation markers and functional phagocytic activity as well as DNA damage and cell survival in the presence and absence of BRCA-1. LPS and CMC6, but not by IL-4, increased DNA damage in macrophages, and this effect was more pronounced in BRCA-1-depleted cells, including M(IL-4). BRCA-1 depletion impaired expression of pro-inflammatory cytokines, TNF-α and IL-6, and reduced the phagocytic activity of macrophages in response to LPS. In CMC6-induced differentiation, BRCA-1 knockdown inhibited TNF-α and IL-6 expression which was accompanied by upregulation of the anti-inflammatory markers IL-10 and TGF-ß and reduced phagocytosis. In contrast, M(IL-4) phenotype was not affected by BRCA-1 status. Molecular docking predicted that the conserved BRCA-1 domain BRCT can interact with the p65 subunit of NF-κB. Immunofluorescence assays showed that BRCA-1 and p65 co-localize in the nucleus of LPS-treated macrophages and reporter gene assay showed that depletion of BRCA-1 decreased LPS and CMC6-induced NF-κB transactivation. IL-4 had no effect upon NF-κB. Taken together, our findings suggest a role of BRCA-1 in macrophage differentiation and phagocytosis induced by LPS and tumor cells secretoma, but not IL-4, in a mechanism associated with inhibition of NF-κB.


Assuntos
Proteína BRCA1/metabolismo , Polaridade Celular , Inflamação/patologia , Ativação de Macrófagos , Macrófagos/metabolismo , Macrófagos/patologia , NF-kappa B/metabolismo , Animais , Biomarcadores/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Polaridade Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Dano ao DNA , Inflamação/metabolismo , Lipopolissacarídeos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Ratos
20.
Nutrients ; 11(8)2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31362418

RESUMO

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are chronic disorders of the gastrointestinal tract, although the exact causes of IBD remain unknown. Present treatments for IBDs have poor tolerability and insufficient therapeutic efficacy, thus, alternative therapeutic approaches are required. Soybean-derived isoflavones have multiple bioactivities such as anti-inflammation. However, the low water solubility of soybean isoflavones limits their bioavailability and practical use. Therefore, in order to study the preventive effects of water-soluble soybean isoflavones on colonic inflammatory status, we examined soybean-derived isoflavone glycosides (SIFs) in a dextran sodium sulfate (DSS)-induced murine colitis model and in lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Oral administration of SIF (0.5 w/v%) attenuated DSS-induced colitis in terms of body weight decrease, colon shortening, epithelial apoptosis, histological score, mRNA levels of inflammatory cytokines, and immune cell infiltration in colon tissues. In the in vitro assessment, we observed the inhibitory effects of SIF on the production of nitric oxide and prostaglandin E2, via suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression in RAW264.7 macrophages in response to LPS. Furthermore, we confirmed that the expression of inflammatory cytokines and chemokines were decreased by pre-treatment with SIF in LPS-activated RAW264.7 macrophages. Moreover, we demonstrated that SIF suppressed inflammatory mediators involved in nuclear factor-κB signaling pathway via inhibitory κB kinase phosphorylation and degradation of inhibitory κB. Our results suggested that SIF may be beneficial for the remission of colonic inflammatory status including IBDs.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colite/prevenção & controle , Colo/efeitos dos fármacos , Sulfato de Dextrana , Isoflavonas/administração & dosagem , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Soja , Animais , Anti-Inflamatórios/isolamento & purificação , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Isoflavonas/isolamento & purificação , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Células RAW 264.7 , Indução de Remissão , Transdução de Sinais , Soja/química
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