RESUMO
The fraction of nitric oxide in exhaled gas (FENO) is decreased after exposure to hyperoxia in vivo, although the mechanisms for this decrease is not clear. A key co-factor for nitric oxide synthase (NOS), tetrahydrobiopterin (BH4), has been shown to be oxidized in vitro when exposed to hyperoxia. We hypothesized that the decrease of FENO is due to decreased enzymatic generation of NO due to oxidation of BH4. The present study was performed to investigate the relationship between levels of FENO and plasma BH4 following hyperoxic exposure in humans. Two groups of healthy subjects were exposed to 100% oxygen for 90 minutes. FENO was measured before and 10 minutes (n = 13) or 60 minutes (n = 14) after the exposure. Blood samples were collected at the same time points for quantification of biopterin levels (BH4, BH2 and B) using LC-MS/MS. Each subject was his or her own control, breathing air for 90 minutes on a separate day. Hyperoxia resulted in a 28.6 % decrease in FENO 10 minutes after exposure (p < 0.001), confirming previous findings. Moreover, hyperoxia also caused a 14.2% decrease in plasma BH4 (p = 0.012). No significant differences were observed in the group measured 60 minutes after exposure. No significant correlation was found between the changes in FENO and BH4 after the hyperoxic exposure (r = 0.052, p = 0.795), this might be due to the recovery of BH4 being faster than the recovery of FENO.
Assuntos
Biopterinas/análogos & derivados , Hiperóxia/metabolismo , Óxido Nítrico/análise , Pressão Atmosférica , Biopterinas/sangue , Expiração , Feminino , Voluntários Saudáveis , Humanos , Masculino , Oxirredução , Oxigênio/administração & dosagem , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVES: Polycystic ovary syndrome (PCOS) is associated with an increased cardiometabolic risk that might not necessarily translate into adverse cardiovascular outcome later in life. Recently, alterations in gut microbial composition have been reported in the syndrome. Microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and its precursors are closely linked with development of atherosclerotic cardiovascular disease, independently of traditional risk factors. We aimed to assess whether TMAO and its precursors are altered in PCOS and to determine potential impact of treatment on these metabolites. DESIGN: Prospective study. PATIENTS: Twenty-seven overweight/obese patients with PCOS and 25 age- and BMI-matched healthy control women. MEASUREMENTS: At baseline, fasting serum TMAO and its precursors were measured after a 3-day standardized diet. Patients received 3-month OC therapy along with general dietary advice after which all measurements were repeated. RESULTS: Patients had higher total testosterone (T) and free androgen index (FAI) whereas whole-body fat mass, fasting plasma glucose, insulin and lipids were similar between the groups. PCOS group showed significantly higher serum levels of TMAO and its precursors; choline, betaine and carnitine. TMAO and choline showed correlations with T. After 3 months of OC use, TMAO and its precursors significantly decreased along with reductions in BMI, T and FAI. CONCLUSIONS: This study reports for the first time that TMAO and its precursors are elevated in PCOS which might contribute to increased cardiometabolic risk of the syndrome and that short-term OC use along with lifestyle intervention is associated with reduction of these microbiome-dependent metabolites.
Assuntos
Doenças Cardiovasculares/sangue , Microbioma Gastrointestinal/fisiologia , Metilaminas/sangue , Síndrome do Ovário Policístico/sangue , Adolescente , Adulto , Betaína/análogos & derivados , Betaína/sangue , Glicemia/metabolismo , Carnitina/sangue , Colina/sangue , Feminino , Humanos , Obesidade/sangue , Estudos Prospectivos , Fatores de Risco , Testosterona/sangue , Adulto JovemRESUMO
Purpose: Nitric oxide (NO) has been shown to protect against bubble formation and the risk of decompression sickness. We hypothesize that oxidation of tetrahydrobiopterin (BH4) leads to a decreased production of NO during simulated diving. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to hyperoxia or simulated diving for 24 hours. The levels of biopterins (BH4, BH2 and B) were determined by LC-MS/MS, and the production of NO by monitoring the conversion of L-arginine to L-citrulline. Results: Exposure to hyperoxia decreased BH4 in a dose-dependent manner; by 48 ± 15% following exposure to 40 kPa O2 (P⟨0.001 vs. control at 20 kPa O2), and 70 ± 16% following exposure to 60 kPa O2. Exposure to 40 kPa O2 decreased NO production by 25 ± 9%, but there was no further decrease when increasing oxygen exposure to 60 kPa (25 ± 10%). No additional effects of simulated diving were observed, indicating no additive or synergistic effects of hyperbaria and hyperoxia on the BH4 level or NO generation. Conclusion: NO generation in intact human endothelial cells was decreased by simulated diving, as well as by hyperoxic exposure, while BH4 levels seem to be affected only by hyperoxia. Hence, the results suggest that BH4 is not the sole determinant of NO generation in HUVEC.
