RESUMO
Exaggerated blood excursions of nutrients and endogenous molecules in response to food intake may have health consequences if they repeatedly exceed the capacity of homeostatic mechanisms. Here, I discuss the significance of abnormally high postprandial metabolic fluctuations, the role of some influencing factors, and suggest ways to avoid them.
Assuntos
Ingestão de Alimentos , Humanos , Ingestão de Alimentos/fisiologiaRESUMO
BACKGROUND & AIM: When considered separately, long-term immediate-release niacin and fatty meals enriched in monounsaturated fatty acids (MUFA) decrease postprandial triglycerides, but their effects on postprandial inflammation, which is common in individuals with metabolic syndrome, are less known. Moreover, successful combination is lacking and its impact on acute disorders of the innate immune cells in the metabolic syndrome remains unclear. Here, we aimed to establish the effects from combination with niacin of different fats [butter, enriched in saturated fatty acids (SFA), olive oil, enriched in MUFA, and olive oil supplemented with eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] on plasma inflammatory markers and circulating monocyte subsets, activation and priming at the postprandial period in individuals with metabolic syndrome. METHODS: A random-order within-subject crossover experiment was performed, in which 16 individuals with metabolic syndrome and 16 age-matched healthy volunteers took 2 g immediate-release niacin together with the corresponding fatty meal or a meal with no fat as control. In total, 128 postprandial curves were analysed. We sampled hourly over 6 h for plasma concentrations of soluble inflammatory markers and triglycerides. Circulating monocyte subsets (CD14/CD16 balance), activation (CCL2/CCR2 axis) and priming (M1/M2-like phenotype) at the time of postprandial hypertriglyceridemic peak were also addressed. RESULTS: Dietary SFA (combined with niacin) promote postprandial excursions of circulating IL-6, IL-1ß, TNF-α and CD14/CCR2-rich monocytes with a pro-inflammatory M1-like phenotype, particularly in individuals with metabolic syndrome. In contrast, dietary MUFA (combined with niacin) postprandially increased circulating CD16-rich monocytes with an anti-inflammatory M2-like phenotype. Omega-3 PUFA did not add to the effects of MUFA. CONCLUSION: The co-administration of a single-dose of immediate-release niacin with a fatty meal rich in MUFA, in contrast to SFA, suppresses postprandial inflammation at the levels of both secretory profile and monocyte response in individuals with metabolic syndrome. These findings highlight a potential role of combining niacin and dietary MUFA for the homeostatic control of inflammation and the innate immune system, identifying a new search direction for the management of disorders associated with the metabolic syndrome.
Assuntos
Síndrome Metabólica , Niacina , Masculino , Humanos , Ácidos Graxos Monoinsaturados/farmacologia , Monócitos/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Gorduras na Dieta/metabolismo , Niacina/metabolismo , Azeite de Oliva , Período Pós-Prandial , Ácidos Graxos/metabolismo , Triglicerídeos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , RefeiçõesRESUMO
Chronic administration of a high-fat diet in mice has been established to influence the generation and trafficking of immune cells such as neutrophils in the bone marrow, the dysregulation of which may contribute to a wide range of diseases. However, no studies have tested the hypothesis that a short-term, high-fat diet could early modulate the neutrophil release from bone marrow at fasting and at postprandial in response to a high-fat meal challenge, and that the predominant type of fatty acids in dietary fats could play a role in both context conditions. Based on these premises, we aimed to establish the effects of different fats [butter, enriched in saturated fatty acids (SFAs), olive oil, enriched in monounsaturated fatty acids (MUFAs), and olive oil supplemented with eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] on neutrophil navigation from bone marrow to blood in mice. The analysis of cellular models for mechanistic understanding and of postprandial blood samples from healthy volunteers for translational purposes was assessed. The results revealed a powerful effect of dietary SFAs in promotion the neutrophil traffic from bone marrow to blood via the CXCL2-CXCR2 axis. Dietary SFAs, but not MUFAs or EPA and DHA, were also associated with increased neutrophil apoptosis and bone marrow inflammation. Similar dietary fatty-acid-induced postprandial neutrophilia was observed in otherwise healthy humans. Therefore, dietary MUFAs might preserve bone marrow health and proper migration of bone marrow neutrophils early in the course of high-fat diets even after the intake of high-fat meals.
