RESUMO
Delayed wound healing is a devastating complication of diabetes and supplementation with fish oil, a source of anti-inflammatory omega-3 (ω-3) fatty acids including eicosapentaenoic acid (EPA), seems an appealing treatment strategy. However, some studies have shown that ω-3 fatty acids may have a deleterious effect on skin repair and the effects of oral administration of EPA on wound healing in diabetes are unclear. We used streptozotocin-induced diabetes as a mouse model to investigate the effects of oral administration of an EPA-rich oil on wound closure and quality of new tissue formed. Gas chromatography analysis of serum and skin showed that EPA-rich oil increased the incorporation of ω-3 and decreased ω-6 fatty acids, resulting in reduction of the ω-6/ω-3 ratio. On the tenth day after wounding, EPA increased production of IL-10 by neutrophils in the wound, reduced collagen deposition, and ultimately delayed wound closure and impaired quality of the healed tissue. This effect was PPAR-γ-dependent. EPA and IL-10 reduced collagen production by fibroblasts in vitro. In vivo, topical PPAR-γ-blockade reversed the deleterious effects of EPA on wound closure and on collagen organization in diabetic mice. We also observed a reduction in IL-10 production by neutrophils in diabetic mice treated topically with the PPAR-γ blocker. These results show that oral supplementation with EPA-rich oil impairs skin wound healing in diabetes, acting on inflammatory and non-inflammatory cells.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ácidos Graxos Ômega-3 , Animais , Camundongos , Ácido Eicosapentaenoico/farmacologia , Interleucina-10/farmacologia , PPAR gama , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cicatrização , Colágeno/metabolismo , Suplementos NutricionaisRESUMO
The growing rates of obesity worldwide call for intervention strategies to help control the pathophysiological consequences of weight gain. The use of natural foods and bioactive compounds has been suggested as such a strategy because of their recognized antioxidant and anti-inflammatory properties. For example, polyphenols, especially anthocyanins, are candidates for managing obesity and its related metabolic disorders. Obesity is well known for the presence of metainflammation, which has been labeled as an inflammatory activation that leads to a variety of metabolic disorders, usually related to increased oxidative stress. Considering this, anthocyanins may be promising natural compounds able to modulate several intracellular mechanisms, mitigating oxidative stress and metainflammation. A wide variety of foods and extracts rich in anthocyanins have become the focus of research in the field of obesity. Here, we bring together the current knowledge regarding the use of anthocyanins as an intervention tested in vitro, in vivo, and in clinical trials to modulate metainflammation. Most recent research applies a wide variety of extracts and natural sources of anthocyanins, in diverse experimental models, which represents a limitation of the research field. However, the literature is sufficiently consistent to establish that the in-depth molecular analysis of gut microbiota, insulin signaling, TLR4-triggered inflammation, and oxidative stress pathways reveals their modulation by anthocyanins. These targets are interconnected at the cellular level and interact with one another, leading to obesity-associated metainflammation. Thus, the positive findings with anthocyanins observed in preclinical models might directly relate to the positive outcomes in clinical studies. In summary and based on the entirety of the relevant literature, anthocyanins can mitigate obesity-related perturbations in gut microbiota, insulin resistance, oxidative stress and inflammation and therefore may contribute as a therapeutic tool in people living with obesity.
Assuntos
Antocianinas , Resistência à Insulina , Humanos , Antocianinas/farmacologia , Antocianinas/uso terapêutico , Antocianinas/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Inflamação/tratamento farmacológicoRESUMO
Macrophages and lymphocytes demonstrate metabolic plasticity, which is dependent partly on their state of activation and partly on the availability of various energy yielding and biosynthetic substrates (fatty acids, glucose, and amino acids). These substrates are essential to fuel-based metabolic reprogramming that supports optimal immune function, including the inflammatory response. In this review, we will focus on metabolism in macrophages and lymphocytes and discuss the role of fatty acids in governing the phenotype, activation, and functional status of these important cells. We summarize the current understanding of the pathways of fatty acid metabolism and related mechanisms of action and also explore possible new perspectives in this exciting area of research.
