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1.
PLoS One ; 15(3): e0230780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214349

RESUMO

Calprotectin is a heterodimeric protein complex with two subunits called S100A8/A9. The protein has an essential role in inflammation process and various human diseases. It has the ability to bind to unsaturated fatty acids including Arachidonic acid, Oleic acid and etc., which could be considered as a major carrier for fatty acids. In this study we aimed to appraise the thermodynamics and structural changes of Calprotectin in presence of Arachidonic acid/Oleic acid) using docking and molecular dynami simulation method. To create the best conformation of Calprotectin-Oleic acid/Arachidonic acid complexes, the docking process was performed. The complexes with the best binding energy were selected as the models for molecular dynamics simulation process. Furthermore, the structural and thermodynamics properties of the complexes were evaluated too. The Root Mean Square Deviation and Root Mean Square Fluctuation results showed that the binding of Arachidonic acid/Oleic acid to Calprotectin can cause the protein structural changes which was confirmed by Define Secondary Structure of Proteins results. Accordingly, the binding free energy results verified that binding of Oleic acid to Calprotectin leads to instability of S100A8/A9 subunits in the protein. Moreover, the electrostatic energy contribution of the complexes (Calprotectin-Oleic acid/Arachidonic acid) was remarkably higher than van der Waals energy. Thus, the outcome of this study confirm that Oleic acid has a stronger interaction with Calprotectin in comparison with Arachidonic acid. Our findings indicated that binding of unsaturated fatty acids to Calprotectin leads to structural changes of the S100A8/A9 subunits which could be beneficial to play a biological role in inflammation process.


Assuntos
Ácido Araquidônico/farmacologia , Complexo Antígeno L1 Leucocitário/química , Complexo Antígeno L1 Leucocitário/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ácidos Oleicos/farmacologia , Ácido Araquidônico/metabolismo , Ligação de Hidrogênio , Ácidos Oleicos/metabolismo , Conformação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos
2.
Food Chem ; 317: 126384, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32078997

RESUMO

This study investigated the capability of selected autochthonous lactic acid bacteria to enrich the portfolio of bioactive compounds of avocado fruit (Persea americana Mill.), with the perspective of producing dietary supplements or pharmaceutical preparations. Fermented avocado puree resulted in high levels of total free amino acids. Fermentation also led to a marked increase of antioxidant activity, with the highest levels found in water and hexane soluble extracts. Bio-converted phenolic compounds and fatty acids derivatives resulting from bacterial metabolism were likely responsible for the increased antioxidant activity. Fermentation caused the fortification of avocado puree with some hydroxy fatty acids, which deserved marked attention due to their health-promoting activities. Oleic and linoleic acids were highly metabolized by Lactobacillus plantarum AVEF17, leading to high levels of mono, di-, and tri-hydroxy-octadecenoic acids.


Assuntos
Antioxidantes/metabolismo , Ácidos Graxos/química , Ácido Láctico/metabolismo , Lactobacillus plantarum/metabolismo , Persea/química , Fenóis/química , Fermentação , Frutas/química , Ácido Linoleico/metabolismo , Ácido Oleico/metabolismo , Ácidos Oleicos/metabolismo , Extratos Vegetais/química
3.
Ann Surg ; 271(3): 509-518, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30702457

RESUMO

OBJECTIVE: The aim of this study was to determine whether downstream [peroxisome proliferator-activated-receptor alpha (PPARα) and the G-protein coupled receptor, GPR119] and upstream (a fatty acid translocase, CD36) signaling targets of N-oleoylethanolamide (OEA) were necessary for weight loss, metabolic improvements, and diet preference following vertical sleeve gastrectomy (VSG). SUMMARY BACKGROUND DATA: OEA is an anorectic N-acylethanolamine produced from dietary fats within the intestinal lumen that can modulate lipid metabolism, insulin secretion, and energy expenditure by activating targets such as PPARα and GPR119. METHODS: Diet-induced obese mice, including wild-type or whole body knockout (KO) of PPARα, GPR119, and CD36, were stratified to either VSG or sham surgery before body weight, body composition, diet preference, and glucose and lipid metabolic endpoints were assessed. RESULTS: We found increased duodenal production of OEA and expression of both GPR119 and CD36 were upregulated in wild-type mice after VSG. However, weight loss and glucose tolerance were improved in response to VSG in PPARαKO, GPR119KO, and CD36KO mice. In fact, VSG corrected hepatic triglyceride dysregulation in CD36KO mice, and circulating triglyceride and cholesterol levels in PPARαKO mice. Lastly, we found PPARα-mediated signaling contributes to macronutrient preference independent of VSG, while removal of CD36 signaling blunts the VSG-induced shift toward carbohydrate preference. CONCLUSIONS: In the search for more effective and less invasive therapies to help reverse the global acceleration of obesity and obesity-related disease OEA is a promising candidate; however, our data indicate that it is not an underlying mechanism of the effectiveness of VSG.


