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1.
Nat Commun ; 12(1): 1704, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731716

RESUMO

GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37-/- mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.


Assuntos
Macrófagos/metabolismo , Dor/prevenção & controle , Receptores Acoplados a Proteínas-G/metabolismo , Sepse/prevenção & controle , Transferência Adotiva , Animais , Artesunato/metabolismo , Artesunato/farmacologia , Artesunato/uso terapêutico , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Lipopolissacarídeos/toxicidade , Listeria monocytogenes/patogenicidade , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Macrófagos/transplante , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Simulação de Acoplamento Molecular , Dor/imunologia , Dor/mortalidade , Fagocitose/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Receptores Acoplados a Proteínas-G/deficiência , Sepse/imunologia , Sepse/mortalidade , Sepse/terapia
2.
Mol Aspects Med ; 77: 100943, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33551236

RESUMO

The health of the individual and the population in general is the result of interaction between genetics and various environmental factors, of which diet/nutrition is the most important. The focus of this paper is on the association of high n-6 PUFA or low n-3 PUFA due to genetic variation and/or dietary intake, with changes in specialized pro-resolving mediators (SPMs), cytokine storm, inflammation-resolution and Covid-19. Human beings evolved on a diet that was balanced in the n-6 and n-3 essential fatty acids with a ratio of n-6/n-3 of 1-2/1 whereas today this ratio is 16/1. Such a high ratio due to high amounts of n-6 fatty acids leads to a prothrombotic and proinflammatory state and is associated with obesity, diabetes, cardiovascular disease, and some forms of cancer. In addition to the high intake of n-6 fatty acids that increases inflammation there is genetic variation in the biosynthesis of n-6 linoleic acid (LA) to arachidonic acid (ARA) and of linolenic (ALA) to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Present day humans have two common FADS haplotypes that differ dramatically in their ability to generate long-chain fatty acids. The more efficient, evolutionary derived haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and could have provided an advantage in environments with limited access to dietary long-chain fatty acids ARA, EPA and DHA. In the modern world this haplotype has been associated with lifestyle-related diseases, such as cardiovascular disease, obesity, diabetes, all of which are characterized by increased levels of inflammation. African Americans and Latino populations have increased susceptibility and higher death rates from SARS-CoV-2 than whites. These populations are characterized by increased numbers of persons (about 80%) that are fast metabolizers, leading to increased production of ARA, as well as poor intake of fruits and vegetables. The combinations of fast metabolism and high n-6 intake increases their inflammatory status and possibly susceptibility of SARS-CoV-2. In vitro and human studies indicate that the specialized pro-resolving mediators (SPM) produced from the n-3, EPA and DHA influence the resolution of inflammation, allowing the tissues to return to function and homeostasis. The SPMs each counter-regulate cytokine storms, as well as proinflammatory lipid mediators via NFκB and inflammasome down regulation and reduce the proinflammatory eicosanoids produced from ARA. The nutritional availability of dietary n-3 fatty acids from marine oils enriched with SPM intermediate precursors, along with increasing local biosynthesis of SPMs to functional concentrations may be an approach of value during SARS-CoV2 infections, as well as in prevention, and shortening their recovery from infections. It is evident that populations differ in their genetic variants and their frequencies and their interactions with the food they eat. Gene-nutrient interactions is a very important area of study that provides specific dietary advice for individuals and subgroups within a population in the form of Precision Nutrition. Nutritional science needs to focus on Precision Nutrition, genetic variants in the population and a food supply composed of Nutrients that have been part of our diet throughout evolution, which is the diet that our genes are programmed to respond.


Assuntos
/dietoterapia , /genética , /metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Essenciais/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Predisposição Genética para Doença/genética , Haplótipos , Humanos , Inflamação/dietoterapia , Inflamação/genética , Inflamação/metabolismo , Ácido Linoleico/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , /patogenicidade
3.
Arterioscler Thromb Vasc Biol ; 41(3): 1062-1075, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472399

