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1.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614433

RESUMO

Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on the activation of cells from both the innate and the adaptive immune system, although the mechanisms for such regulation are diverse. First, as a constitutive part of the cellular membrane, omega-3 fatty acids can regulate cellular membrane properties, such as membrane fluidity or complex assembly in lipid rafts. In recent years, however, a new role for omega-3 fatty acids and their derivatives as signaling molecules has emerged. In this review, we describe the latest findings describing the effects of omega-3 fatty acids on different cells from the immune system and their possible molecular mechanisms.

2.
Atherosclerosis ; 287: 122-133, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31260875

RESUMO

BACKGROUND AND AIMS: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects. METHODS: AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro. RESULTS: α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983 decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages. CONCLUSIONS: This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/-mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans.

3.
Infect Immun ; 87(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085706

RESUMO

Neutrophils are the most abundant circulating leukocytes in humans and are essential for the defense against invading pathogens. Like many other cells of an organism, neutrophils can be highly influenced by the diet. We have previously described that mice fed a high-fat diet rich in polyunsaturated fatty acids (HFD-P) present a higher frequency of neutrophils in bone marrow than mice fed a high-fat diet rich in saturated fatty acids (HFD-S). Interestingly, such an increase correlated with improved survival against bacterium-induced sepsis. In this study, we aimed to investigate the effects of dietary polyunsaturated and saturated fatty acids on neutrophil homeostasis. We found that HFD-P specifically induced the accumulation of neutrophils in the marginal pools of the spleen and liver. The accumulation of neutrophils in the spleen was a result of a dual effect of polyunsaturated fatty acids on neutrophil homeostasis. First, polyunsaturated fatty acids enhanced the recruitment of neutrophils from the circulation into the spleen via chemokine secretion. Second, they delayed neutrophil cell death in the spleen. Interestingly, these effects were not observed in mice fed a diet rich in saturated fatty acids, suggesting that the type of fat rather than the amount of fat mediates the alterations in neutrophil homeostasis. In conclusion, our results show that dietary polyunsaturated fatty acids have a strong modulatory effect on neutrophil homeostasis that may have future clinical applications.


Assuntos
Morte Celular , Quimiotaxia/imunologia , Ácidos Graxos Insaturados/administração & dosagem , Neutrófilos/imunologia , Baço/patologia , Animais , Diferenciação Celular , Dieta Hiperlipídica , Fator Estimulador de Colônias de Granulócitos/fisiologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/fisiologia , Homeostase , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/fisiologia
4.
Antioxid Redox Signal ; 30(4): 489-504, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29471681

RESUMO

AIMS: Human α1-microglobulin (A1M) is an endogenous reductase and radical- and heme-binding protein with physiological antioxidant protective functions. Recombinant human A1M (rA1M) has been shown to have therapeutic properties in animal models of preeclampsia, a pregnancy disease associated with oxidative stress. Recombinant A1M, however, lacks glycosylation, and shows lower solubility and stability than A1M purified from human plasma. The aims of this work were to (i) use site-directed mutagenesis to improve the physicochemical properties of rA1M, (ii) demonstrate that the physicochemically improved rA1M displays full in vitro cell protective effects as recombinant wild-type A1M (rA1M-wt), and (iii) show its therapeutic potential in vivo against acute kidney injury (AKI), another disease associated with oxidative stress. RESULTS: A novel recombinant A1M-variant (rA1M-035) with three amino acid substitutions was constructed, successfully expressed, and purified. rA1M-035 had improved solubility and stability compared with rA1M-wt, and showed intact in vitro heme-binding, reductase, antioxidation, and cell protective activities. Both rA1M-035 and rA1M-wt showed, for the first time, potential in vivo protective effects on kidneys using a mouse rhabdomyolysis glycerol injection model of AKI. INNOVATION: A novel recombinant A1M-variant, rA1M-035, was engineered. This protein showed improved solubility and stability compared with rA1M-wt, full in vitro functional activity, and potential protection against AKI in an in vivo rhabdomyolysis mouse model. CONCLUSION: The new rA1M-035 is a better drug candidate than rA1M-wt for treatment of AKI and preeclampsia in human patients.