Assuntos
Endocanabinoides/metabolismo , Etanolaminas/metabolismo , Gastrectomia/métodos , Obesidade/metabolismo , Obesidade/cirurgia , Ácidos Oleicos/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Expressão Gênica , Teste de Tolerância a Glucose , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/metabolismo , Ratos , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Depuradores Classe B/metabolismo , Regulação para Cima
4.
J Appl Microbiol ; 128(1): 191-201, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31561280

RESUMO

AIMS: To investigate the genetic determinates for conjugated linolenic acid (CLNA) production in Lactobacillus plantarum ZS2058, a high CLNA producer. METHODS AND RESULTS: After culturing with α-linolenic acid (ALA) in the medium, the fatty acid compositions of supernatant fluid and cell pellets were analysed via GC-MS. cis9,trans11,cis15-CLNA was identified to be the predominant isomer. And during CLNA production, 10-hydroxy-cis12-cis15-octadecenoic acid (10-HOEA) and 10-oxo-cis12-cis15-octadecenoic acid (10-OXOA) were accumulated. The E. coli recombinants harbouring genes encoding myosin-cross-reactive antigen (MCRA), short-chain dehydrogenase/oxidoreductase (DH) and acetoacetate decarboxylase (DC), respectively, were analysed for their roles in CLNA production. The results indicated that MCRA converted ALA to 10-HOEA, following converted to 10-OXOA by DH. While with the combination of three recombinants, ALA could be transformed into CLNA plus 10-HOEA and 10-OXOA. When the three genes were deleted, none of the L. plantarum ZS2058 knockout mutants could produce any CLNA, after complementation, and all the complementary mutants recovered the CLNA-production ability at similar levels as the wild strain. CONCLUSIONS: Lactobacillus plantarum ZS2058 produced CLNA from ALA with 10-HOEA and 10-OXOA as intermediates. The triple-component isomerase of MCRA, DH and DC was the unique genetic determinant for CLNA generation. SIGNIFICANCE AND IMPACT OF THE STUDY: The current results firstly provided conclusive evidence that the triple-component isomerase complex was shared by both CLA and CLNA production in lactobacilli.


Assuntos
Lactobacillus plantarum/genética , Lactobacillus plantarum/metabolismo , Ácidos Linoleicos Conjugados/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/genética , Ácidos Graxos/análise , Isomerases/genética , Isomerases/metabolismo , Ácidos Linoleicos Conjugados/química , Complexos Multienzimáticos , Ácidos Oleicos/química , Ácidos Oleicos/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ácido alfa-Linoleico/metabolismo
5.
J Dairy Sci ; 103(1): 368-378, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733843

RESUMO

Isotopic tracers are used to directly quantify the effect of mammary Δ9-desaturation on milk fatty acid (FA) composition, but very few studies have applied this method to measuring the endogenous synthesis of rumenic acid (RA; cis-9,trans-11 conjugated linoleic acid) in cows and goats, and no publications exist in ewes. In sheep, knowledge about the contribution of stearoyl-coenzyme A desaturase (SCD) to milk FA secretion is derived mostly from indirect estimates based on inhibition of the enzyme by oral administration of cobalt, a cost-effective method that has not been validated to date. To fill both gaps, we conducted an isotopic tracer assay in sheep to quantify the proportion of endogenous RA in milk for the first time in this species. We then compared the results with estimates derived from a Co administration assay performed on the same animals. First, 5 lactating ewes received an intravenous injection of 200 mg of [1-13C]trans-11 18:1 (vaccenic acid, VA), the precursor for RA production by SCD activity. At -24, -15, 0, 9, 24, 33, 48, 57, 72, 81, and 96 h post-injection, we recorded milk yield and collected milk samples to examine fat concentration and FA profile. We conducted compound-specific isotope analysis of VA and RA by gas chromatography-combustion isotope ratio mass spectrometry. Afterward, in the Co administration assay, ewes received a daily dose of 7 mg of Co/kg of body weight for 5 d. We analyzed milk samples for composition before and on the last days of cobalt dosing. On average, 17% of the injected amount of [1-13C]VA was transferred to milk within 96 h post-injection, and up to 29% of the VA taken up by the mammary gland was desaturated to milk RA. Under our conditions, the mean proportion of this conjugated linoleic acid isomer deriving from Δ9-desaturation represented 82 to 90% of the amount secreted in milk. However, the proportion estimated in the Co assay with calculations based on individual FA concentrations was lower (on average, 46%). When we calculated the same estimates based on changes in Δ9-desaturation ratios after Co dosing, the higher values of endogenous RA (75%) did not differ from the results of the isotopic tracer assay. Nevertheless, correlation analysis between the results obtained through [1-13C]VA or Co administration revealed no significant relationship, which would prevent acceptance of the latter as a reliable alternative to isotopic labeling to examine mammary Δ9-desaturation in dairy ewes.