RESUMO
Obesity is associated with disruptions in the adaptive immune system; however, dietary fatty acids in high-fat diets (HFDs) that induce obesity have consequences that are currently unclear regarding T-cell maintenance in bone marrow (BM). C57BL/6J mice were randomly assigned to isocaloric HFDs formulated with dietary fats rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or MUFAs supplemented with eicosapentaenoic and docosahexaenoic acids for 20 weeks, followed by an analysis of the immunophenotypic feature of lymphocytes (CD3+) T and their subsets CD4+ and CD8+ T cells in spleen and BM, identification of fatty acids in BM extracellular fluid and analysis of the correspondence between fatty acids with the frequency of T-cell subsets in BM. Splenic CD3+ T cells were reduced irrespective of HFDs. In BM, CD3+ T cells were reduced after HFD-SFAs, while CD4+ T cells were increased after HFDs enriched in MUFAs and CD8+ T cells were reduced irrespective of HFDs. In BM extracellular fluid, the content of palmitic and myristic acids increased after HFD-SFAs and that of oleic acid increased after HFDs enriched in MUFAs. There was a statistical correspondence between HFD-induced changes in fatty acids in BM extracellular fluid and HFD-induced changes in the frequency of CD3+ and CD4+ T cells in BM. These findings reveal an undervalued critical role for dietary fatty acids in the selective acquisition of T-cell subsets in BM, highlighting that oleic acid existing in the surroundings of T-cell niches during HFD-induced obesity could be instrumental in the maintenance of CD4+ T cells.
Assuntos
Dieta Hiperlipídica , Ácidos Graxos , Animais , Medula Óssea/química , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/análise , Ácidos Graxos Monoinsaturados , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Ácidos OleicosRESUMO
OBJECTIVES: Neuroinflammation is a complex inflammatory process in the central nervous system (CNS) where microglia may play a critical role. GPETAFLR is a peptide isolated from Lupinus angustifolius L. protein hydrolysates with functional activity in mononuclear phagocytes. However, it is unknown whether GPETAFLR has neuroprotective effects. METHODS: We analysed the potential anti-neuroinflammatory activity of GPETAFLR by using two different models of neuroinflammation: BV-2 microglial cells and mice with high-fat diet (HFD)-induced obesity. RESULTS: GPETAFLR hampered LPS-induced upregulation of pro-inflammatory and M1 marker genes in BV-2 cells. This effect was accompanied by an unchanged expression of anti-inflammatory IL-10 gene and by an increased expression of M2 marker genes. GPETAFLR also increased the transcriptional activity of M2 marker genes, while the microglia population remained unchanged in number and M1/M2 status in brain of mice with high-fat diet (HFD)-induced obesity. Furthermore, GPETAFLR counteracted HFD-induced downregulation of IL-10 and upregulation of pro-inflammatory markers in the mouse brain, both at gene and protein levels. DISCUSSION: This is the first report describing that a peptide from plant origin robustly restrained the pro-inflammatory activation of microglial cells in cultures and in brain. Our data suggest that GPETAFLR might be instrumental in maintaining CNS homeostasis by inhibiting neuroinflammation.
Assuntos
Lupinus , Microglia , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Inflamação/induzido quimicamente , Lipopolissacarídeos/farmacologia , Lupinus/metabolismo , Camundongos , Neuroproteção , PeptídeosRESUMO
SCOPE: The role of dietary fatty acids in the generation of bone marrow (BM) immune cells and their trafficking to extramedullary compartments in the obesity is not yet fully understood. METHODS AND RESULTS: C57BL/6J mice are randomly assigned to isocaloric high-fat diets (HFDs) formulate with dietary fats rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs fortified with eicosapentaenoic and docosahexaenoic acids for 20 weeks, followed by profiling of the obese metabolic phenotype and immunophenotypic features of immune cells in blood, spleen, and BM. All HFDs induce an obese phenotype, but it becomes largely less disruptive after the HFDs are enriched in MUFAs, which also induce signs of granulopoiesis and an expansion of long-term hematopoietic stem and granulocyte-macrophage progenitor cells in BM. In contrast, a HFD enriched in SFAs disturbs the fitness of medullary lymphocytes and promotes monopoiesis in favor of pro-inflammatory activated subsets. CONCLUSION: The reshaping of the fatty acid pools with MUFAs from the diet serves to manipulate the generation and trafficking of immune cells that are biased during obesity. These findings reveal a novel strategy by which dietary MUFAs may be instrumental in combating HFD-induced dysfunctional immune systems.