5.
Nat Commun ; 9(1): 2067, 2018 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-29802242

RESUMO

Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.


Assuntos
Doenças Autoimunes/metabolismo , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Testosterona/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Doenças Autoimunes/imunologia , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Castração , Humanos , Masculino , Camundongos , Camundongos Knockout , Modelos Animais , Norepinefrina/metabolismo , Oxidopamina/farmacologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Testosterona/sangue , Testosterona/deficiência , Testosterona/imunologia
6.
Proc Natl Acad Sci U S A ; 115(2): 427-432, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29279372

RESUMO

Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.


Assuntos
Tecido Adiposo/metabolismo , Peso Corporal/fisiologia , Homeostase/efeitos dos fármacos , Leptina/farmacologia , Obesidade/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase/fisiologia , Leptina/administração & dosagem , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/etiologia , Obesidade/genética , Osteócitos/metabolismo , Ratos Sprague-Dawley , Perda de Peso/efeitos dos fármacos , Perda de Peso/fisiologia
7.
PLoS One ; 12(4): e0174974, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28376102

RESUMO

BACKGROUND: Autonomic dysfunction is a risk factor for cardiovascular disease (CVD), however, the exact mechanism linking autonomic dysfunction to cardiovascular disease is not known. In this study we hypothesized that autonomic dysfunction increases inflammation, which subsequently accelerates atherosclerosis. The aim of the current study was to investigate the association between autonomic tone, inflammation and atherosclerosis. METHODS: 124 men under investigation for carotid atherosclerosis were examined for autonomic function (heart rate variability; HRV and baroreflex sensitivity; BRS), inflammatory markers (white blood cell count; WBCC and C-reactive protein; CRP) and degree of carotid atherosclerosis. The direct or indirect associations between autonomic function, inflammatory parameters and carotid plaque area were investigated with multiple linear regressions. RESULTS: Male subjects with prevalent CVD showed larger carotid plaque area, higher WBCC, and reduced BRS compared to subjects with no history of CVD. Further, BRS was inversely associated with carotid plaque area (r = -0.21, p = 0.018) as well as inflammatory parameters WBCC and CRP (r = -0.29, p = 0.001, and r = -0.23, p = 0.009, respectively), whereas HRV only was inversely associated with WBCC (r = -0.22, p = 0.014). To investigate if inflammation could provide a link between autonomic function and carotid atherosclerosis we adjusted the associations accordingly. After adjusting for WBCC and CRP the inverse association between BRS and carotid plaque area was attenuated and did not remain significant, while both WBCC and CRP remained significantly associated with carotid plaque area, indicating that low-grade inflammation can possibly link BRS to atherosclerosis. Also, after adjusting for age, antihypertensive treatment and cardiovascular risk factors, BRS was independently inversely associated with both WBCC and CRP, and HRV independently inversely associated with WBCC. WBCC was the only inflammatory marker independently associated with carotid plaque area after adjustment. CONCLUSIONS: We demonstrate that autonomic dysfunction is associated with atherosclerosis and that inflammation could play an important role in mediating this relationship.


Assuntos
Aterosclerose/complicações , Doenças do Sistema Nervoso Autônomo/complicações , Estenose das Carótidas/complicações , Inflamação/complicações , Adulto , Idoso , Aterosclerose/fisiopatologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo , Proteína C-Reativa/metabolismo , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Frequência Cardíaca , Humanos , Inflamação/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Diabetologia ; 60(3): 553-567, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27981357