Assuntos
Cobalto , Ácidos Linoleicos Conjugados/química , Leite/química , Ácidos Oleicos/metabolismo , Ovinos/fisiologia , Animais , Isótopos de Carbono , Cobalto/administração & dosagem , Feminino , Lactação/efeitos dos fármacos , Ácidos Linoleicos Conjugados/análise , Ácidos Linoleicos Conjugados/metabolismo , Ácidos Oleicos/química , Estearoil-CoA Dessaturase
6.
Molecules ; 25(1)2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31861351

RESUMO

Immunotherapies have emerged as promising complementary treatments for ovarian cancer (OC), but its effective and direct role on OC cells is unclear. This study examined the combinatory effects of the protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride, known as P-MAPA, and the human recombinant interleukin-12 (hrIL-12) on cell migration/invasion, apoptosis, toll-like receptor (TLR)-mediated inflammation, and cytokine/chemokine profile in human OC cell line SKOV-3. P-MAPA and IL-12 showed cancer cell toxicity under low doses after 48 h. Although apoptosis/necrosis and the cell cycle were unchanged by the treatments, P-MAPA enhanced the sensitivity to paclitaxel (PTX) and P-MAPA associated with IL-12 significantly reduced the migratory potential and invasion capacity of SKOV-3 cells. P-MAPA therapy reduced TLR2 immunostaining and the myeloid differentiation factor 88 (MyD88), but not the TLR4 levels. Moreover, the combination of P-MAPA with IL-12 attenuated the levels of MyD88, interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-kB p65). The IL-12 levels were increased and P-MAPA stimulated the secretion of cytokines IL-3, IL-9, IL-10, and chemokines MDC/CCL22 and, regulated on activation, normal T cells expressed and secreted (RANTES)/CCL5. Conversely, combination therapy reduced the levels of IL-3, IL-9, IL-10, MDC/CCL22, and RANTES/CCL5. Collectively, P-MAPA and IL-12 reduce cell dynamics and effectively target the TLR-related downstream molecules, eliciting a protective effect against chemoresistance. P-MAPA also stimulates the secretion of anti-inflammatory molecules, possibly having an immune response in the OC microenvironment.


Assuntos
Mediadores da Inflamação/metabolismo , Interleucina-12/metabolismo , Ácidos Linoleicos/metabolismo , Ácidos Oleicos/metabolismo , Neoplasias Ovarianas/metabolismo , Receptores Toll-Like/metabolismo , Apoptose , Movimento Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Humanos , Imunofenotipagem , Modelos Biológicos , Neoplasias Ovarianas/etiologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Transdução de Sinais/efeitos dos fármacos
7.
Proc Natl Acad Sci U S A ; 116(49): 24770-24778, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31740614

RESUMO

Fatty acid amide hydrolase (FAAH) degrades 2 major classes of bioactive fatty acid amides, the N-acylethanolamines (NAEs) and N-acyl taurines (NATs), in central and peripheral tissues. A functional polymorphism in the human FAAH gene is linked to obesity and mice lacking FAAH show altered metabolic states, but whether these phenotypes are caused by elevations in NAEs or NATs is unknown. To overcome the problem of concurrent elevation of NAEs and NATs caused by genetic or pharmacological disruption of FAAH in vivo, we developed an engineered mouse model harboring a single-amino acid substitution in FAAH (S268D) that selectively disrupts NAT, but not NAE, hydrolytic activity. The FAAH-S268D mice accordingly show substantial elevations in NATs without alterations in NAE content, a unique metabolic profile that correlates with heightened insulin sensitivity and GLP-1 secretion. We also show that N-oleoyl taurine (C18:1 NAT), the most abundant NAT in human plasma, decreases food intake, improves glucose tolerance, and stimulates GPR119-dependent GLP-1 and glucagon secretion in mice. Together, these data suggest that NATs act as a class of lipid messengers that improve postprandial glucose regulation and may have potential as investigational metabolites to modify metabolic disease.