Assuntos
Biopterinas/análogos & derivados , Mergulho , Endotélio Vascular/metabolismo , Óxido Nítrico/biossíntese , Arginina/metabolismo , Biopterinas/metabolismo , Citrulina/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperóxia/metabolismo , Óxido Nítrico Sintase/metabolismo , Oxirredução , Pressão/efeitos adversos , Fatores de TempoRESUMO
Hepatic mitochondrial function, APOC-III, and LPL are potential targets for triglyceride (TG)-lowering drugs. After 3 weeks of dietary treatment with the compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), the hepatic mitochondrial FA oxidation increased more than 5-fold in male Wistar rats. Gene expression analysis in liver showed significant downregulation of APOC-III and upregulation of LPL and the VLDL receptor. This led to lower hepatic (53%) and plasma (73%) TG levels. Concomitantly, liver-specific biomarkers related to mitochondrial biogenesis and function (mitochondrial DNA, citrate synthase activity, and cytochrome c and TFAM gene expression) were elevated. Interestingly, 1-triple TTA lowered plasma acetylcarnitine levels, whereas the concentration of ß-hydroxybutyrate was increased. The hepatic energy state was reduced in 1-triple TTA-treated rats, as reflected by increased AMP/ATP and decreased ATP/ADP ratios, whereas the energy state remained unchanged in muscle and heart. The 1-triple TTA administration induced gene expression of uncoupling protein (UCP)2 and UCP3 in liver. In conclusion, the 1-triple TTA-mediated clearance of blood TG may result from lowered APOC-III production, increased hepatic LPL gene expression, mitochondrial FA oxidation, and (re)uptake of VLDL facilitating drainage of FAs to the liver for ß-oxidation and production of ketone bodies as extrahepatic fuel. The possibility that UCP2 and UCP3 mediate a moderate degree of mitochondrial uncoupling should be considered.
Assuntos
Apolipoproteína C-III/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Proteínas de Desacoplamento Mitocondrial/metabolismo , Triglicerídeos/sangue , Ácido Acético/química , Ácido Acético/farmacologia , Acetilcarnitina/metabolismo , Animais , Carnitina/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Oxirredução , Ratos , Ratos Wistar , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Increased incidence of cardiovascular diseases (CVD) in both HIV infection and type 2 diabetes (T2D) compared to the general population has been described. Little is known about the combined effect of HIV infection and T2D on inflammation and endothelial function, both of which may contribute to elevated risk of CVD. METHODS: Cross-sectional study including 50 HIV-infected persons on combination anti-retroviral therapy (cART), with HIV RNA <200 copies/mL (n = 25 with T2D (HIV + T2D+), n = 25 without T2D (HIV + T2D-)) and 50 uninfected persons (n = 22 with T2D (HIV-T2D+) and n = 28 without T2D (HIV-T2D-)). Groups were matched on age and sex. High sensitive C-reactive protein (hsCRP) was used to determine inflammation (cut-off 3 mg/L). The marker of endothelial dysfunction asymmetric dimethylarginine (ADMA) was measured using high performance liquid chromatography. Trimethylamine-N-oxide (TMAO), a microbiota-dependent, pro-atherogenic marker was measured using stable isotope dilution LC/MS/MS. RESULTS: The percentage of HIV + T2D+, HIV + T2D-, HIV-T2D+, and HIV-T2D- with hsCRP above cut-off was 50%, 19%, 47%, and 11%, respectively. HIV + T2D+ had elevated ADMA (0.67 µM (0.63-0.72) compared to HIV + T2D- (0.60 µM (0.57-0.64) p = 0.017), HIV-T2D+ (0.57 µM (0.51-63) p = 0.008), and HIV-T2D- (0.55 µM (0.52-0.58) p < 0.001). No differences in TMAO between groups were found. However, a positive correlation between ADMA and TMAO was found in the total population (rs = 0.32, p = 0.001), which was mainly driven by a close correlation in HIV + T2D+ (rs = 0.63, p = 0.001). CONCLUSION: Elevated inflammation and evidence of endothelial dysfunction was found in HIV-infected persons with T2D. The effect on inflammation was mainly driven by T2D, while both HIV infection and T2D may contribute to endothelial dysfunction. Whether gut microbiota is a contributing factor to this remains to be determined.
Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Endotélio Vascular/fisiopatologia , Infecções por HIV/fisiopatologia , Inflamação/etiologia , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Masculino , Metilaminas/sangue , Pessoa de Meia-Idade , Fatores de Risco , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Carnitine plays an essential role in fatty acid metabolism, exerts substantial antioxidant action and regulates immune functions. We hypothesized that a disturbed carnitine metabolism could be involved in progression of HIV infection. MATERIALS AND METHODS: Plasma levels of L-carnitine, its precursors, and short-, medium- and long-chain acylcarnitines were analysed with HPLC/mass spectrometry in HIV-infected patients with various disease severities including patients who acquired Mycobacterium avium complex (MAC) infection. In vitro, we examined the MAC-purified protein derivate (PPD)-induced release of TNF-α and IFN-γ in peripheral blood mononuclear cells (PBMCs) from patients with either high or low plasma levels of acylcarnitines. RESULTS: Plasma levels of the short-chain (e.g. propionyl-carnitine) and medium-chain (e.g. octanoyl-carnitine) acylcarnitines were reduced in patients with advanced HIV infection. These acylcarnitines gradually decreased in rapid progressors, while minimal changes were observed in the nonprogressors. Plasma levels of propionyl-carnitine and octanoyl-carnitine significantly increased during antiretroviral therapy (ART). However, ART did not restore levels to those observed in healthy controls. Depletion of propionyl-carnitine and octanoyl-carnitine was observed prior to MAC infection, and the release of TNF-α and IFN-γ from PBMC was decreased after stimulation with MAC-PPD in samples from HIV-infected patients with low levels of propionyl-carnitine or octanoyl-carnitine. CONCLUSIONS: Our findings suggest an association between disturbed acylcarnitine metabolism, immune dysregulation and disease progression in HIV-infected patients. Low levels of propionyl-carnitine and octanoyl-carnitine were associated with increased susceptibility to MAC infection in HIV patients with advanced disease.
Assuntos
Carnitina/análogos & derivados , Carnitina/sangue , Infecções por HIV/sangue , Infecção por Mycobacterium avium-intracellulare/sangue , Adulto , Terapia Antirretroviral de Alta Atividade , Estudos de Casos e Controles , Progressão da Doença , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Interferon gama , Testes de Liberação de Interferon-gama , Estudos Longitudinais , Masculino , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/complicações , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: Hepatic mitochondrial dysfunction plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methyl donor supplementation has been shown to alleviate NAFLD, connecting the condition to the one-carbon metabolism. Thus, the objective was to investigate regulation of homocysteine (Hcy) and metabolites along the choline oxidation pathway during induction of hepatic steatosis by the fatty acid analogue tetradecylthiopropionic acid (TTP), an inhibitor of mitochondrial fatty acid oxidation. METHODS: Mice were fed a control diet, or diets containing 0.3 %, 0.6 %, or 0.9 % (w/w) TTP for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, lipid and fatty acid composition in liver and plasma, one-carbon metabolites, B-vitamin status, carnitine and acylcarnitines were analyzed in plasma. RESULTS: Liver mitochondrial fatty acid oxidation decreased by 40 % and steatosis was induced in a dose dependent manner; total lipids increased 1.6-fold in animals treated with 0.3 % TTP, 2-fold with 0.6 % TTP and 2.1 fold with 0.9 % TTP compared to control. The higher hepatic concentration of fatty acids was associated with shortening of carbon-length. Furthermore, the inhibited fatty acid oxidation led to a 30-fold decrease in plasma carnitine and 9.3-fold decrease in acetylcarnitine at the highest dose of TTP, whereas an accumulation of palmitoylcarnitine resulted. Compared to the control diet, TTP administration was associated with elevated plasma total Hcy (control: 7.2 ± 0.3 umol/L, 0.9 % TTP: 30.5 ± 5.9 umol/L) and 1.4-1.6 fold increase in the one-carbon metabolites betaine, dimethylglycine, sarcosine and glycine, accompanied by changes in gene expression of the different B-vitamin dependent pathways of Hcy and choline metabolism. A positive correlation between total Hcy and hepatic triacylglycerol resulted. CONCLUSIONS: The TTP-induced inhibition of mitochondrial fatty acid oxidation was not associated with increased hepatic oxidative stress or inflammation. Our data suggest a link between mitochondrial dysfunction and the methylation processes within the one-carbon metabolism in mice.