RESUMO

AIMS/HYPOTHESIS: Understanding the molecular networks controlling ectopic lipid deposition and insulin responsiveness in skeletal muscle is essential for developing new strategies to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of liver steatosis, hepatic lipid metabolism and whole body glucose and insulin homeostasis. Here, we assessed the role of STK25 in control of ectopic fat storage and insulin responsiveness in skeletal muscle. METHODS: Skeletal muscle morphology was studied by histological examination, exercise performance and insulin sensitivity were assessed by treadmill running and euglycaemic-hyperinsulinaemic clamp, respectively, and muscle lipid metabolism was analysed by ex vivo assays in Stk25 transgenic and wild-type mice fed a high-fat diet. Lipid accumulation and mitochondrial function were also studied in rodent myoblasts overexpressing STK25. Global quantitative phosphoproteomics was performed in skeletal muscle of Stk25 transgenic and wild-type mice fed a high-fat diet to identify potential downstream mediators of STK25 action. RESULTS: We found that overexpression of STK25 in transgenic mice fed a high-fat diet increases intramyocellular lipid accumulation, impairs skeletal muscle mitochondrial function and sarcomeric ultrastructure, and induces perimysial and endomysial fibrosis, thereby reducing endurance exercise capacity and muscle insulin sensitivity. Furthermore, we observed enhanced lipid accumulation and impaired mitochondrial function in rodent myoblasts overexpressing STK25, demonstrating an autonomous action for STK25 within cells. Global phosphoproteomic analysis revealed alterations in the total abundance and phosphorylation status of different target proteins located predominantly to mitochondria and sarcomeric contractile elements in Stk25 transgenic vs wild-type muscle, respectively, providing a possible molecular mechanism for the observed phenotype. CONCLUSIONS/INTERPRETATION: STK25 emerges as a new regulator of the complex interplay between lipid storage, mitochondrial energetics and insulin action in skeletal muscle, highlighting the potential of STK25 antagonists for type 2 diabetes treatment.


Assuntos
Resistência à Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metabolismo dos Lipídeos/fisiologia , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Western Blotting , Cromatografia Líquida , Dieta Hiperlipídica , Resistência à Insulina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/patologia , Proteínas Serina-Treonina Quinases/genética , Proteômica , Ratos , Reação em Cadeia da Polimerase em Tempo Real
9.
Biosci Rep ; 36(6)2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27780892

RESUMO

Type 2 diabetic (T2D) patients often develop early cognitive and sensorimotor impairments. The pathophysiological mechanisms behind these problems are largely unknown. Recent studies demonstrate that dysfunctional γ-aminobutyric acid (GABAergic) neurons are involved in age-related cognitive decline. We hypothesized that similar, but earlier dysfunction is taking place under T2D in the neocortex and striatum (two brain areas important for cognition and sensorimotor functions). We also hypothesized that the T2D-induced effects are pharmacologically reversible by anti-diabetic drugs targeting the glucagon-like peptide-1 receptor (GLP-1R). We determined the effect of T2D on cortical and striatal GABAergic neurons positive for glutamic acid decarboxylase-67 (GAD67), calbindin (CB), parvalbumin (PV) and calretinin (CR) by using immunohistochemistry and quantitative microscopy. Young and middle-aged T2D Goto-Kakizaki (GK) (a model of spontaneous T2D) and Wistar rats were used. Furthermore, we determined the therapeutic potential of the GLP1-R agonist exendin-4 (Ex-4) by treating middle-aged GK rats for 6 weeks with 0.1 µg/kg Ex-4 twice daily. We show that T2D reduced the density of GAD67-positive neurons in the striatum and of CB-positive neurons in both striatum and neocortex. T2D also increased the average volume of PV-positive interneurons in the striatum. Ex-4 treatment increased the density of CB-positive neurons in the striatum of GK rats. Our data demonstrate that T2D negatively affects GAD67 and CB-positive GABAergic neurons in the brain during aging, potentially identifying some of the pathophysiological mechanisms to explain the increased prevalence of neurological complications in T2D. We also show a specific, positive effect of Ex-4 on striatal CB-positive neurons, which could be exploited in therapeutic perspective.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus/metabolismo , Neurônios GABAérgicos/metabolismo , Peptídeos/metabolismo , Peçonhas/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Calbindina 2/metabolismo , Calbindinas/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Exenatida , Neurônios GABAérgicos/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glutamato Descarboxilase/metabolismo , Neocórtex/metabolismo , Neocórtex/fisiopatologia , Parvalbuminas/metabolismo , Ratos , Ratos Wistar
10.
Endocrinology ; 157(10): 3915-3923, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27533884

RESUMO

Intimal hyperplasia is a vascular pathological process involved in the pathogenesis of atherosclerosis. Data suggest that T, the most important sex steroid hormone in males, protects men from atherosclerotic cardiovascular disease. T mainly acts via the androgen receptor (AR), and in this study we evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular smooth muscle cells with a physiological T concentration inhibited both migration and proliferation of the cells. Analyzing the expression of central regulators of cell proliferation and migration, we found that mRNA and protein levels of p27 were lower in uninjured arteries from ARKO mice and that T replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells.