RESUMO

OBJECTIVE: Plaque necrosis is a key feature of defective resolution in atherosclerosis. Recent evidence suggests that necroptosis promotes plaque necrosis; therefore, we sought to determine how necroptotic cells (NCs) impact resolution programs in plaques. Approach and Results: To investigate the role(s) of necroptosis in advanced atherosclerosis, we used mice deficient of Mlkl, an effector of necroptosis. Mlkl-/- mice that were injected with a gain-of-function mutant PCSK9 (AAV8-gof-PCSK9) and fed a Western diet for 16 weeks, showed significantly less plaque necrosis, increased fibrous caps and improved efferocytosis compared with AAV8-gof-PCSK9 injected wt controls. Additionally, hypercholesterolemic Mlkl-/- mice had a significant increase in proresolving mediators including resolvin D1 (RvD1) and a decrease in prostanoids including thromboxane in plaques and in vitro. We found that exuberant thromboxane released by NCs impaired the clearance of both apoptotic cells and NCs through disruption of oxidative phosphorylation in macrophages. Moreover, we found that NCs did not readily synthesize RvD1 and that exogenous administration of RvD1 to macrophages rescued NC-induced defective efferocytosis. RvD1 also enhanced the uptake of NCs via the activation of p-AMPK (AMP-activated protein kinase), increased fatty acid oxidation, and enhanced oxidative phosphorylation in macrophages. CONCLUSIONS: These results suggest that NCs derange resolution by limiting key SPMs and impairing the efferocytic repertoire of macrophages. Moreover, these findings provide a molecular mechanism for RvD1 in directing proresolving metabolic programs in macrophages and further suggests RvD1 as a potential therapeutic strategy to limit NCs in tissues. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos/metabolismo , Macrófagos/metabolismo , Necroptose/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Feminino , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fosforilação Oxidativa , Fagocitose , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Prostaglandinas/metabolismo , Proteínas Quinases/deficiência , Proteínas Quinases/genética
4.
Essays Biochem ; 64(3): 443-462, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32885825

RESUMO

Today, persistent and uncontrolled inflammation is appreciated to play a pivotal role in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other diseases of public health concern (e.g. Coronavirus Disease 2019 (COVID-19) and periodontal disease). The ideal response to initial challenge in humans is a self-limited inflammatory response leading to complete resolution. The resolution phase is now widely recognized as a biosynthetically active process, governed by a superfamily of endogenous chemical mediators that stimulate resolution of inflammatory responses, namely specialized proresolving mediators (SPMs). Because resolution is the natural ideal response, the SPMs have gained attention. SPMs are mediators that include ω-6 arachidonic acid-derived lipoxins, ω-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-derived resolvins, protectins and maresins, cysteinyl-SPMs, as well as n-3 docosapentaenoic acid (DPA)-derived SPMs. These novel immunoresolvents, their biosynthetic pathways and receptors have proven to promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via specific cellular and molecular mechanisms. As of 17 August, 2020, PubMed.gov reported >1170 publications for resolvins, confirming their potent protective actions from many laboratories worldwide. Since this field is rapidly expanding, we provide a short update of advances within 2-3 years from human and preclinical animal studies, together with the structural-functional elucidation of SPMs and identification of novel SPM receptors. These new discoveries indicate that SPMs, their pathways and receptors could provide a basis for new approaches for treating inflammation-associated diseases and for stimulating tissue regeneration via resolution pharmacology and precision nutrition.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Animais , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Humanos , Inflamação/metabolismo , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
5.
PLoS One ; 15(7): e0236601, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730353

RESUMO

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exhibit antibacterial and anti-inflammatory activities. Furthermore, diets rich in n-3 PUFAs are known to improve disease resistance and limit pathogen infection in commercial aquaculture fishes. In this study, we examined the effects of transgenic overexpression of n-3 PUFA biosynthesis genes on the physiological response to bacterial infection in tilapia. We first established tilapia strains with single or dual expression of salmon delta-5 desaturase and/or delta-6 desaturase and then challenged the fish with Vibrio vulnificus infection. Interestingly, our data suggest that n-3 PUFA-mediated alterations in gut microbiota may be important in determining disease outcome via effects on immune response of the host. Both liver- and muscle-specific single and dual expression of delta-5 desaturase and delta-6 desaturase resulted in higher n-3 PUFA content in transgenic fish fed with a LO basal diet. The enrichment of n-3 PUFAs in dual-transgenic fish is likely responsible for their improved survival rate and comparatively reduced expression of inflammation- and immune-associated genes after V. vulnificus infection. Gut microbiome analysis further revealed that dual-transgenic tilapia had high gut microbiota diversity, with low levels of inflammation-associated microbiota (i.e., Prevotellaceae). Thus, our findings indicate that dual expression of transgenic delta-5 and delta-6 desaturase in tilapia enhances disease resistance, an effect that is associated with increased levels of n-3 PUFAs and altered gut microbiota composition.