Assuntos
Fígado Gorduroso/induzido quimicamente , Homocisteína/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Propionatos/farmacologia , Sulfetos/farmacologia , Animais , Fígado Gorduroso/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
BACKGROUND: Amount and type of dietary protein have been shown to influence blood lipids. The present study aimed to evaluate the effects of a water-soluble fraction of chicken protein (CP) on plasma and hepatic lipid metabolism in normolipidemic rats. METHODS: Male Wistar rats were fed either a control diet with 20 % w/w casein as the protein source, or an experimental diet where casein was replaced with CP at 6, 14, or 20 % w/w for 4 weeks. RESULTS: Rats fed CP had markedly reduced levels of triacylglycerols (TAG) and cholesterol in both plasma and liver, accompanied by stimulated hepatic mitochondrial fatty acid oxidation and carnitine palmitoyltransferase 2 activity in the 20 % CP group compared to the control group. In addition, reduced activities and gene expression of hepatic enzymes involved in lipogenesis were observed. The gene expression of sterol regulatory element-binding transcription factor 1 was reduced in the 20 % CP-fed rats, whereas gene expression of peroxisome proliferator-activated receptor alpha was increased. Moreover, 6, 14, and 20 % CP-fed rats had significantly increased free carnitine and acylcarnitine plasma levels compared to control rats. The plasma methionine/glycine and lysine/arginine ratios were reduced in 20 % CP-treated rats. The mRNA level of ATP-binding cassette 4 was increased in the 20 % CP group, accompanied by the increased level of plasma bile acids. CONCLUSIONS: The present data suggest that the hypotriglyceridemic property of a water-soluble fraction of CP is primarily due to effects on TAG synthesis and mitochondrial fatty acid oxidation. The cholesterol-lowering effect by CP may be linked to increased bile acid formation.
Assuntos
Ácidos e Sais Biliares/metabolismo , Galinhas , Proteínas Alimentares/uso terapêutico , Suplementos Nutricionais , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos , Fígado/metabolismo , Aminoácidos/análise , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Caseínas/administração & dosagem , Colesterol/sangue , Colesterol/metabolismo , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/química , Suplementos Nutricionais/análise , Regulação Enzimológica da Expressão Gênica , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/prevenção & controle , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Fígado/enzimologia , Masculino , Produtos da Carne/análise , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Solubilidade , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
BACKGROUND: Lipid abnormalities, enhanced inflammation and oxidative stress seem to represent a vicious circle in atherogenesis, and therapeutic options directed against these processes seems like a reasonable approach in the management of atherosclerotic disorders. Krill oil (RIMFROST Sublime®) is a phospholipid-rich oil with eicosapentaenoic acid (EPA): docosahexaenoic acid (DHA) ratio of 1.8:1. In this pilot study we determined if krill oil could favourable affect plasma lipid parameters and parameters involved in the initiation and progression of atherosclerosis. METHODS: The study was conducted as a 28 days intervention study examining effect-parameters of dietary supplementation with krill oil (832.5 mg EPA and DHA per day). 17 healthy volunteers in the age group 18-36 (mean age 23 ± 4 years) participated. Plasma lipids, lipoprotein particle sizes, fatty acid composition in plasma and red blood cells (RBCs), plasma cytokines, antioxidant capacity, acylcarntines, carnitine, choline, betaine, and trimethylamine-N-oxide (TMAO) were measured before and after supplementation. RESULTS: Plasma triacylglycerol (TAG) and large very-low density lipoprotein (VLDL) & chylomicron particle concentrations decreased after 28 days of krill oil intake. A significant reduction in the TAG/HDL cholesterol resulted. Krill oil supplementation decreased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio both in plasma and RBCs. This was due to increased EPA, DHA and docosapentaenoic acid (DPA) and reduced amount of arachidonic acid (AA). The increase of n-3 fatty acids and wt % of EPA and DHA in RBC was of smaller magnitude than found in plasma. Krill oil intake increased the antioxidant capacity, double bond index (DBI) and the fatty acid anti-inflammatory index. The plasma atherogenicity index remained constant whereas the thrombogenicity index decreased. Plasma choline, betaine and the carnitine precursor, γ-butyrobetaine were increased after krill oil supplementation whereas the TMAO and carnitine concentrations remained unchanged. CONCLUSION: Krill oil consumption is considered health beneficial as it decreases cardiovascular disease risk parameters through effects on plasma TAGs, lipoprotein particles, fatty acid profile, redox status and possible inflammation. Noteworthy, no adverse effects on plasma levels of TMAO and carnitine were found.