Assuntos
Ácidos Graxos/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Animais , Ácidos Graxos/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Ativação Linfocitária , Linfócitos/metabolismo , Ativação de Macrófagos , Macrófagos/metabolismoRESUMO
Monocyte recruitment and activation of macrophages are essential for homeostasis but are also related to the development and progression of cardiometabolic diseases. The management of inflammation with dietary components has been widely investigated. Two components that may influence inflammation are unsaturated fatty acids such as oleic acid (OA; 18:1cis-9) and antioxidant compounds like anthocyanins. Molecular and metabolic effects of such bioactive compounds are usually investigated in isolation, whereas they may be present in combination in foods or the diet. Considering this, we aimed to analyze the effects of OA and the anthocyanin keracyanin (AC) alone and in combination on toll-like receptor-mediated inflammatory responses in monocytes and macrophages. For this, THP-1-derived macrophages and monocytes were exposed to 3 treatments: OA, AC, or the combination (OAAC) and then stimulated with lipopolysaccharide. Inflammation-related gene expression and protein concentrations of IL-1ß, TNF-α, IL-6, MCP-1, and IL-10 were assessed. Also, NFκBp65, IκBα, and PPAR-γ protein expression were determined. OA, AC, and OAAC decreased pNFκBp65, PPARγ, IκBα, TNF-α, IL-1ß, IL-6, and MCP-1 and increased IL-10. MCP-1 protein expression was lower with OAAC than with either OA and AC alone. Compared to control, OAAC decreased mRNA for TLR4, IκKα, IκBα, NFκB1, MCP-1, TNF-α, IL-6, and IL-1ß more than OA or AC did alone. Also, IL-10 mRNA was increased by OAAC compared with control, OA, and AC. In summary, OA and AC have anti-inflammatory effects individually but their combination (OAAC) exerts a greater effect.
Assuntos
Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Inflamação/imunologia , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , NF-kappa B/imunologia , Ácido Oleico/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/imunologia , NF-kappa B/genética , PPAR gama/genética , PPAR gama/imunologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Necrotizing enterocolitis (NEC) is an inflammatory bowel disease and a leading cause of morbidity and mortality in preterm infants. In this study, a randomized double-blind parallel-group (1:1) trial was carried out in two neonatal intensive care units of two tertiary hospitals. Two hundred and twenty-five preterm newborns with an expected functional gastrointestinal tract were recruited and received an enteral dose of 75 mg of docosahexaenoic acid (DHA)/kg body weight or high-oleic sunflower oil daily for 14 days from the first enteral feed after birth. Confirmed NEC was evaluated with Bell's scale from stage ≥ IIa. Two hundred and fourteen randomized infants were analyzed in terms of the intent-to-treat (DHA-group: n = 105; control-group: n = 109); data for two hundred infants were analysed per protocol. Confirmed NEC was lower in infants from the DHA-group compared with the control-group (0/100 vs. 7/100; p = 0.007), with RR = 0.93 (95% CI 0.881 to 0.981), risk difference = -7%, (95% CI -12.00 to -1.99), and number needed-to-treat = 15 (95% CI 8.3 to 50). Intent-to-treat analysis showed a lower level of treatment failure in the DHA-group compared with the control-group (6/105 (6%) vs. 16/109 (15%); p = 0.03, RR = 0.905, (95% CI 0.826 to 0.991)). The results after multivariate-regression analysis remained significant. Adverse events (apart from the incidence of NEC) were not different between groups. A daily dose of DHA for 14 days starting with the first enteral feed may prevent NEC in preterm infants.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Enterocolite Necrosante/prevenção & controle , Método Duplo-Cego , Nutrição Enteral , Eritrócitos/química , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Leite Humano/químicaRESUMO
BACKGROUND: The addition of medium-chain triglycerides (MCTs) into parenteral lipid emulsions rich in fatty acids from fish oil (FOLEs) has been shown to improve their clearance and extrahepatic uptake. We assessed whether this effect could favor the leukocyte uptake of ω-3 polyunsaturated fatty acids (PUFAs) for immunomodulatory purposes METHODS: Following 5-day adaptation in metabolic cages, 42 male Lewis rats fed with AIN-93M chow were killed (baseline control group [BC]) or submitted to central venous catheterization and distributed into (1) surgical control group without parenteral infusion (chow group), (2) test emulsion (MCT/LCT/FO) group with the parenteral infusion of a FOLE containing 40% MCT, and (3) control emulsion group (LCT/FO) with the parenteral infusion of an FOLE without MCT. The 2 FOLEs had similar ω-3 PUFA contents and ω-6/ω-3 PUFA ratios and were infused during 48 and 72 hours. Concentrations of ω-3 and ω-6 PUFAs in plasma, liver, and blood mononuclear and polymorphonuclear leukocytes were assessed by gas chromatography RESULTS: In both FOLE groups, leukocyte concentrations of ω-3 PUFAs peaked after 48 hours' infusion (vs BC). At this time point, plasma concentrations of ω-3 PUFAs were higher in MCT/LCT/FO group than in LCT/FO group and the opposite was found in the liver (P<.05), but no differences in PUFA concentrations were observed between these groups in leukocytes (P>.05) CONCLUSION: The ω-3 PUFAs provided by FOLEs rich in MCT were less incorporated by liver and remained more available for extrahepatic cell delivery, but this did not result in a clear benefit in increasing their incorporation by peripheral leukocytes.