Assuntos
Linhagem da Célula , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Monoinsaturados/farmacologia , Células-Tronco Hematopoéticas/citologia , Obesidade/prevenção & controle , Animais , Medula Óssea , Gorduras na Dieta , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Ácidos Graxos , Hematopoese , Sistema Imunitário/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Nicho de Células-TroncoRESUMO
During chronic inflammation, macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) have well established effects on gene networks that stimulate osteoclastogenesis, which is the culprit of several bone diseases. In this study, we investigated the anti-osteoclastogenic effects in vitro of oleuropein (OL) and its peracetylated derivative (Per-OL) by exploring the expression level of key hub genes involved in fate decision and lineage commitment, differentiation, and function of human blood monocyte-derived osteoclasts. Monocytes were purified from peripheral blood mononuclear cells of healthy individuals using commercial antibodies coated with magnetic beads and treated with M-CSF/RANKL in the presence or absence of OL or Per-OL (25 and 50 µM) for 6 days. We demonstrated that OL and especially Per-OL impair transcriptional gene circuits able to support osteoclastogenesis from human blood monocytes. Our results indicate that OL and notably Per-OL are promising candidates to control osteoclastogenesis.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Iridoides/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Glucosídeos Iridoides , Iridoides/química , Estrutura Molecular , Monócitos/fisiologia , Osteoclastos/fisiologiaRESUMO
We have analyzed the effects of minor compounds found in the unsaponifiable fraction (UF) and in the phenolic fraction (PF) of virgin olive oil (VOO) on LPS-induced inflammatory response via visfatin modulation in human monocytes. For this purpose, monocytes were incubated with UF and PF at different concentrations and the pro-inflammatory stimulus LPS for 24 hr; squalene (SQ) and hydroxytyrosol (HTyr), the main components in UF and PF, respectively, were also used. The relative expression of both pro-inflammatory and anti-inflammatory genes, as well as other genes related to the NAD+-biosynthetic pathway was evaluated by RT-qPCR; and the secretion of some of these markers was assessed by ELISA procedures. We found that UF, SQ, PF, and HTyr prevented from LPS-induced dysfunctional gene expression and secretion via visfatin-related gene modulation in human monocytes. These findings unveil a potential beneficial role for minor compounds of VOO in the prevention of inflammatory-disorders. PRACTICAL APPLICATION: In this project, potential health benefits of VOO micronutrients (unsaponifiable and phenolic compounds) were confirmed through anti-inflammatory assays. Our results reveal new interesting researching goals concerning nutrition by considering the role of bioactive VOO compounds in the prevention and progress of diseases related to inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/enzimologia , Monócitos/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/imunologia , Azeite de Oliva/química , Células Cultivadas , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/imunologia , Monócitos/imunologia , Nicotinamida Fosforribosiltransferase/genética , Fenóis/análise , Fenóis/farmacologiaRESUMO
SCOPE: Obesity is a principal causative factor of metabolic syndrome. Niacin potently regulates lipid metabolism. Replacement of saturated fatty acids by MUFAs or inclusion of omega-3 long-chain PUFAs in the diet improves plasma lipid levels. However, the potential benefits of niacin in combination with MUFAs or omega-3 long-chain PUFAs against white adipose tissue (WAT) dysfunction in the high fat diet (HFD)-induced metabolic syndrome are unknown. METHODS AND RESULTS: Male Lepob/ob LDLR-/- mice are fed a chow diet or HFDs based on milk cream (21% kcal), olive oil (21% kcal), or olive oil (20% kcal) plus 1% kcal from eicosapentaenoic and docosahexaenoic acids, including immediate-release niacin (1% w/v) in drinking water, for 8 weeks. Mice are then phenotyped. Dietary MUFAs are identified as positive regulators of adipose NAD+ signaling pathways by triggering NAD+ biosynthesis via the salvage pathway. This coexists with overexpression of genes involved in recognition of NAD+ and fatty acids, a surrounding lipid environment dominated by exogenous oleic acid and an alternatively activated macrophage profile, which culminate in a healthy expansion of WAT and improvement of several hallmarks that typify the metabolic syndrome. CONCLUSION: Niacin in combination with dietary MUFAs can favor WAT homeostasis in the development of HFD-induced obesity and metabolic syndrome.