Assuntos
Gorduras Insaturadas na Dieta/sangue , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Euphausiacea/química , Ácidos Graxos Insaturados/sangue , Adolescente , Adulto , Animais , Aterosclerose/sangue , Aterosclerose/prevenção & controle , Betaína/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Colina/sangue , Quilomícrons/sangue , Citocinas/sangue , Gorduras Insaturadas na Dieta/administração & dosagem , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Ácidos Graxos Insaturados/administração & dosagem , Feminino , Humanos , Lipoproteínas VLDL/sangue , Masculino , Metilaminas/sangue , Tamanho da Partícula , Projetos Piloto , Triglicerídeos/sangueRESUMO
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC's content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis.
Assuntos
Carnitina/sangue , Euphausiacea/química , Homocisteína/sangue , Metilaminas/sangue , Fosfolipídeos/química , Fosfolipídeos/farmacologia , Ração Animal/análise , Animais , Dieta , Proteínas Alimentares/farmacologia , Homocisteína/metabolismo , Masculino , Metionina/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Herring roe is an underutilized source of n-3 polyunsaturated fatty acids (PUFAs) for human consumption with high phospholipid (PL) content. Studies have shown that PL may improve bioavailability of n-3 PUFAs. Arctic Nutrition's herring roe product MOPL™30 is a PL: docosahexaenoic acid (DHA)-rich fish oil mixture, with a DHA:eicosapentaenoic acid (EPA) ratio of about 3:1, which is also rich in choline. In this pilot study, we determined if MOPL30 could favorably affect plasma lipid parameters and glucose tolerance in healthy young adults. METHODS: Twenty female and one male adults, between 22 and 26 years of age, participated in the study. Participants took encapsulated MOPL30, 2.4 g/d EPA + DHA, for 14 days, and completed a three-day weighed food record before and during the capsule intake. Plasma lipids and their fatty acid (FA) composition, plasma and red blood cell (RBC) phosphatidylcholine (PC) FA composition, acylcarnitines, choline, betaine and insulin were measured before and after supplementation (n = 21), and one and four weeks after discontinuation of supplementation (n = 14). An oral glucose tolerance test was performed before and after supplementation. RESULTS: Fasting plasma triacylglycerol and non-esterified fatty acids decreased and HDL-cholesterol increased after 14 days of MOPL30 intake (p < 0.05). The dietary records showed that PUFA intake prior to and during capsule intake was not different. Fasting plasma glucose was unchanged from before to after supplementation. However, during oral glucose tolerance testing, blood glucose at both 10 and 120 min was significantly lower after supplementation with MOPL30 compared to baseline measurements. Plasma free choline and betaine were increased, and the n-6/n-3 polyunsaturated (PUFA) ratio in plasma and RBC PC were decreased post-supplementation. Four weeks after discontinuation of MOPL30, most parameters had returned to baseline, but a delayed effect was observed on n-6 PUFAs. CONCLUSIONS: Herring roe rich in PL improved the plasma lipid profile and glycemic control in young adults with an overall healthy lifestyle.