Assuntos
Lesões das Artérias Carótidas/complicações , Neointima/etiologia , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Animais , Lesões das Artérias Carótidas/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Masculino , Camundongos Knockout , Miócitos de Músculo Liso/fisiologia , Neointima/metabolismo
11.
PLoS One ; 11(5): e0155099, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27166587

RESUMO

Dietary polyunsaturated fatty acids (PUFA) are suggested to modulate immune function, but the effects of dietary fatty acids composition on gene expression patterns in immune organs have not been fully characterized. In the current study we investigated how dietary fatty acids composition affects the total transcriptome profile, and especially, immune related genes in two immune organs, spleen (SPL) and bone marrow cells (BMC). Four tissues with metabolic function, skeletal muscle (SKM), white adipose tissue (WAT), brown adipose tissue (BAT), and liver (LIV), were investigated as a comparison. Following 8 weeks on low fat diet (LFD), high fat diet (HFD) rich in saturated fatty acids (HFD-S), or HFD rich in PUFA (HFD-P), tissue transcriptomics were analyzed by microarray and metabolic health assessed by fasting blood glucose level, HOMA-IR index, oral glucose tolerance test as well as quantification of crown-like structures in WAT. HFD-P corrected the metabolic phenotype induced by HFD-S. Interestingly, SKM and BMC were relatively inert to the diets, whereas the two adipose tissues (WAT and BAT) were mainly affected by HFD per se (both HFD-S and HFD-P). In particular, WAT gene expression was driven closer to that of the immune organs SPL and BMC by HFDs. The LIV exhibited different responses to both of the HFDs. Surprisingly, the spleen showed a major response to HFD-P (82 genes differed from LFD, mostly immune genes), while it was not affected at all by HFD-S (0 genes differed from LFD). In conclusion, the quantity and composition of dietary fatty acids affected the transcriptome in distinct manners in different organs. Remarkably, dietary PUFA, but not saturated fat, prompted a specific regulation of immune related genes in the spleen, opening the possibility that PUFA can regulate immune function by influencing gene expression in this organ.


Assuntos
Dieta Hiperlipídica , Ácidos Graxos Insaturados/farmacologia , Perfilação da Expressão Gênica , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/genética , Baço/imunologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Biomarcadores/metabolismo , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Jejum/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Sistema Imunitário/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Fenótipo , Análise de Componente Principal , Baço/efeitos dos fármacos , Baço/metabolismo , Coloração e Rotulagem , Transcriptoma/genética
12.
Infect Immun ; 84(4): 1205-1213, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26857576

RESUMO

Sepsis caused by Staphylococcus aureus is increasing in incidence. With the alarming use of antibiotics,S. aureus is prone to become methicillin resistant. Antibiotics are the only widely used pharmacological treatment for sepsis. Interestingly, mice fed high-fat diet (HFD) rich in polyunsaturated fatty acids have better survival of S. aureus-induced sepsis than mice fed HFD rich in saturated fatty acids (HFD-S). To investigate what component of polyunsaturated fatty acids, i.e., omega-3 or omega-6 fatty acids, exerts beneficial effects on the survival of S. aureus-induced sepsis, mice were fed HFD rich in omega-3 or omega-6 fatty acids for 8 weeks prior to inoculation with S. aureus Further, mice fed HFD-S were treated with omega-3 fatty acid metabolites known as resolvins. Mice fed HFD rich in omega-3 fatty acids had increased survival and decreased bacterial loads compared to those for mice fed HFD-S after S. aureus-induced sepsis. Furthermore, the bacterial load was decreased in resolvin-treated mice fed HFD-S after S. aureus-induced sepsis compared with that in mice treated with vehicle. Dietary omega-3 fatty acids increase the survival of S. aureus-induced sepsis by reversing the deleterious effect of HFD-S on mouse survival.