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Monoinsaturados/administração & dosagem , Síndrome Metabólica/fisiopatologia , Niacina/administração & dosagem , Tecido Adiposo Branco/imunologia , Animais , Feminino , Inflamação/prevenção & controle , Resistência à Insulina , Leptina/deficiência , Leptina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , NAD/metabolismo , Obesidade/etiologia , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de LDL/fisiologiaRESUMO
Stroke is one of the leading causes of death worldwide and while there is increasing evidence that a Mediterranean diet might decrease the risk of a stroke, the effects of dietary fat composition on stroke outcomes have not been fully explored. We hypothesize that the brain damage provoked by a stroke would be different depending on the source of dietary fat. To test this, male C57BL/6J mice were fed for 4 weeks with a standard low-fat diet (LFD), a high-fat diet (HFD) rich in saturated fatty acids (HFD-SFA), an HFD containing monounsaturated fatty acids (MUFAs) from olive oil (HFD-OO), or an HFD containing MUFAs from olive oil plus polyunsaturated fatty acids (PUFAs) docosahexaenoic acid/eicosapentaenoic acid (DHA/EPA) (HFD-OO-ω3). These mice were then subjected to transient middle cerebral artery occlusion (tMCAo). Behavioural tests and histological analyses were performed 24 and/or 48 h after tMCAo in order to elucidate the impact of these diets with different fatty acid profiles on the ischemic lesion and on neurological functions. Mice fed with HFD-OO-ω3 displayed better histological outcomes after cerebral ischemia than mice that received an HFD-SFA or LFD. Furthermore, PUFA- and MUFA-enriched diets improved the motor function and neurological performance of ischemic mice relative to those fed with an LFD or HFD-SFA. These findings support the use of DHA/EPA-omega-3-fatty acid supplementation and olive oil as dietary source of MUFAs in order to reduce the damage and protect the brain when a stroke occurs.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Azeite de Oliva/farmacologia , Animais , Antioxidantes/metabolismo , Comportamento Animal , Dieta Hiperlipídica/efeitos adversos , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ingestão de Alimentos , Ácido Eicosapentaenoico/administração & dosagem , Marcha , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média , Azeite de Oliva/administração & dosagem , Redução de Peso/efeitos dos fármacosRESUMO
Monocytes and macrophages are critical effectors and regulators of inflammation and innate immune response, which appear altered in different autoimmune diseases such as systemic lupus erythematosus (SLE). Recent studies suggested that virgin olive oil (VOO) and particularly its phenol compounds might possess preventive effects on different immune-inflammatory diseases, including SLE. Here, we evaluated the effects of VOO (and sunflower oil) on lipopolysaccharide (LPS)-activated peritoneal macrophages from a model of pristane-induced SLE in BALB/c mice, as well as those of the phenol fraction (PF) from VOO on the immune-inflammatory activity and plasticity in monocytes and monocyte-derived macrophages from healthy volunteers. The release of nitrite and inflammatory cytokines was lower in LPS-treated peritoneal macrophages from pristane-SLE mice fed the VOO diet when compared with the sunflower oil diet. PF from VOO similarly decreased the secretion of nitrite and inflammatory cytokines and expression of inducible nitric oxide, PPARγ and Toll-like receptor 4 in LPS-treated human monocytes. PF from VOO also prevented the deregulation of human monocyte subset distribution by LPS and blocked the genetic signature of M1 macrophages while favouring the phenotype of M2 macrophages upon canonical polarisation of naïve human macrophages. For the first time, our study provides several lines of in vivo and in vitro evidence that VOO and PF from VOO target and counteract inflammatory pathways in the monocyte-macrophage lineage of mice with pristane-induced SLE and of healthy subjects, which is a meaningful foundation for further development and application in preclinical and clinical use of PF from VOO in patients with SLE.