Assuntos
Amidoidrolases/genética , Glicemia/metabolismo , Síndrome Metabólica/metabolismo , Ácidos Oleicos/metabolismo , Taurina/análogos & derivados , Amidoidrolases/metabolismo , Substituição de Aminoácidos , Animais , Glicemia/análise , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Etanolaminas/sangue , Etanolaminas/metabolismo , Feminino , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Teste de Tolerância a Glucose , Humanos , Injeções Intravenosas , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/sangue , Período Pós-Prandial/efeitos dos fármacos , Período Pós-Prandial/fisiologia , Receptores Acoplados a Proteínas-G/metabolismo , Taurina/administração & dosagem , Taurina/sangue , Taurina/metabolismo
8.
Am J Physiol Endocrinol Metab ; 317(6): E1094-E1107, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31638854

RESUMO

Clinical and animal studies have reported an association between low birth weight and the development of nonalcoholic fatty liver disease (NAFLD) in offspring. Using a model of prenatal maternal 70% food restriction diet (FR30) in the rat, we previously showed that maternal undernutrition predisposes offspring to altered lipid metabolism in adipose tissue, especially on a high-fat (HF) diet. Here, using microarray-based expression profiling combined with metabolic, endocrine, biochemical, histological, and lipidomic approaches, we assessed whether FR30 procedure sensitizes adult male offspring to impaired lipid metabolism in the liver. No obvious differences were noted in the concentrations of triglycerides, cholesterol, and bile acids in the liver of 4-mo-old FR30 rats whichever postweaning diet was used. However, several clues suggest that offspring's lipid metabolism and steatosis are modified by maternal undernutrition. First, lipid composition was changed (i.e., higher total saturated fatty acids and lower elaidic acid) in the liver, whereas larger triglyceride droplets were observed in hepatocytes of undernourished rats. Second, FR30 offspring exhibited long-term impact on hepatic gene expression and lipid metabolism pathways on a chow diet. Although the transcriptome profile was globally modified by maternal undernutrition, cholesterol and bile acid biosynthesis pathways appear to be key targets, indicating that FR30 animals were predisposed to impaired hepatic cholesterol metabolism. Third, the FR30 protocol markedly modifies hepatic gene transcription profiles in undernourished offspring in response to postweaning HF. Overall, FR30 offspring may exhibit impaired metabolic flexibility, which does not enable them to properly cope with postweaning nutritional challenges influencing the development of nonalcoholic fatty liver.


Assuntos
Fígado Gorduroso/genética , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Desnutrição , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Gotículas Lipídicas/patologia , Fígado/patologia , Masculino , Ácidos Oleicos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Ratos , Triglicerídeos/metabolismo
9.
J Agric Food Chem ; 67(41): 11420-11427, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31545039

RESUMO

Experimental and clinical findings suggest that olive oil has a protective effect, whereas oleic acid consumption induces colorectal cancer (CRC). Considering this apparent contradiction and that olive oil is a complex mix of fatty acids, mainly oleic acid and minor compounds such as phenolic compounds, lignans, hydrocarbons, and triterpenes, we study its effects on intestinal epithelial cell growth. Our results show that oleic acid (1-100 µM) but not elaidic acid induced DNA synthesis and Caco-2 cell growth (2-fold higher than cells without growth factors, p < 0.05). These effects were inhibited by 5-lipoxygenase inhibitors as well as the leukotriene antagonist (p < 0.05), suggesting the implication of this pathway in this mitogenic action. Hydroxytyrosol, oleuropein, pinoresinol, squalene, and maslinic acid (0.1-10 µM) reverted DNA synthesis and Caco-2 cell growth induced by oleic acid. These effects were not the consequence of the cell cycle arrest or the impairment of cell viability with the exception of hydroxytyrosol and maslinic acid that induced cell detachment and apoptosis (35.6 ± 2.3 and 43.2 ± 2.4%, respectively) at the higher concentration assayed. Oleuropein effects can be related with hydroxytyrosol release as a consequence of oleuropein hydrolysis by Caco-2 cells (up to 25%). Furthermore, hydroxytyrosol modulates the arachidonic acid cascade, and this event can be associated with its antimitogenic action. In conclusion, oleic acid and oleic acid in the presence of olive oil representative minor components have opposite effects, suggesting that the consumption of seed oils, high oleic acid seed oils, or olive oil will probably have different effects on CRC.