Assuntos
Carga Bacteriana/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Sepse/microbiologia , Infecções Estafilocócicas/dietoterapia , Staphylococcus aureus , Tecido Adiposo , Animais , Citocinas/genética , Citocinas/metabolismo , Ácidos Graxos/administração & dosagem , Ácidos Graxos/farmacologia , Ácidos Graxos Ômega-3/administração & dosagem , Inflamação/metabolismo , Camundongos , Distribuição Aleatória , Sepse/dietoterapia , Infecções Estafilocócicas/microbiologia
13.
PLoS One ; 10(9): e0138111, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26368565

RESUMO

Preeclampsia (PE) complicates 3-8% of all pregnancies and manifests clinically as hypertension and proteinuria in the second half of gestation. The pathogenesis of PE is not fully understood but recent studies have described the involvement of cell-free fetal hemoglobin (HbF). Hypothesizing that PE is associated with prolonged hemolysis we have studied the response of the cell-free Hb- and heme defense network. Thus, we have investigated the levels of cell-free HbF (both free, denoted HbF, and in complex with Hp, denoted Hp-HbF) as well as the major human endogenous Hb- and heme-scavenging systems: haptoglobin (Hp), hemopexin (Hpx), α1-microglobulin (A1M) and CD163 in plasma of PE women (n = 98) and women with normal pregnancies (n = 47) at term. A significant increase of the mean plasma HbF concentration was observed in women with PE. Plasma levels of Hp and Hpx were statistically significantly reduced, whereas the level of the extravascular heme- and radical scavenger A1M was significantly increased in plasma of women with PE. The Hpx levels significantly correlated with maternal blood pressure. Furthermore, HbF and the related scavenger proteins displayed a potential to be used as clinical biomarkers for more precise diagnosis of PE and are candidates as predictors of identifying pregnancies with increased risk of obstetrical complications. The results support that PE pathophysiology is associated with increased HbF-concentrations and an activation of the physiological Hb-heme defense systems.


Assuntos
Pressão Sanguínea , Heme/metabolismo , Hemoglobinas/metabolismo , Hemólise , Pré-Eclâmpsia , Adulto , alfa-Globulinas/metabolismo , Biomarcadores/sangue , Feminino , Haptoglobinas/metabolismo , Hemopexina/metabolismo , Humanos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/fisiopatologia , Gravidez
14.
Infect Immun ; 83(2): 514-21, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25404025

RESUMO

Severe infection, including sepsis, is an increasing clinical problem that causes prolonged morbidity and substantial mortality. At present, antibiotics are essentially the only pharmacological treatment for sepsis. The incidence of resistance to antibiotics is increasing; therefore, it is critical to find new therapies for sepsis. Staphylococcus aureus is a major cause of septic mortality. Neutrophils play an important role in the defense against bacterial infections. We have shown that a diet with high levels of dietary saturated fatty acids decreases survival in septic mice, but the mechanisms behind this remain elusive. The aim of the present study was to investigate how the differences in dietary fat composition affect survival and bacterial load after experimental septic infection and neutrophil function in uninfected mice. We found that, after S. aureus infection, mice fed a polyunsaturated high-fat diet (HFD-P) for 8 weeks had increased survival and decreased bacterial load during sepsis compared with mice fed a saturated high-fat diet (HFD-S), similar to mice fed a low-fat diet (LFD). Uninfected mice fed HFD-P had a higher frequency of neutrophils in bone marrow than mice fed HFD-S. In addition, mice fed HFD-P had a higher frequency of neutrophils recruited to the site of inflammation in response to peritoneal injection of thioglycolate than mice fed HFD-S. Differences between the proportion of dietary protein and carbohydrate did not affect septic survival at all. In conclusion, polyunsaturated dietary fat increased both survival and efficiency of bacterial clearance during septic S. aureus infection. Moreover, this diet increased the frequency and chemotaxis of neutrophils, key components of the immune response to S. aureus infections.