Assuntos
Ácidos Graxos Ômega-3 , Óleos de Peixe , Animais , Emulsões Gordurosas Intravenosas , Ácidos Graxos , Masculino , Ratos , Ratos Endogâmicos Lew , TriglicerídeosRESUMO
Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, 300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.
Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Inflamação/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/genética , Quinases Proteína-Quinases Ativadas por AMP , Animais , Antígeno B7-2/genética , Antígeno CD11c/genética , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Monoinsaturados/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Resistência à Insulina/genética , Lectinas Tipo C/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Receptor de Manose , Lectinas de Ligação a Manose/genética , Camundongos , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ácido Oleico/metabolismo , Ácido Oleico/farmacologia , Proteínas Quinases/genética , Receptores de Superfície Celular/genéticaRESUMO
In this letter we discuss the proposition of Bristian BR (2020) to use the intravenous administration of fish-oil emulsions in critically ill patients with Coronavirus Disease 2019 (COVID-19). We consider that immune-modulatory properties of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, rapidly provided in high amounts by fish-oil emulsions, may be important to change the course of COVID-19's death pathway. Prescriptions should be based on body weight (eg, 0.2-g pure fish-oil lipid emulsion/kg body weight/d) and also should consider combining the parenteral administration of fish-oil emulsions with low oral aspirin intake to trigger resolvin synthesis from EPA and DHA.
Assuntos
COVID-19 , Óleos de Peixe , Animais , Estado Terminal , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Emulsões , Emulsões Gordurosas Intravenosas , Humanos , SARS-CoV-2RESUMO
There is no consensus on the effects of omega-3 (ω-3) fatty acids (FA) on cutaneous repair. To solve this problem, we used 2 different approaches: (1) FAT-1 transgenic mice, capable of producing endogenous ω-3 FA; (2) wild-type (WT) mice orally supplemented with DHA-enriched fish oil. FAT-1 mice had higher systemic (serum) and local (skin tissue) ω-3 FA levels, mainly docosahexaenoic acid (DHA), in comparison with WT mice. FAT-1 mice had increased myeloperoxidase (MPO) activity and content of CXCL-1 and CXCL-2, and reduced IL-10 in the skin wound tissue three days after the wound induction. Inflammation was maintained by an elevated TNF-α concentration and presence of inflammatory cells and edema. Neutrophils and macrophages, isolated from FAT-1 mice, also produced increased TNF-α and reduced IL-10 levels. In these mice, the wound closure was delayed, with a wound area 6-fold bigger in relation with WT group, on the last day of analysis (14 days post-wounding). This was associated with poor orientation of collagen fibers and structural aspects in repaired tissue. Similarly, DHA group had a delay during late inflammatory phase. This group had increased TNF-α content and CD45+F4/80+ cells at the third day after skin wounding and increased concentrations of important metabolites derived from ω-3, like 18-HEPE, and reduced concentrations of those from ω-6 FA. In conclusion, elevated DHA content, achieved in both FAT-1 and DHA groups, slowed inflammation resolution and impaired the quality of healed skin tissue.
Assuntos
Ácidos Docosa-Hexaenoicos/fisiologia , Cicatrização , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Suplementos Nutricionais , Ácidos Graxos Dessaturases/genética , Inflamação , Macrófagos/fisiologia , Masculino , Camundongos Transgênicos , Neutrófilos/fisiologia , Pele/metabolismoRESUMO
Endothelial dysfunction is a pro-inflammatory state characterized by chronic activation of the endothelium, which leads to atherosclerosis and cardiovascular disease (CVD). Intake of trans fatty acids (TFAs) is associated with an increased risk of CVD. This risk is usually associated with industrial TFAs (iTFAs) rather than ruminant TFAs (rTFAs); however it is not clear how specific TFA isomers differ in their biological activity and mechanisms of action with regard to inflammation. Here we review the literature on 18carbon TFAs, including the research associating their intake or levels with CVD and studies relating 18carbon TFA exposure to modulation of inflammatory processes. The evidence associating iTFAs with CVD risk factors is fairly consistent and studies in humans usually show a relation between iTFAs and higher levels of inflammatory markers. In contrast, studies in humans, animals and in vitro suggest that rTFAs have null or mildly beneficial effects in cardiovascular health, metabolic parameters and inflammatory markers, although the evidence is not always consistent. More studies are needed to better identify the beneficial and detrimental effects of the different TFAs, including those with 18 carbons.