Assuntos
Óleos de Peixe/administração & dosagem , Glucose/metabolismo , Fosfolipídeos/administração & dosagem , Adulto , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Peixes , Teste de Tolerância a Glucose , Humanos , Masculino , Triglicerídeos/sangue , Adulto JovemRESUMO
PURPOSE: Biological effects of marine oils, fish oil (FO) and krill oil (KO), are mostly attributed to the high content of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The study was aimed to investigate the influence of FO and KO on lipid homeostasis and inflammation in an animal model of persistent low-grade exposure to human tumor necrosis factor α (hTNF-α) and to evaluate whether these effects depend on the structural forms of EPA and DHA [triacylglycerols (TAG) vs. phospholipids]. METHODS: Male C57BL/6 hTNF-α mice were fed for 6 weeks a high-fat control diet (24.50 % total fats, w/w) or high-fat diets containing either FO or KO at similar doses of n-3 PUFAs (EPA: 5.23 vs. 5.39 wt%, DHA: 2.82 vs. 2.36 wt% of total fatty acids). RESULTS: We found that KO, containing bioactive n-3 PUFAs in the form of phospholipids, was capable of modulating lipid metabolism by lowering plasma levels of TAG and cholesterol and stimulating the mitochondrial and peroxisomal fatty acid ß-oxidation, as well as improving the overall carnitine turnover. Though the administration of FO was not as effective as KO in the lowering of plasma TAG, FO significantly improved the levels of all cholesterol classes in plasma. Except from the increase in the levels of IL-17 in FO-fed mice and a trend to decrease in MCP-1 levels in KO-fed animals, the levels of pro-inflammatory cytokines were not substantially different between treatment groups. CONCLUSION: Our findings demonstrate that FO and KO are comparable dietary sources of n-3 PUFAs. However, when quantitatively similar doses of n-3 PUFAs are administered, KO seems to have a greater potential to promote lipid catabolism. The effect of dietary oils on the levels of inflammatory markers in hTNF-α transgenic mice fed a high-fat diet needs further investigations.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Euphausiacea/química , Óleos de Peixe/uso terapêutico , Hipertrigliceridemia/prevenção & controle , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos , Óleos/uso terapêutico , Animais , Carnitina/sangue , Carnitina/metabolismo , Citocinas/metabolismo , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/sangue , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/imunologia , Fígado/imunologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfolipídeos/sangue , Fosfolipídeos/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: There is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα). METHODS: hTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma. RESULTS: The n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal ß-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice. CONCLUSIONS: The FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Carnitina/sangue , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Proteínas de Peixes/administração & dosagem , Fígado/efeitos dos fármacos , Ovário/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Carnitina/análogos & derivados , Caseínas/administração & dosagem , Doença Crônica , Dieta Hiperlipídica , Feminino , Proteínas de Peixes/química , Peixes/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/sangue , Inflamação/dietoterapia , Inflamação/genética , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Ovário/metabolismo , Proteólise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Nitric oxide (NO) seems to be related to bubble formation and endothelial dysfunction resulting in decompression sickness. Bubble formation can be affected by aerobic exercise or manipulating NO. A prior heat stress (HS) has been shown to confer protection against decompression sickness in rats. An important question was if the oxidative environment experienced during diving limits the availability of the nitric oxide synthase (NOS) cofactor tetrahydrobiopterin (BH4). Human endothelial cells were used to investigate how HS and simulated diving affected NO synthesis and defense systems such as heat shock protein 70 (HSP70) and glutathione (GSH). BH4 was measured using a novel LC-MS/MS method and NOS by monitoring the conversion of radiolabeled L-arginine to L-citrulline. Increased pO2 reduced BH4 levels in cells in a dose-dependent manner independently of high pressure. This effect may result in decreased generation of NO by NOS. The BH4 decrease seemed to be abolished when cells were exposed to HS prior to hyperoxia. NOS enzyme was unaffected by increased pO2 but substantially reduced after HS. The BH4 level seemed to a minor extent to be dependent upon GSH and probably to a higher degree dependent on other antioxidants such as ascorbic acid. A simulated dive at 60 kPa O2 had a potentiating effect on the heat-induced HSP70 expression, whereas GSH levels were unaffected by hyperoxic exposure. HS, hyperoxia, and dive affected several biochemical parameters that may play important roles in the mechanisms protecting against the adverse effects of saturation diving.
Assuntos
Biopterinas/análogos & derivados , Descompressão , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiperóxia/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Biopterinas/metabolismo , Glutationa/metabolismo , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Resposta ao Choque Térmico , Humanos , Hiperóxia/enzimologia , Óxido Nítrico/metabolismo , Oxigênio/metabolismoRESUMO
A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method was developed for the quantification of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), and biopterin (B) in human umbilical vein endothelial cells (HUVECs). Freshly prepared cell samples were treated with a mixture consisting of 0.2M trichloroacetic acid (TCA) and a cocktail of various antioxidants in order to precipitate proteins and other cellular components and to stabilize red/ox conditions in the lysates. Chromatography of the cell lysates was performed on a Poroshell 120 SB-C18 column (2.7µm, 150×2.1mm) using a stepwise gradient elution made from two mobile phases. Quantification was performed on a triple quadrupole mass spectrometer employing electrospray ionization with the operating conditions as multiple reaction monitoring (MRM) at positive ion mode. Total chromatographic run time was 23min. The method was validated for analysis in HUVECs, and the limits of quantification were 1nM for BH4 and BH2 and 2.5nM for B. Standard curves were linear in the concentration ranges of 1 to 100nM for BH4 and BH2 and 2.5 to 100nM for B. The current study reports a novel method for the simultaneous and direct quantification of BH4, BH2, and B in a single injection.