Assuntos
Carga Bacteriana/efeitos dos fármacos , Gorduras Insaturadas na Dieta/imunologia , Ácidos Graxos Insaturados/administração & dosagem , Neutrófilos/imunologia , Infecções Estafilocócicas/imunologia , Animais , Células da Medula Óssea/imunologia , Catepsina D/biossíntese , Quimiotaxia/imunologia , Dieta , Dieta Hiperlipídica/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/imunologia , Sepse/microbiologia , Staphylococcus aureus/imunologia , Tioglicolatos
15.
Arterioscler Thromb Vasc Biol ; 34(12): 2632-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25324572

RESUMO

OBJECTIVE: Cholinergic pathways of the autonomic nervous system are known to modulate inflammation. Because atherosclerosis is a chronic inflammatory condition, we tested whether cholinergic signaling operates in this disease. We have analyzed the expression of the α7 nicotinic acetylcholine receptor (α7nAChR) in human atherosclerotic plaques and studied its effects on the development of atherosclerosis in the hypercholesterolemic Ldlr(-/-) mouse model. APPROACH AND RESULTS: α7nAChR protein was detected on T cells and macrophages in surgical specimens of human atherosclerotic plaques. To study the role of α7nAChR signaling in atherosclerosis, male Ldlr(-/-) mice were lethally irradiated and reconstituted with bone marrow from wild-type or α7nAChR-deficient animals. Ablation of hematopoietic cell α7nAChR increased aortic atherosclerosis by 72%. This was accompanied by increased aortic interferon-γ mRNA, implying increased Th1 activity in the absence of α7nAChR signaling. CONCLUSIONS: The present study shows that signaling through hematopoietic α7nAChR inhibits atherosclerosis and suggests that it operates by modulating immune inflammation. Given the observation that α7nAChR is expressed by T cells and macrophages in human plaques, our findings support the notion that cholinergic regulation may act to inhibit disease development also in man.


Assuntos
Aterosclerose/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Transplante de Medula Óssea , Estenose das Carótidas/genética , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Modelos Animais de Doenças , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais , Linfócitos T/metabolismo , Quimeras de Transplante , Receptor Nicotínico de Acetilcolina alfa7/deficiência , Receptor Nicotínico de Acetilcolina alfa7/genética
16.
PLoS One ; 9(8): e103114, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25101679

RESUMO

Exendin-4 is a glucagon-like receptor 1 agonist clinically used against type 2 diabetes that has also shown neuroprotective effects in experimental stroke models. However, while the neuroprotective efficacy of Exendin-4 has been thoroughly investigated if the pharmacological treatment starts before stroke, the therapeutic potential of the Exendin-4 if the treatment starts acutely after stroke has not been clearly determined. Further, a comparison of the neuroprotective efficacy in normal and aged diabetic mice has not been performed. Finally, the cellular mechanisms behind the efficacy of Exendin-4 have been only partially studied. The main objective of this study was to determine the neuroprotective efficacy of Exendin-4 in normal and aged type 2 diabetic mice if the treatment started after stroke in a clinically relevant setting. Furthermore we characterized the Exendin-4 effects on stroke-induced neuroinflammation. Two-month-old healthy and 14-month-old type 2 diabetic/obese mice were subjected to middle cerebral artery occlusion. 5 or 50 µg/kg Exendin-4 was administered intraperitoneally at 1.5, 3 or 4.5 hours thereafter. The treatment was continued (0.2 µg/kg/day) for 1 week. The neuroprotective efficacy was assessed by stroke volume measurement and stereological counting of NeuN-positive neurons. Neuroinflammation was determined by gene expression analysis of M1/M2 microglia subtypes and pro-inflammatory cytokines. We show neuroprotective efficacy of 50 µg/kg Exendin-4 at 1.5 and 3 hours after stroke in both young healthy and aged diabetic/obese mice. The 5 µg/kg dose was neuroprotective at 1.5 hour only. Proinflammatory markers and M1 phenotype were not impacted by Exendin-4 treatment while M2 markers were significantly up regulated. Our results support the use of Exendin-4 to reduce stroke-damage in the prehospital/early hospitalization setting irrespectively of age/diabetes. The results indicate the polarization of microglia/macrophages towards the M2 reparative phenotype as a potential mechanism of neuroprotection.