Assuntos
Dieta , Inflamação/prevenção & controle , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Azeite de Oliva/química , Fenóis/farmacologia , Animais , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos , Lúpus Eritematoso Sistêmico/dietoterapia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Olea/química , PPAR gama/metabolismo , Fenol , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Terpenos , Receptor 4 Toll-Like/metabolismoRESUMO
Grape (Vitis vinifera L.) seed has well-known potential for production of oil as a byproduct of winemaking and is a rich source of bioactive compounds. Herein, we report that the unsaponifiable fraction (UF) isolated from grape seed oil (GSO) possesses anti-oxidative and anti-inflammatory properties towards human primary monocytes. The UF isolated from GSO was phytochemically characterized by GC-MS and HPLC. Freshly obtained human monocytes were used to analyse the effects of GSOUF (10-100 µg mL-1) on oxidative and inflammatory responses using FACS analysis, RT-qPCR, and ELISA procedures. GSOUF skewed the monocyte plasticity towards the anti-inflammatory non-classical CD14+CD16++ monocytes and reduced the inflammatory competence of LPS-treated human primary monocytes diminishing TNF-α, IL-1ß, and IL-6 gene expression and secretion. In addition, GSOUF showed a strong reactive oxygen species (ROS)-scavenging activity, reducing significantly nitrite levels with a significant decrease in Nos2 gene expression. Our results suggest that the UF isolated from GSO has significant potential for the management of inflammatory and oxidative conditions and offer novel benefits derived from the consumption of GSO in the prevention of inflammation-related diseases.
Assuntos
Monócitos/efeitos dos fármacos , Monócitos/imunologia , Estresse Oxidativo/efeitos dos fármacos , Óleos de Plantas/química , Óleos de Plantas/farmacologia , Vitis/química , Adulto , Células Cultivadas , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Monócitos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Óleos de Plantas/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Sementes/química , Resíduos/análiseRESUMO
The postprandial hypertriglyceridemia is an important and largely silent disturbance involved in the genesis of numerous pathological conditions. Exaggerated and prolonged states of postprandial hypertriglyceridemia are frequently related to the ingestion of meals enriched in saturated fatty acids (SFAs). MicroRNAs are noncoding RNAs that function as gene regulators and play significant roles in both health and disease. However, differential miRNA expression between fasting and postprandial states has never been elucidated. Here, we studied the impact of a high-saturated-fat meal, mainly rich in palmitic acid, on the miRNA signature in peripheral blood mononuclear cells (PBMCs) of nine male healthy individuals in the postprandial period by using a two-step analysis: miRNA array and validation through quantitative real-time polymerase chain reaction. Compared with miRNA expression signature in PBMCs at fasting, 36 miRNAs were down-regulated and 43 miRNAs were up-regulated in PBMCs at postprandial hypertriglyceridemic peak. Six chromosomes (3, 7, 8, 12, 14 and 19) had nearly half (48.1%) of dysregulated miRNA-gene-containing regions. Down-regulated miR-300 and miR-369-3p and up-regulated miR-495-3p, miR-129-5p and miR-7-2-3p had the highest number of target genes. The differentially expressed miRNAs and their predicted target genes involved pathways in cancer, MAPK signaling pathway, endocytosis and axon guidance. Only down-regulated miRNAs notably targeted PI3K-Akt signaling pathways, whereas only up-regulated miRNAs targeted focal adhesion, Wnt signaling pathway, transcriptional misregulation in cancer and ubiquitin-mediated proteolysis. This is the first study of miRNA expression analysis of human PBMCs during postprandial hypertriglyceridemia and offers insight into new potential mechanisms by which dietary SFAs influence health or disease.
Assuntos
Ácidos Graxos/farmacologia , MicroRNAs , Período Pós-Prandial/genética , Adolescente , Simulação por Computador , Ácidos Graxos/farmacocinética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipertrigliceridemia/genética , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Ácido Palmítico/farmacologia , Adulto JovemRESUMO
Tyrosol (Tyr) is a phenolic compound found in virgin olive oil. After ingestion, Tyr undergoes extensive first pass intestinal/hepatic metabolism. However, knowledge about the biological effects of Tyr metabolites is scarce. We chemically synthesized Tyr glucuronate (Tyr-GLU) and sulphate (Tyr-SUL) metabolites and explored their properties against oxidative stress and inflammation in TNF-α-treated human umbilical vein endothelial cells (hECs). Tyr and Tyr-SUL prevented the rise of reactive oxygen species, the depletion of glutathione, and the down-regulation of glutathione peroxidase 1, glutamate-cysteine ligase catalytic subunit, and heme oxygenase-1 genes. Tyr-SUL and to a lower extent Tyr and Tyr-GLU prevented the phosphorylation of NF-κB signaling proteins. Tyr-GLU and Tyr-SUL also prevented the over-expression of adhesion molecules at gene, protein, and secretory levels, and the adhesion (Tyr-SUL > Tyr-GLU) of human monocytes to hECs. In vivo, Tyr, and most notably Tyr-SUL in a dose-dependent manner, ameliorated plantar and ear edemas in mice models of acute and chronic inflammation. This study demonstrates the antioxidant and/or anti-inflammatory properties of Tyr metabolites, with Tyr-SUL being the most effective.
Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Endoteliais/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Anti-Inflamatórios/metabolismo , Antioxidantes/metabolismo , Células Endoteliais/imunologia , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/imunologia , Heme Oxigenase-1/genética , Heme Oxigenase-1/imunologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/metabolismo , Álcool Feniletílico/farmacologia , Espécies Reativas de Oxigênio/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
OBJECTIVE: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)+ generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPThi), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPThi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor γ. Finally, iNAMPT and peroxisome proliferator-activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor γ pathway also in human carotid atherosclerosis. CONCLUSIONS: This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.
Assuntos
Aterosclerose/prevenção & controle , Diferenciação Celular , Citocinas/metabolismo , Leucócitos/enzimologia , Macrófagos/metabolismo , Monócitos/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , PPAR gama/metabolismo , Idoso , Animais , Apoptose , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/genética , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Feminino , Predisposição Genética para Doença , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/efeitos dos fármacos , Monócitos/patologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/genética , Fenótipo , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais , Sirtuína 1/metabolismo , Fatores de Tempo , Regulação para CimaRESUMO
SCOPE: Postprandial triglyceride-rich lipoproteins (TRLs) promote atherosclerosis. Recent research points the bone marrow (BM) as a primary site in atherosclerosis. We elucidated how the acute administration of monounsaturated fatty acids (MUFAs) MUFAs, omega-3 polyunsaturated fatty acids (PUFAs) PUFAs and saturated fatty acids (SFAs) affects human circulating and murine BM neutrophil lipid accumulation and functionality. METHODS AND RESULTS: Postprandial hypertriglyceridemia was induced in healthy subjects and Apoe-/- mice by the acute administration of dietary fats enriched in MUFAs, PUFAs, or SFAs. Postprandial hypertriglyceridemia increased apolipoprotein-B48 receptor (ApoB48R) transcriptional activity that was linearly correlated with intracellular triglycerides (TGs) TGs accumulation in human circulating and murine BM neutrophils. MUFA and omega-3 PUFAs attenuated ApoB48R gene expression and intracellular TG accumulation compared to SFAs. TRLs induced apoB48R-dependent TG accumulation in human neutrophils ex vivo. Murine BM neutrophils showed a decrease in surface L-selectin and an increase in TNF-α and IL-1ß mRNA expressions only after SFAs administration. TRLs enriched in SFAs induced BM neutrophil degranulation ex vivo suggesting cell priming/activation. CONCLUSION: Postprandial TRLs disrupts the normal biology and function of circulating and BM neutrophils. MUFA- and omega-3 PUFA-rich dietary fats such as virgin olive oil or fish oil has the potential to prevent excessive neutrophil lipid accumulation and activation by targeting the fatty acid composition of TRLs.
Assuntos
Gorduras na Dieta/administração & dosagem , Metabolismo dos Lipídeos , Lipoproteínas/fisiologia , Neutrófilos/metabolismo , Período Pós-Prandial , Receptores de Lipoproteínas/genética , Triglicerídeos/fisiologia , Adulto , Animais , Células da Medula Óssea/metabolismo , Ácidos Graxos/administração & dosagem , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transcrição GênicaRESUMO
Metabolic syndrome (MetS) is associated with obesity, dyslipidemia, type 2 diabetes, and chronic low-grade inflammation. The aim of this study was to determine the role of high-fat low-cholesterol diets (HFLCDs) rich in SFAs (HFLCD-SFAs), MUFAs (HFLCD-MUFAs) or MUFAs plus omega-3 long-chain PUFAs (HFLCD-PUFAs) on vascular calcification by the modulation of the RANKL/RANK/OPG system in the aortic roots of Lepob/obLDLR-/- mice. Animals fed with HFLCD-SFAs had increased weight and a greater atheroma plaque size, calcification, and RANKL/CATHK expression in the aortic root than mice on MUFA-enriched diets, with an increasing OPG expression in the aortic roots of the latter. Our study demonstrates that compared to dietary SFAs, MUFAs from olive oil protect against atherosclerosis by interfering with vascular calcification via the RANKL/RANK/OPG system in the setting of MetS. These findings open opportunities for developing novel nutritional strategies with olive oil as the most important dietary source of MUFAs (notably oleic acid) to prevent cardiovascular complications in MetS.