Assuntos
Resistência à Doença , Ácidos Graxos Dessaturases/metabolismo , Proteínas de Peixes/metabolismo , Microbioma Gastrointestinal , Linoleoil-CoA Desaturase/metabolismo , Tilápia/microbiologia , Vibrio vulnificus/patogenicidade , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/microbiologia , Dieta/veterinária , Análise Discriminante , Resistência à Doença/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Ômega-3/metabolismo , Doenças dos Peixes/microbiologia , Doenças dos Peixes/patologia , Proteínas de Peixes/genética , Expressão Gênica , Análise dos Mínimos Quadrados , Linoleoil-CoA Desaturase/genética , Tilápia/genética , Vibrioses/patologia , Vibrioses/veterinária
6.
Life Sci ; 257: 118036, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622949

RESUMO

AIMS: Anti-obesity effects and improved leptin sensitivity from n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported in diet-induced obese animals. This study sought to determine the beneficial central effects and mechanism of docosahexaenoic acid (DHA, 22:6 n-3) in high-fat (HF) diet fed mice. MAIN METHODS: Male C57BL/6J mice were given HF diet with or without intracerebroventricular (icv) injection of docosahexaenoic acid (DHA, 22:6 n-3) for two days. Central leptin sensitivity, hypothalamic inflammation, leptin signaling molecules and tyrosine hydroxylase (TH) were examined by central leptin sensitivity test and Western blot. Furthermore, the expression of hepatic genes involved in lipid metabolism was examined by RT-PCR. KEY FINDINGS: We found that icv administration of DHA not only reduced energy intake and body weight gain but also corrected the HF diet-induced hypothalamic inflammation. DHA decreased leptin signaling inhibitor SOCS3 and improved the leptin JAK2-Akt signaling pathways in the hypothalamus. Furthermore, icv administration of DHA improved the effects of leptin in the regulation of mRNA expression of enzymes related to lipogenesis, fatty acid ß-oxidation, and cholesterol synthesis in the liver. DHA increased leptin-induced activation of TH in the hypothalamus. SIGNIFICANCE: Therefore, increasing central DHA concentration may prevent the deficit of hypothalamic regulation, which is associated with disorders of energy homeostasis in the liver as a result of a high-fat diet.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Leptina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Food Chem ; 330: 127225, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32569931

RESUMO

The whole genome of Streptomyces violascens (=ATCC 27968) was sequenced and the cloning and expression of OUC-Lipase 6 were conducted in Bacillus subtilis WB800. The recombinant enzyme belongs to the lipolytic enzymes family V. OUC-Lipase 6 showed optimal activity at 30 °C and pH 9.0, and retained 90.2% of its activity in an alkaline buffer (pH 8.0, 30 °C and 96 h). OUC-Lipase 6 showed good stability under medium temperature conditions (residual activity of 68.8%, pH 8.0, 45 °C and 96 h). OUC-Lipase 6 could selectively hydrolyze fatty acids on the glyceride backbone, thus improving the contents of DHA and EPA in codfish oil. OUC-Lipase 6 also showed regioselectivity, resulting in a better enrichment efficiency for EPA than DHA. After hydrolyzing for 36 h via OUC-Lipase 6, the contents of EPA and DHA were improved to 3.24-fold and 1.98-fold, respectively.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Lipase/metabolismo , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Genoma Bacteriano , Glicerídeos/química , Hidrólise , Streptomyces/química , Streptomyces/genética , Streptomyces/metabolismo , Especificidade por Substrato
8.
Proc Natl Acad Sci U S A ; 117(25): 14354-14364, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513697