Assuntos
Neoplasias do Colo/fisiopatologia , Mitógenos/metabolismo , Ácido Oleico/metabolismo , Azeite de Oliva/metabolismo , Apoptose , Células CACO-2 , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Neoplasias do Colo/dietoterapia , Neoplasias do Colo/metabolismo , Humanos , Ácido Oleico/química , Ácidos Oleicos/química , Ácidos Oleicos/metabolismo , Azeite de Oliva/química
10.
Nat Commun ; 10(1): 4007, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488836

RESUMO

Gut microbiota mediates the effects of diet, thereby modifying host metabolism and the incidence of metabolic disorders. Increased consumption of omega-6 polyunsaturated fatty acid (PUFA) that is abundant in Western diet contributes to obesity and related diseases. Although gut-microbiota-related metabolic pathways of dietary PUFAs were recently elucidated, the effects on host physiological function remain unclear. Here, we demonstrate that gut microbiota confers host resistance to high-fat diet (HFD)-induced obesity by modulating dietary PUFAs metabolism. Supplementation of 10-hydroxy-cis-12-octadecenoic acid (HYA), an initial linoleic acid-related gut-microbial metabolite, attenuates HFD-induced obesity in mice without eliciting arachidonic acid-mediated adipose inflammation and by improving metabolic condition via free fatty acid receptors. Moreover, Lactobacillus-colonized mice show similar effects with elevated HYA levels. Our findings illustrate the interplay between gut microbiota and host energy metabolism via the metabolites of dietary omega-6-FAs thereby shedding light on the prevention and treatment of metabolic disorders by targeting gut microbial metabolites.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Gorduras Insaturadas na Dieta/uso terapêutico , Ácidos Graxos Insaturados/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/metabolismo , Tecido Adiposo/patologia , Animais , Linhagem Celular , Dieta Ocidental , Suplementos Nutricionais , Metabolismo Energético , Ácidos Graxos Ômega-6/metabolismo , Ácidos Graxos Ômega-6/uso terapêutico , Ácidos Graxos Insaturados/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/metabolismo , Lactobacillus/metabolismo , Ácido Linoleico/metabolismo , Doenças Metabólicas/dietoterapia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Ácidos Oleicos/metabolismo
11.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261727

RESUMO

Flexibility in carbon metabolism is pivotal for the survival and propagation of many human fungal pathogens within host niches. Indeed, flexible carbon assimilation enhances pathogenicity and affects the immunogenicity of Candida albicans. Over the last decade, Candida glabrata has emerged as one of the most common and problematic causes of invasive candidiasis. Despite this, the links between carbon metabolism, fitness, and pathogenicity in C. glabrata are largely unexplored. Therefore, this study has investigated the impact of alternative carbon metabolism on the fitness and pathogenic attributes of C. glabrata. We confirm our previous observation that growth on carbon sources other than glucose, namely acetate, lactate, ethanol, or oleate, attenuates both the planktonic and biofilm growth of C. glabrata, but that biofilms are not significantly affected by growth on glycerol. We extend this by showing that C. glabrata cells grown on these alternative carbon sources undergo cell wall remodeling, which reduces the thickness of their ß-glucan and chitin inner layer while increasing their outer mannan layer. Furthermore, alternative carbon sources modulated the oxidative stress resistance of C. glabrata as well as the resistance of C. glabrata to an antifungal drug. In short, key fitness and pathogenic attributes of C. glabrata are shown to be dependent on carbon source. This reaffirms the perspective that the nature of the carbon sources available within specific host niches is crucial for C. glabrata pathogenicity during infection.


Assuntos
Biofilmes , Candida glabrata/metabolismo , Metabolismo dos Carboidratos , Parede Celular/metabolismo , Farmacorresistência Fúngica , Estresse Oxidativo , Acetatos/metabolismo , Candida glabrata/efeitos dos fármacos , Candida glabrata/fisiologia , Parede Celular/ultraestrutura , Etanol/metabolismo , Ácido Láctico/metabolismo , Ácidos Oleicos/metabolismo
12.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(11): 1563-1579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31301433