Assuntos
Biopterinas/análogos & derivados , Biopterinas/análise , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas por Ionização por Electrospray , Antioxidantes/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Leite Humano/química , Ácido Tricloroacético/químicaRESUMO
OBJECTIVE: To evaluate the effects of krill oil (KO) on inflammation and redox status in dextran sulfate sodium (DSS)-induced colitis in rats. MATERIALS AND METHODS: Thirty male Wistar rats were divided into three groups: Control, DSS, and DSS + KO 5% in a 4-week diet study. Colitis was induced by 5% DSS in the drinking water the last week of the experiment. Weight and disease activity index (DAI), colon length, histological combined score (HCS), colon levels of selected cytokines and prostaglandins, markers of protein oxidative damage, fatty acid profile, and expression of selected genes were measured. RESULTS: Rats in the DSS group increased their DAI and HCS compared with healthy controls. The colon length was significantly preserved after KO diet. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were elevated in the DSS group compared with controls. Cytokines and HCS were nonsignificantly lower in the KO versus the DSS group. Prostaglandin (PG)E(3) increased significantly in the KO versus the other groups. Peroxisome proliferator-activated receptor (PPAR)-γ expression was nonsignificantly increased while PPAR-γ coactivator 1α (Pparg1α) expression increased significantly after KO. The levels of protein oxidation markers decreased significantly. CONCLUSIONS: KO showed protective potential against DSS colitis based on the preservation of colon length, reduction of oxidative markers and the consistent beneficial changes of HCS, cytokine, and (PG)E(3) levels, as well as PPAR-γ and Pparg1α expression compared with DSS alone. These findings indicate an anti-inflammatory and a protein antioxidant effect of KO.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/patologia , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Alprostadil/análogos & derivados , Alprostadil/metabolismo , Animais , Quimiocina CXCL1/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Sulfato de Dextrana , Euphausiacea , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Masculino , Tamanho do Órgão , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas de Ligação a RNA/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Ratos , Ratos Wistar , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
PURPOSE: The beneficial effects of a seafood-rich diet are highly documented and can be attributed to both n-3 polyunsaturated fatty acids and other less studied nutritional components including protein and antioxidants. The aim of the work was to investigate whether an under-utilized seafood source, eggs (roe) and sperm (milt) from herring (Clupea harengus), can affect lipid metabolism and inflammation in a mouse model transgenic for human tumor necrosis factor alpha (hTNFα). METHODS: A high-fat control diet (25% total fats, 20% protein, w/w) or high-fat diets supplemented with herring roe (3.7% fat, 15% protein, w/w), or milt (1.3% fat, 15% protein) were administered to female C57BL/6 hTNFα mice. After 2 weeks, hepatic enzyme activity, gene expression, lipid and fatty acid composition, fatty acid composition of epididymal adipose tissue, and plasma lipid and cytokine levels were determined. RESULTS: Animals fed herring roe and milt displayed an increased hepatic fatty acid ß-oxidation and reduced fatty acid synthase activity. However, while plasma TAG was reduced, hepatic TAG and plasma and hepatic cholesterol levels were increased by the herring diets. Both herring diets led to a substantial shift in the n-6:n-3 ratio in both liver and ovarian white adipose tissue. The herring diets also increased plasma carnitine and reduced the carnitine precursor trimethyllysine. Plasma short-chained acylcarnitine esters were significantly increased, which may reflect an increased ß-oxidation of long-chained fatty acids. In addition, the diets tended to reduce the plasma levels of pro-inflammatory cytokines. CONCLUSION: Herring roe or milt diets enhanced lipid catabolism and influenced the chronic inflammatory state in hTNFα-transgenic mice.