RESUMO

Ischemic injury initiates a sterile inflammatory response that ultimately participates in the repair and recovery of tissue perfusion. Macrophages are required for perfusion recovery during ischemia, in part because they produce growth factors that aid in vascular remodeling. The input signals governing this pro-revascularization phenotype remain of interest. Here we found that hindlimb ischemia increases levels of resolvin D1 (RvD1), an inflammation-resolving lipid mediator that targets macrophages via its receptor, ALX/FPR2. Exogenous RvD1 enhances perfusion recovery during ischemia, and mice deficient in Alx/Fpr2 have an endogenous defect in this process. Mechanistically, RNA sequencing revealed that RvD1 induces a transcriptional program in macrophages characteristic of a pro-revascularization phenotype. Vascularization of ischemic skeletal muscle, as well as cutaneous wounds, is impaired in mice with myeloid-specific deficiency of Alx/Fpr2, and this is associated with altered expression of pro-revascularization genes in skeletal muscle and macrophages isolated from skeletal muscle. Collectively, these results uncover a role of ALX/FPR2 in revascularization that may be amenable to therapeutic targeting in diseases associated with altered tissue perfusion and repair.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Isquemia/imunologia , Neovascularização Fisiológica/imunologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Cicatrização/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Humanos , Isquemia/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Cultura Primária de Células , RNA-Seq , Receptores de Formil Peptídeo/genética , Receptores de Lipoxinas/genética , Transdução de Sinais/imunologia , Pele/irrigação sanguínea , Pele/imunologia , Pele/lesões , Pele/patologia , Transcrição Genética/imunologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-32466294

RESUMO

Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 1`2 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.


Assuntos
Neoplasias da Mama/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Colesterol , Regulação para Baixo , Humanos , Transcriptoma , Regulação para Cima
10.
Adv Exp Med Biol ; 1260: 33-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304030

RESUMO

Our own studies and those of others have shown that defects in essential fatty acid (EFA) metabolism occurs in age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, immune dysfunction and cancer. It has been noted that in all these disorders there could occur a defect in the activities of desaturases, cyclo-oxygenase (COX), and lipoxygenase (LOX) enzymes leading to a decrease in the formation of their long-chain products gamma-linolenic acid (GLA), arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). This leads to an increase in the production of pro-inflammatory prostaglandin E2 (PGE2), thromboxanes (TXs), and leukotrienes (LTs) and a decrease in anti-inflammatory lipoxin A4, resolvins, protectins and maresins. All these bioactive molecules are termed as bioactive lipids (BALs). This imbalance in the metabolites of EFAs leads to low-grade systemic inflammation and at times acute inflammatory events at specific local sites that trigger the development of various age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, coronary heart disease, atherosclerosis, and immune dysfunction as seen in rheumatoid arthritis, lupus, nephritis and other localized inflammatory conditions. This evidence implies that methods designed to restore BALs to normal can prevent age-related disorders and enhance longevity and health.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Doença , Ácidos Graxos Essenciais/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Inflamação/metabolismo , Inflamação/patologia
12.
Biomed Res Int ; 2020: 5393041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149115

RESUMO

Resveratrol (Resv) offers health benefits in cancer and has been reported to modulate important enzymes of lipid metabolism. Studies of its effects on lipid composition in different subtypes of breast-cancer cells are scarce. Thus, we investigated the alterations in phospholipids (PL), fatty acids (FA), and lipid metabolism enzymes in two breast-cancer cell lines after Resv treatment. MCF-7 and MDA-MB-231 cells were treated with 80 and 200 µM of Resv, respectively, for 24 hours. We analyzed PL with radiolabeled inorganic phosphate (32Pi) by thin-layer chromatography, FA by gas chromatography-mass spectrometry, and lipid metabolism enzymes (DGAT2, FAS, ρACCß, pAMPKα, and AMPK) by Western blot. Resv treated MDA-MB-231 phospholipids showed a reduction in phosphatidylcholine (63%) and phosphatidylethanolamine (35%). We observed an increase in eicosapentaenoic acid (EPA) (73%) and docosahexaenoic acid (DHA) (65%) in MCF-7 cells after Resv treatment. Interestingly, the same treatment caused 50% and 90% increases in EPA and DHA, respectively, in MDA-MB-231 cells. In MCF-7 cells, Resv increased the expression of ρACCß (3.3-fold) and AMPKα/ρAMPKα (1.5-fold) and in MDA-MB-231 cells it inhibited the expression of ρACCß (111.8-fold) and AMPKα/ρAMPKα (1.2 fold). Our results show that Resv modified PL and saturated and unsaturated FA especially in MDA-MB-231 cells, and open new perspectives to the understanding of the reported anticancer effect of Resv on these cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Resveratrol/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados , Feminino , Humanos , Lipídeos/análise , Células MCF-7 , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/metabolismo , Resveratrol/uso terapêutico
13.
Biochem Biophys Res Commun ; 526(1): 246-252, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32204912