RESUMO

BACKGROUND: The discovery of N­acylethanolamines (NAEs) has prompted an increase in research aimed at understanding their biological roles including regulation of appetite and energy metabolism. However, a knowledge gap remains to understand the effect of dietary components on NAE levels, in particular, heterogeneity in dietary fatty acid (DFA) profile, on NAE levels across various organs. OBJECTIVE: To identify and elucidate the impact of diet on NAE levels in seven different tissues/organs of male hamsters, with the hypothesis that DFA will act as precursors for NAE synthesis in golden Syrian male hamsters. METHOD: A two-month feeding trial was performed, wherein hamsters were fed various dietary oil blends with different composition of 18-C fatty acid (FA). RESULTS: DFA directly influences tissue FA and NAE levels. After C18:1n9-enriched dietary treatments, marked increases were observed in duodenal C18:1n9 and oleoylethanolamide (OEA) concentrations. Among all tissues; adipose tissue brown, adipose tissue white, brain, heart, intestine-duodenum, intestine-jejunum, and liver, a negative correlation was observed between gut-brain OEA concentrations and body weight. CONCLUSION: DFA composition influences FA and NAE levels across all tissues, leading to significant shifts in intestinal-brain OEA concentrations. The endogenously synthesized increased OEA levels in these tissues enable the gut-brain-interrelationship. Henceforth, we summarize that the brain transmits anorexic properties mediated via neuronal signalling, which may contribute to the maintenance of healthy body weight. Thus, the benefits of OEA can be enhanced by the inclusion of C18:1n9-enriched diets, pointing to the possible nutritional use of this naturally occurring bioactive lipid-amide in the management of obesity.


Assuntos
Gorduras na Dieta/metabolismo , Etanolaminas/metabolismo , Ácidos Graxos/metabolismo , Acilação , Tecido Adiposo/metabolismo , Ração Animal/análise , Animais , Encéfalo/metabolismo , Cricetinae/sangue , Cricetinae/metabolismo , Endocanabinoides/análise , Endocanabinoides/sangue , Endocanabinoides/metabolismo , Metabolismo Energético , Etanolaminas/análise , Etanolaminas/sangue , Ácidos Graxos/análise , Ácidos Graxos/sangue , Mucosa Intestinal/metabolismo , Masculino , Mesocricetus , Miocárdio/metabolismo , Ácidos Oleicos/análise , Ácidos Oleicos/sangue , Ácidos Oleicos/metabolismo
13.
J Agric Food Chem ; 67(29): 8191-8196, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31282662

RESUMO

Conversion of free fatty acids into monoacylglycerol gives rise to new structural properties, particularly amphipathic property. Therefore, monoacylglycerols are widely used in pharmaceutical and food industries and are also reported to facilitate better absorption into the human body. A functional fatty acid when transformed into a monoacylglycerol will possibly conserve both the original functionality and amphipathic property. The compound 7,10-dihydroxy-8(E)-octadecenoic acid (DOD) was generated from oleic acid by Pseudomonas aeruginosa PR3 and was known to contain antimicrobial activities against a broad range of food-borne and plant pathogenic bacteria. Here, we attempted to convert DOD into its monoacylglycerol form using lipase for producing an amphipathic antibacterial agent. Consequently, the monoacylglycerol of DOD (DOD-MAG) was successfully produced by coincubating DOD, glycerol, and lipase at 30 °C. The maximum conversion yield reached 70% after 12 h of incubation. Antibacterial activity of DOD-MAG was enhanced by 8 times from the original activity of DOD against food-borne bacteria.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Monoglicerídeos/química , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Pseudomonas aeruginosa/química , Antibacterianos/metabolismo , Microbiologia de Alimentos , Ácidos Oleicos/metabolismo , Pseudomonas aeruginosa/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
14.
Can J Physiol Pharmacol ; 97(11): 1035-1041, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31283890

RESUMO

The cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats.


Assuntos
Acetaminofen/farmacologia , Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Dipirona/farmacologia , Endocanabinoides/metabolismo , Etanolaminas/metabolismo , Ácidos Oleicos/metabolismo , Ácidos Palmíticos/metabolismo , Medula Espinal/efeitos dos fármacos , Acetaminofen/administração & dosagem , Analgésicos/administração & dosagem , Animais , Encéfalo/metabolismo , Encéfalo/fisiologia , Dipirona/administração & dosagem , Masculino , Nociceptividade/efeitos dos fármacos , Ratos Wistar , Medula Espinal/metabolismo , Medula Espinal/fisiologia
15.
J Colloid Interface Sci ; 553: 820-833, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284226

RESUMO

Despite increasing interests in non-lamellar liquid crystalline dispersions, such as hexosomes, for drug delivery, little is known about their interactions with cells and mechanism of cell entry. Here we examine the cellular uptake of hexosomes based on phytantriol and mannide monooleate by HeLa cells using live cell microscopy in comparison to conventional liposomes. To investigate the importance of specific endocytosis pathways upon particle internalization, we silenced regulatory proteins of major endocytosis pathways using short interfering RNA. While endocytosis plays a significant role in liposome internalization, hexosomes are not taken up via endocytosis but through a mechanism that is dependent on cell membrane tension. Biophysical studies using biomembrane models highlighted that hexosomes have a high affinity for membranes and an ability to disrupt lipid layers. Our data suggest that direct biomechanical interactions of hexosomes with membrane lipids play a crucial role and that the unique morphology of hexosomes is vital for their membrane activity. Based on these results, we propose a mechanism, where hexosomes destabilize the bilayer, allowing them to "phase through" the membrane. Understanding parameters that influence the uptake of hexosomes is critical to establish them as carrier systems that can potentially deliver therapeutics efficiently to intracellular sites of action.