Assuntos
Suplementos Nutricionais , Ovos , Fígado Gorduroso/dietoterapia , Peixes , Metabolismo dos Lipídeos , Fígado/metabolismo , Espermatozoides , Tecido Adiposo Branco/imunologia , Tecido Adiposo Branco/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Carnitina/sangue , Citocinas/sangue , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais/análise , Ovos/análise , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Fígado Gorduroso/sangue , Fígado Gorduroso/imunologia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Fígado/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica , Proteínas Recombinantes/metabolismo , Espermatozoides/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Decompression sickness (DCS) may result from damage to the endothelium caused by the gas bubbles formed during decompression and may be related to nitric oxide (NO) production by nitric oxide synthase (NOS). Heat stress prior to diving has been shown to protect animals from DCS, and by simulating this treatment in human endothelial cells (HUVEC) we have shown that a simulated dive performed subsequent to a heat stress potentiated the heat-induced expression of HSP70 and increased the level of the antioxidant glutathione (GSH). Since operational saturation diving is performed at an increased oxygen level, HUVEC have been exposed to heat stress and simulated diving at 40 kPa O(2), comparing the response on HSP70, HSP90 and GSH level to the effects previously observed at 20 kPa O(2). In addition, we wanted to investigate the effect on both endothelial NOS (eNOS) protein and enzymatic activity. The present results showed that a heat stress (45°C, 1 h) decreased the NOS activity and the protein markedly. Hyperoxia (40 kPa) alone or a dive either at 20 or 40 kPa O(2),had no effects on NOS activity or protein. At 40 kPa O(2) a simulated dive after heat stress potentiated the HS-induced HSP70 response, whereas the heat-induced HSP90 response decreased. GSH levels were found to be inversely related to NOS activity and protein expression, and might be explained by a possible post-translational regulation by glutathionylation of eNOS protein. The results add to the limited knowledge of these critical factors in cellular defence mechanisms that can prevent injury during decompression.
Assuntos
Mergulho/fisiologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glutationa/metabolismo , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/fisiologia , Óxido Nítrico Sintase/metabolismo , Células Cultivadas , HumanosRESUMO
Background: Acylcarnitines are essential for mitochondrial fatty acid oxidation. Earlier studies suggest that impaired energy metabolism may be implicated in the pathogenesis of microvascular angina. We explored metabolites from the carnitine pathway as predictors of cardiovascular disease (CVD) - and all-cause mortality among patients with non-obstructive coronary artery disease (NOCAD). Methods: A total of 1046 patients with suspected stable coronary syndrome underwent coronary angiography during 2000-2004, with findings of NOCAD. Serum levels of 8 selected carnitine metabolites were analyzed through liquid chromatography tandem mass spectrometry. Associations with CVD- and all-cause mortality were assessed by multivariable Cox regression models. Results: Median age at inclusion was 57 years. 51.5% were men. During median (25th- 75th percentiles), 14.1 (13.2-15.4) years of follow-up, 5.7% of the participants died from CVD and the incidence of all-cause mortality was 17.3%. Serum acetyl, octanoyl- and palmitoylcarnitine predicted CVD mortality with multivariable HR and 95% CI (per SD increment log transformed) of 1.36 (1.01-1.83), 1.49 (1.15-1.93) and 2.07 (1.49-2.85), p ≤ 0.04, respectively. Higher serum acetyl- and palmitoylcarnitines were also associated with increased risk of all-cause mortality (HR (95% CI): 1.27 (1.01-1.50), and 1.51 (1.26-1.81), p ≤ 0.007. Baseline levels of the precursors trimethyllysine and Æ´-butyrobetaine, carnitine or the odd chained propionylcarnitine and (iso)valerylcarnitine were not associated with adverse outcomes. Conclusion: Elevated serum even-chained acylcarnitines predicted adverse long-term prognosis in NOCAD. The strongest risk estimates were observed for palmitoylcarnitine, which predicted both CVD- and all-cause mortality after extensive multivariable adjustments. Underlying pathomechanisms should be further elucidated.
RESUMO
Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases with several pathogenic pathways in common. Evidence supports an association between the diseases, but the exact underlying mechanisms behind the connection are still under investigation. Lipid, fatty acid (FA) and metabolic profile alterations have been associated with several chronic inflammatory diseases, including RA and periodontitis. Mitochondria have a central role in regulating cellular bioenergetic and whole-body metabolic homeostasis, and mitochondrial dysfunction has been proposed as a possible link between the two disorders. The aim of this cross-sectional study was to explore whole-blood FA, serum lipid composition, and carnitine- and choline derivatives in 78 RA outpatients with different degrees of periodontal inflammation. The main findings were alterations in lipid, FA, and carnitine- and choline derivative profiles. More specifically, higher total FA and total cholesterol concentrations were found in active RA. Elevated phospholipid concentrations with concomitant lower choline, elevated medium-chain acylcarnitines (MC-AC), and decreased ratios of MC-AC and long-chain (LC)-AC were associated with prednisolone medication. This may indicate an altered mitochondrial function in relation to the increased inflammatory status in RA disease. Our findings may support the need for interdisciplinary collaboration within the field of medicine and dentistry in patient stratification to improve personalized treatment. Longitudinal studies should be conducted to further assess the potential impact of mitochondrial dysfunction on RA and periodontitis.