RESUMO

Glycerophospholipids, one of the main constituents of biological membranes, are synthesized from glycerol-3-phosphate through the de novo pathway, and are reconstituted through the remodeling pathway. Lysophosphatidylethanolamine acyltransferase 2 (LPEAT2), one of the enzymes that play a role in the remodeling pathway, has been previously reported to have LPEAT, lysophosphatidylcholine acyltransferase (LPCAT) and lysophosphatidylglycerol acyltransferase (LPGAT) activities with 16:0-CoA, 18:0-CoA, and 18:1-CoA as donors. In this study, we found that LPEAT2 is active with 22:6-CoA. Knockdown studies using Neuro 2A cells showed that LPEAT2 has endogenous LPEAT activity with 22:6-CoA, and that LPEAT2 has functions for modulating 22:6/20:4 ratios of phospholipids. In addition, we demonstrated that Neuro 2A cells overexpressing LPEAT2 underwent cell death with necrotic morphology when differentiated into neuron-like cells, with supplementation with 22:6 (DHA). These results suggest that LPEAT2 plays a role in inducing cell death DHA-dependently. This study will lead to better understand how DHA levels are regulated in phospholipids, especially in the brain where LPEAT2 is highly expressed. Our study also provides insight to understand the mechanism of cell death induced by DHA.


Assuntos
Aciltransferases/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Fosfolipídeos/metabolismo , Acil Coenzima A/metabolismo , Animais , Encéfalo/metabolismo , Células CHO , Morte Celular , Cricetinae , Cricetulus , Cinética , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/metabolismo , Distribuição Tecidual
14.
Artigo em Inglês | MEDLINE | ID: mdl-32058894

RESUMO

INTRODUCTION: Omega-3 DHA is important for the prevention of preterm birth, however there is limited knowledge of the determinants of omega-3 status during pregnancy. The primary objective of this systematic review was to synthesise data from existing studies assessing relationships between clinical factors and maternal DHA status. MATERIALS AND METHODS: The Medline, Embase, Amed, and CINAHL databases were searched for studies reporting measures of maternal omega-3 status and one or more clinical characteristics. RESULTS: Eighteen studies were included in the final analyses. Factors associated with a higher BMI (overweight, higher gestational weight gain, gestational diabetes), or lower parity were each associated with higher omega-3 status in the majority of studies, with mixed findings for other comparisons. DISCUSSION: Inconsistent findings between studies make it difficult to draw clear conclusions about the relationship between clinical factors and maternal omega-3 DHA status. However, maternal overweight and associated metabolic conditions may increase lipid metabolism.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Nascimento Prematuro/prevenção & controle , Índice de Massa Corporal , Feminino , Idade Gestacional , Humanos , Metabolismo dos Lipídeos , Gravidez , Resultado da Gravidez
15.
Nutr Metab Cardiovasc Dis ; 30(4): 709-716, 2020 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-32007335

RESUMO

BACKGROUND AND AIMS: Mediterranean diet has been associated with decreased cardiovascular morbidity and mortality. Both fish and olive oil are key components of this diet. Therefore, we compared their effects on nonalcoholic fatty liver disease (NAFLD) and atherogenesis in a mouse model, fed a high fat diet. METHODS AND RESULTS: Forty nine, female LDL receptor knockout (LDLR KO) mice were allocated into 3 groups and fed an atherogenic high fat (HF) diet for 9 weeks. The HF group was fed a high fat diet alone. A HF + OO group was fed a HF diet with added olive oil (60 ml/kg feed), and the third group (HF + FO) was fed a HF diet with added fish oil (60 ml/kg feed). Both additions of fish and olive oil, significantly decreased plasma cholesterol elevation compared to HF diet. Nevertheless, only fish oil addition reduced significantly atherosclerotic lesion area by 51% compared to HF group. Liver levels of eicosapentenoic (EPA) and docosahexaenoic (DHA) acids were several folds higher in HF + FO group than in HF and HF + OO groups. Liver levels of oleic acid were higher in HF + OO compared to the other groups. Moreover, Fish oil addition significantly decreased NAFLD scores related to steatosis and inflammation and lowered the expression of the inflammatory genes interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP1). CONCLUSION: These results suggest that fish oil addition on top of an atherogenic, HF diet, is beneficial, while olive oil is not, in its effect on plaque formation and NAFLD in LDLR KO mice.