Assuntos
Coloides/metabolismo , Endocitose , Álcoois Graxos/metabolismo , Transporte Biológico , Coloides/síntese química , Coloides/química , Sistemas de Liberação de Medicamentos , Álcoois Graxos/síntese química , Álcoois Graxos/química , Células HeLa , Humanos , Lipossomos/química , Manitol/análogos & derivados , Manitol/síntese química , Manitol/química , Manitol/metabolismo , Ácidos Oleicos/síntese química , Ácidos Oleicos/química , Ácidos Oleicos/metabolismo
16.
Appl Microbiol Biotechnol ; 103(17): 7151-7160, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31250059

RESUMO

10-hydroxy-cis-12 octadecenoic acid (10-HOE) is a type of octadecenoic acid with a hydroxyl on the C10 carbon. It is generated from linoleic acid (LA) catalyzed by linoleate hydratase in lactobacilli, which was initially named as myosin-cross-reactive antigen (MCRA). In lactobacilli, 10-HOE is the first intermediate in the production of conjugated LA (CLA). Although MCRA from bifidobacteria can generate 10-HOE, the precise role of 10-HOE in CLA production in bifidobacteria remains unknown. In the current work, 10-HOE and LA were added to the medium as the substrate both separately and synchronously to analyze their influence on CLA production. Using 10-HOE as the substrate, bifidobacteria were able to generate CLA by first converting it to LA, followed by CLA accumulation. Recombinant MCRA catalyzed the conversion of 10-HOE to LA, indicating that bifidobacterial MCRA can account for the reversible conversion between LA and 10-HOE. This is the first report to demonstrate the precise role of 10-HOE in the process of CLA production among bifidobacteria.


Assuntos
Bifidobacterium/metabolismo , Ácido Linoleico/metabolismo , Ácidos Oleicos/metabolismo , Proteínas de Bactérias/metabolismo , Bifidobacterium/enzimologia , Biotransformação , Hidroliases/metabolismo , Ácidos Linoleicos Conjugados/metabolismo , Especificidade da Espécie
17.
Psychopharmacology (Berl) ; 236(9): 2623-2633, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30993360

RESUMO

RATIONALE: Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice. OBJECTIVES AND METHODS: Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague-Dawley rats. RESULTS: Synthetic OlGly (1-30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm. This effect was reversed by the cannabinoid 1 (CB1) receptor antagonist, AM251 (1 mg/kg, ip), but not the PPARα antagonist, MK886 (1 mg/kg, ip). OlGly (5 or 30 mg/kg, ip) did not interfere with a morphine-induced place preference or reinstatement of a previously extinguished morphine-induced place preference. Ex vivo analysis of tissue (nucleus accumbens, amygdala, prefrontal cortex, and interoceptive insular cortex) collected from rats experiencing naloxone-precipitated MWD revealed that OlGly was selectively elevated in the nucleus accumbens. MWD did not modify levels of the endocannabinoids 2-AG and AEA, nor those of the PPARα ligands, OEA and PEA, in any region evaluated. CONCLUSION: Here, we show that OlGly interferes with the aversive properties of acute naloxone-precipitated morphine withdrawal in rats. These results suggest that OlGly may reduce the impact of MWD and may possess efficacy in treating opiate withdrawal.


Assuntos
Analgésicos Opioides/efeitos adversos , Glicina/análogos & derivados , Morfina/efeitos adversos , Naloxona/toxicidade , Ácidos Oleicos/administração & dosagem , Recompensa , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Relação Dose-Resposta a Droga , Glicina/administração & dosagem , Glicina/metabolismo , Masculino , Camundongos , Antagonistas de Entorpecentes/toxicidade , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ácidos Oleicos/metabolismo , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologia
18.
Neuropharmacology ; 149: 212-220, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30822499