Assuntos
Aorta/patologia , Aterosclerose/patologia , Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Síndrome Metabólica/metabolismo , Animais , Aorta/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Calcinose , Gorduras na Dieta/análise , Ácidos Graxos/química , Humanos , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismoRESUMO
SCOPE: Macrophage plasticity allows adapting to different environments, having a dual activity in inflammatory-related diseases. Our hypothesis is that the type of dietary fatty acids into human postprandial triglyceride-rich lipoproteins (TRLs), alone or in combination with niacin (vitamin B3), could modulate the plasticity of monocytes-macrophages. METHODS AND RESULTS: We isolated TRLs at the postprandial peak from blood samples of healthy volunteers after the ingestion of a meal rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) or MUFAs plus omega-3 long-chain polyunsaturated fatty acids (LCPUFAs). Autologous monocytes isolated at fasting were first induced to differentiate into naïve macrophages. We observed that postprandial TRL-MUFAs, particularly in combination with niacin, enhance competence to monocytes to differentiate and polarise into M2 macrophages. Postprandial TRL-SFAs made polarised macrophages prone to an M1 phenotype. In contrast to dietary SFAs, dietary MUFAs in the meals plus immediate-release niacin primed circulating monocytes for a reduced postprandial pro-inflammatory profile. CONCLUSION: Our study underlines a role of postprandial TRLs as a metabolic entity in regulating the plasticity of the monocyte-macrophage lineage and also brings an understanding of the mechanisms by which dietary fatty acids are environmental factors fostering the innate immune responsiveness in humans.
Assuntos
Ácidos Graxos/farmacologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Niacina/farmacologia , Adulto , Gorduras na Dieta/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Lipoproteínas/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/metabolismo , Masculino , Monócitos/metabolismo , Período Pós-Prandial , Triglicerídeos/metabolismoRESUMO
Niacin activates HCA2 receptor that results in the release of PGD2. However, little is known on PGD2-producing cells and the role of fatty acids. Notably M-CSF macrophages exhibited a timely dependent PGD2 production upon niacin challenge. Short pretreatment of M-CSF macrophages with autologous postprandial TRLs induced the down-regulation of HCA2 gene and up-regulation of genes encoding COX1 and COX2 enzymes in a fatty acid-dependent manner. These effects were paralleled by a higher PGD2 production with postprandial TRL-SFAs. The niacin-mediated transcriptional activity of all genes involved in PGD2 biosynthesis was desensitized in a time-dependent manner by postprandial TRLs, leading to a decreased PGD2 release. In vivo, the net excursions of PGD2 in plasma followed similar fatty acid-dependent patterns as those found for PGD2 release in vitro. The predominant fatty acid class in the diet acutely modulates PGD2 biosynthetic pathway both in vitro and in vivo.
Assuntos
Ácidos Graxos Insaturados/farmacologia , Células Mieloides/efeitos dos fármacos , Niacina/farmacologia , Prostaglandina D2/biossíntese , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Células Cultivadas , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipoproteínas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Células Mieloides/metabolismo , Período Pós-Prandial/efeitos dos fármacos , Prostaglandina D2/sangue , Triglicerídeos/metabolismoRESUMO
Olive oil is the primary source of fat in the Mediterranean diet, which is associated with a significant improvement in health status, as measured by reduced mortality from several chronic diseases. The current pandemic of obesity, metabolic syndrome, and type 2 diabetes is intimately associated with an atherogenic dyslipidemic phenotype. The core components of the dyslipidemia of the metabolic syndrome, which most likely initiate atherosclerosis, are the "lipid triad" consisting of high plasma triglycerides, low levels of high-density lipoproteins, and a preponderance of small, dense low-density lipoproteins at fasting. However, postprandial (non-fasting) TGs (postprandial hyperlipidemia) are also recognized as an important component for atherosclerosis. Herein, the purpose of this review was to provide an update on the effects and mechanisms related to olive oil on postprandial hyperlipidemia and its implications for the onset and progression of atherosclerosis and metabolic syndrome.