Assuntos
Aterosclerose/prevenção & controle , Dieta Hiperlipídica , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Azeite de Oliva/administração & dosagem , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Quimiocina CCL2/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Feminino , Interleucina-6/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácido Oleico/administração & dosagem , Ácido Oleico/metabolismo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo
16.
AAPS PharmSciTech ; 21(3): 77, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970527

RESUMO

Previously, we developed a solid lipid nanoparticle (SLN) formulation of 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), a compound with promising antitumor activity. Herein, we studied the feasibility of administering the DHA-dFdC by the oral route using the solid lipid nanoparticles (i.e., DHA-dFdC-SLNs). In simulated gastrointestinal fluids, the DHA-dFdC-SLNs did not aggregate. The release of the DHA-dFdC from the solid lipid nanoparticles in simulated gastrointestinal fluid was slow, but was slightly faster in simulated intestinal fluid than in simulated gastric fluid. In mice orally administered with DHA-dFdC-SLNs, plasma DHA-dFdC concentration vs. time curve has a Tmax of ~ 1.7 h and a Cmax of 17.01 µg/mL. The absolute oral bioavailability of DHA-dFdC when given as DHA-dFdC-SLNs was ~ 68% (based on AUC0-24 h values), while the relative oral bioavailability DHA-dFdC (compared with DHA-dFdC in a Tween 80/ethanol-in-water solution) was 126%. Finally, in mice with pre-establish B16-F10 murine melanoma, oral DHA-dFdC-SLNs increased their survival significantly, as compared with oral administration of the DHA-dFdC solution. It is concluded that the solid lipid nanoparticle formulation increased the bioavailability of the DHA-dFdC upon oral administration, as compared with the DHA-dFdC solution.


Assuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Polissorbatos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Ácidos Docosa-Hexaenoicos/química , Ácidos Docosa-Hexaenoicos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Composição de Medicamentos/métodos , Feminino , Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/metabolismo , Polissorbatos/química , Polissorbatos/metabolismo , Taxa de Sobrevida/tendências , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
17.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973128

RESUMO

Ocular inflammation contributes to the pathogenesis of blind-causing retinal degenerative diseases, such as age-related macular degeneration (AMD) or photic maculopathy. Here, we report on inflammatory mechanisms that are associated with retinal degeneration induced by bright visible light, which were revealed while using a rabbit model. Histologically and electrophysiologically noticeable degeneration of the retina is preceded and accompanied by oxidative stress and inflammation, as evidenced by granulocyte infiltration and edema in this tissue, as well as the upregulation of total protein, pro-inflammatory cytokines, and oxidative stress markers in aqueous humor (AH). Consistently, quantitative lipidomic studies of AH elucidated increase in the concentration of arachidonic (AA) and docosahexaenoic (DHA) acids and lyso-platelet activating factor (lyso-PAF), together with pronounced oxidative and inflammatory alterations in content of lipid mediators oxylipins. These alterations include long-term elevation of prostaglandins, which are synthesized from AA via cyclooxygenase-dependent pathways, as well as a short burst of linoleic acid derivatives that can be produced by both enzymatic and non-enzymatic free radical-dependent mechanisms. The upregulation of all oxylipins is inhibited by the premedication of the eyes while using mitochondria-targeted antioxidant SkQ1, whereas the accumulation of prostaglandins and lyso-PAF can be specifically suppressed by topical treatment with cyclooxygenase inhibitor Nepafenac. Interestingly, the most prominent antioxidant and anti-inflammatory benefits and overall retinal protective effects are achieved by simultaneous administrating of both drugs indicating their synergistic action. Taken together, these findings provide a rationale for using a combination of mitochondria-targeted antioxidant and cyclooxygenase inhibitor for the treatment of inflammatory components of retinal degenerative diseases.