RESUMO

Oleoylethanolamide (OEA) is a non-cannabinoid acylethanolamide with multiple physiological roles that has been proposed to have antidepressant-like activity in preclinical models. OEA shares biosynthetic pathways with anandamide (AEA) a transmitter involved in affective disorders and anxiety in humans. However, although the participation of OEA in depression has been proposed, both, the contribution of OEA to the depressive phenotype and the effect of antidepressant therapy on circulating levels of this and related non-cannabinoid acylethanolamides in humans are basically unknown. The main objective of this study is to compare the plasma concentrations of OEA and related acylethanolamides in a sample of primary care patients with depression (n = 69) with those of healthy non-depressed patients (n = 47). At the time of admission to the study, 22 patients were under selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and 47 patients were not receiving any type of intervention. In addition, plasma concentrations of the endocannabinoid 2-AG and two related monoacylglycerols were monitored. Plasma OEA concentrations were found to be elevated in depressed patients and to correlate with somatic symptoms of depression. Plasma concentrations of both, AEA and 2-AG, were found to be elevated also in depressed patients. Further analysis demonstrated that the elevation observed in the plasma concentrations of both, OEA and 2-AG, was associated to SSRI antidepressant therapy at the time of recruitment. Further clinical research is needed to understand whether SSRI-induced elevations in OEA levels contribute to the response to SSRI in depressed patients as described in preclinical models.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Endocanabinoides/sangue , Ácidos Oleicos/sangue , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Antidepressivos/metabolismo , Antidepressivos/farmacologia , Ácidos Araquidônicos/sangue , Depressão/metabolismo , Endocanabinoides/metabolismo , Etanolaminas/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Monoglicerídeos/sangue , Ácidos Oleicos/metabolismo , Alcamidas Poli-Insaturadas/sangue , Atenção Primária à Saúde , Inibidores de Captação de Serotonina/metabolismo , Inibidores de Captação de Serotonina/farmacologia
19.
Med Sci Monit Basic Res ; 25: 76-87, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30842391

RESUMO

BACKGROUND The aim of this study was to determine if components of the endocannabinoid system are modulated in uterine leiomyomas (fibroids). Components studied included cannabinoid receptors 1 (CB1) and 2 (CB2); the G protein-coupled receptor GPR55; transient potential vanilloid receptor 1 (TRPV1) and the endocannabinoid modulating enzymes N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and their N-acylethanolamine (NAE) ligands: N-arachidonylethanolamine (AEA), N-oleoylethanolamine (OEA), and N-palmityolethanaolamine (PEA). MATERIAL AND METHODS Transcript levels of CB1, CB2, TRPV1, GPR55, NAPE-PLD, and FAAH were measured using RT-PCR and correlated with the tissue levels of the 3 NAEs in myometrial tissues. The tissues studied were: 1) fibroids, 2) myometrium adjacent/juxtaposed to the fibroid lesions, and 3) normal myometrium. Thirty-seven samples were processed for NAE measurements and 28 samples were used for RT-PCR analyses. RESULTS FAAH expression was significantly lower in fibroids, resulting in a NAPE-PLD: FAAH ratio that favors higher AEA levels in pre-menopausal tissues, whilst PEA levels were significantly lower, particularly in post-menopausal women, suggesting PEA protects against fibroid pathogenesis. The CB1: CB2 ratio was lower in fibroids, suggesting that loss of CB1 expression affects the fibroid cell phenotype. Significant correlations between reduced FAAH, CB1, and GPR55 expression and PEA in fibroids indicate that the loss of these endocannabinoid system components are biomarkers of leiomyomata. CONCLUSIONS Loss of expression of CB1, FAAH, GPR55, and PEA production are linked to the pathogenesis of uterine fibroids and further understanding of this might eventually lead to better disease indicators or the development of therapeutic potentials that might eventually be used in the management of uterine fibroids.


Assuntos
Endocanabinoides/metabolismo , Leiomioma/metabolismo , Leiomioma/fisiopatologia , Adulto , Idoso , Amidoidrolases/análise , Biópsia , Etanolaminas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Pessoa de Meia-Idade , Ácidos Oleicos/metabolismo , Fosfolipase D/análise , Receptor CB1 de Canabinoide/análise , Receptor CB2 de Canabinoide/análise , Receptores Acoplados a Proteínas-G/análise , Canais de Cátion TRPV/análise , Útero/fisiopatologia
20.
Nature ; 566(7744): 403-406, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728499

RESUMO

Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.


Assuntos
Ácidos Graxos/química , Ácidos Graxos/metabolismo , Redes e Vias Metabólicas , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Proliferação de Células , Ácidos Graxos Dessaturases/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Ácidos Oleicos/metabolismo , Palmitatos/metabolismo , Ácidos Palmíticos/metabolismo , Estearoil-CoA Dessaturase/metabolismo
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