Assuntos
Isquemia Encefálica/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Peptídeos/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Peçonhas/farmacologia , Animais , Biomarcadores/metabolismo , Isquemia Encefálica/patologia , Diabetes Mellitus Experimental , Avaliação Pré-Clínica de Medicamentos , Exenatida , Perfilação da Expressão Gênica , Infarto da Artéria Cerebral Média , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Fenótipo , Acidente Vascular Cerebral/patologia , Fatores de Tempo
17.
Biomed Res Int ; 2014: 548783, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25105129

RESUMO

A few studies in animals and humans suggest that metoprolol (ß1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE(-/-) mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE(-/-) mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE(-/-) mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Quimiocina CXCL1/sangue , Metoprolol/farmacologia , Placa Aterosclerótica/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Colesterol/sangue , Colesterol/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Placa Aterosclerótica/sangue , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia
18.
Eur J Immunol ; 44(10): 3081-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25042478

RESUMO

Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-κB-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.


Assuntos
Aterosclerose/imunologia , Aterosclerose/patologia , Imunidade Inata , Inflamação/imunologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Placa Aterosclerótica/imunologia , Animais , Aterosclerose/metabolismo , Western Blotting , Modelos Animais de Doenças , Humanos , Hipercolesterolemia/imunologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Imunidade Inata/imunologia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Knockout , Necrose , Proteína Adaptadora de Sinalização NOD2/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real
19.
Biomed Res Int ; 2014: 718769, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24757672

RESUMO

Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, α 7 nicotinic acetylcholine receptors ( α 7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated α 7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti-inflammatory role of α 7R stimulation in vitro and microglia polarization after α 7R agonist treatment. Real-time PCR analysis showed a 33% reduction in α 7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective α 7R agonist AR-R 17779 significantly attenuated TNF α release and increased α 7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or α 7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after α 7R stimulation. Thus, our data suggest a role for the α 7R also in the neonatal brain and support the anti-inflammatory role of α 7R in microglia, suggesting that α 7R stimulation could enhance the polarization towards a reparative Mox phenotype.


Assuntos
Hipóxia-Isquemia Encefálica/metabolismo , Microglia/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/biossíntese , Animais , Animais Recém-Nascidos , Antígeno B7-2/biossíntese , Regulação da Expressão Gênica , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/patologia , Inflamação/metabolismo , Inflamação/patologia , Lectinas Tipo C/biossíntese , Lectinas de Ligação a Manose/biossíntese , Camundongos , Microglia/patologia , Óxido Nítrico Sintase Tipo II/biossíntese , Receptores de Superfície Celular/biossíntese , Receptor Nicotínico de Acetilcolina alfa7/agonistas
20.
J Neurosci ; 33(29): 12041-51, 2013 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-23864690

RESUMO

Susceptibility and progression of brain injury in the newborn is closely associated with an exacerbated innate immune response, but the underlying mechanisms are often unclear. Toll-like receptors (TLRs) are important innate immune sensors that may influence the vulnerability of the developing brain. In the current study, we provide novel data to show that activation of the viral innate immune receptor TLR-3 sensitizes the neonatal brain to subsequent hypoxic-ischemic (HI) damage. Poly inosinic:poly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, was administered to neonatal mice 14 h before cerebral HI. Activation of TLR-3 before HI increased infarct volume from 3.0 ± 0.5 to 15.4 ± 2.1 mm³ and augmented loss of myelin basic protein from 13.4 ± 6.0 to 70.6 ± 5.3%. The sensitizing effect of Poly I:C was specific for the TLR-3 pathway because mice deficient in the TLR-3 adaptor protein Toll/IL-1R domain-containing adaptor molecule-1 (TRIF) did not develop larger brain damage. The increased vulnerability was associated with a TRIF-dependent heightened inflammatory response, including proinflammatory cytokines, chemokines, and the apoptosis-associated mediator Fas, whereas there was a decrease in reparative M2-like CD11b⁺ microglia and phosphorylation of Akt. Because TLR-3 is activated via double-stranded RNA during most viral infections, the present study provides evidence that viral infections during pregnancy or in the neonate could have great impact on subsequent HI brain injury.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Encéfalo/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Microglia/metabolismo , Receptor 3 Toll-Like/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Hipóxia-Isquemia Encefálica/imunologia , Proteínas I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/imunologia , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos , Poli I-C/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
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