Assuntos
Humor Aquoso/metabolismo , Inflamação/tratamento farmacológico , Luz/efeitos adversos , Retina/metabolismo , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/metabolismo , Animais , Antioxidantes/farmacologia , Ácido Araquidônico/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Edema/patologia , Inflamação/patologia , Peroxidação de Lipídeos , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Masculino , Mitocôndrias/metabolismo , Estresse Oxidativo , Oxilipinas/metabolismo , Plastoquinona/análogos & derivados , Plastoquinona/farmacologia , Fator de Ativação de Plaquetas/análogos & derivados , Fator de Ativação de Plaquetas/metabolismo , Coelhos , Retina/efeitos dos fármacos , Retina/patologia , Retina/efeitos da radiação , Degeneração Retiniana/induzido quimicamente , Degeneração Retiniana/patologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-31835092

RESUMO

Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rorasg/sg) and wildtype littermates (Rora+/+) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-month-old, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.


Assuntos
Encéfalo/crescimento & desenvolvimento , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Animais , Encéfalo/metabolismo , Cromatografia Gasosa , Feminino , Metabolismo dos Lipídeos , Masculino , Camundongos , Fosfolipídeos/metabolismo
19.
Biosci Biotechnol Biochem ; 84(3): 633-639, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31710276

RESUMO

To evaluate the suitability of the new nutritional composition of renewed commercial Formula A (protein reduced to 2.2 g/100 kcal, arachidonic acid increased to 13.2 mg/100 kcal, and docosahexaenoic acid maintained at 20 mg/100 kcal), we examined whether the growth of Formula A-fed infants was equivalent to that of breastfed infants. In this observational study, 1,053 infants were followed-up to 12 months. Growth, stool consistency, and the health condition of 99 infants fed with Formula A and 295 breastfed infants were compared. Body weight, body mass index, and head circumference of Formula A-fed infants were similar to those of breastfed infants. Additionally, there were no differences in the stool consistency and the health condition (infection and allergy prevalence) between the two groups. Formula A-fed infants grew as well as breastfed infants, suggesting the appropriate nutritional composition of Formula A. The findings may contribute to further improvements in infant formulas.


Assuntos
Desenvolvimento Infantil , Proteínas na Dieta/administração & dosagem , Ingestão de Energia , Fórmulas Infantis/química , Ácido Araquidônico/metabolismo , Peso Corporal , Aleitamento Materno , Ácidos Docosa-Hexaenoicos/metabolismo , Seguimentos , Nível de Saúde , Humanos , Lactente , Recém-Nascido
20.
Biochimie ; 169: 69-87, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31786231

RESUMO

Lipid droplets are fat storage organelles present in most eukaryotic cells. They consist of a neutral lipid core containing mostly triglycerides and sterol esters and covered by a monolayer of phospholipids, wherein numerous proteins are embedded. In the cell, lipid droplets have a dynamic life cycle, rapidly altering their size, location, lipid and protein composition in response to environmental stimuli and cell state. Lipid droplets are primarily involved in the coordination of lipid metabolism with cellular requirements for energy production, membrane homeostasis and cell growth. However, they are also directly or indirectly engaged in signalling pathways. On the one hand, lipid droplets sequester lipids and proteins thereby limiting their availability for participation in signalling pathways. On the other hand, the lipolytic machinery provides a highly regulated, on-demand source of signalling lipids: lipids derived from their neutral lipid core, or the phospholipid monolayer, directly act as signalling mediators or are converted into ones. In fact, emerging studies suggest that these organelles are essential for various cellular stress response mechanisms, including inflammation and immunity, acting as hubs that integrate metabolic and inflammatory processes. Here, we discuss the ways in which lipid droplets regulate the availability of fatty acids for the activation of signalling pathways and for the production of polyunsaturated fatty acid-derived lipid mediators. We focus in particular on recent discoveries in immune cells and adipose tissue that have revealed an intricate relationship between lipid droplets and inflammatory signalling and may also be relevant for other tissues and various human diseases.


Assuntos
Tecido Adiposo/metabolismo , Eicosanoides/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Fosfolipídeos/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/imunologia , Animais , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/imunologia , Regulação da Expressão Gênica , Homeostase/genética , Homeostase/imunologia , Humanos , Inflamação , Lipase/genética , Lipase/imunologia , Gotículas Lipídicas/imunologia , Metabolismo dos Lipídeos/imunologia , Fosfolipases/genética , Fosfolipases/imunologia , Fosfolipídeos/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Triglicerídeos/imunologia
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