Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.640
Filtrar
1.
PLoS One ; 15(5): e0233180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437392

RESUMO

Lipoprotein lipase (LPL) is upregulated in atherosclerotic lesions and it may promote the progression of atherosclerosis, but the mechanisms behind this process are not completely understood. We previously showed that the phosphorylation of Akt within THP-1 macrophages is increased in response to the lipid hydrolysis products generated by LPL from total lipoproteins. Notably, the free fatty acid (FFA) component was responsible for this effect. In the present study, we aimed to reveal more detail as to how the FFA component may affect Akt signalling. We show that the phosphorylation of Akt within THP-1 macrophages increases with total FFA concentration and that phosphorylation is elevated up to 18 hours. We further show that specifically the palmitoleate component of the total FFA affects Akt phosphorylation. This is tied with changes to the levels of select molecular species of phosphoinositides. We further show that the total FFA component, and specifically palmitoleate, reduces apolipoprotein A-I-mediated cholesterol efflux, and that the reduction can be reversed in the presence of the Akt inhibitor MK-2206. Overall, our data support a negative role for the FFA component of lipoprotein hydrolysis products generated by LPL, by impairing macrophage cholesterol efflux via Akt activation.


Assuntos
Colesterol/metabolismo , Macrófagos/metabolismo , Ácido Palmítico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apolipoproteína A-I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lipase Lipoproteica/metabolismo , Macrófagos/citologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Células THP-1
2.
PLoS One ; 15(4): e0232164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330189

RESUMO

Maize (Zea mays L) is one of main nutrients sources for humans and animals worldwide. In Africa, storage of maize ensures food resources availability throughout the year. However, it often suffers losses exceeding 20% due to insects such as the larger grain borer, Prostephanus truncatus (Horn) (Coleoptera; Bostrichidae), major pest of stored maize in the tropical countries. This study aims to select resistant varieties to reduce maize storage losses and explain the physicochemical parameters role in grains susceptibility. In the first study, maize grains were artificially infested under no-choice method with insects. Susceptibility parameters such as weight loss, grain damage, number of emerged insects, median development time and susceptibility index varied significantly through maize varieties. Dobie susceptibility index (SI) was assessed as a major indicator of resistance. The most resistant varieties were Early-Thaï, DMR-ES and Tzee-Yellow. Conversely, Synth-9243, Obatampa and Synth-C varieties were susceptible. SWAN, Across-Pool and Tzee-White were classified as moderately resistant varieties. The insect reproductive potential was significantly different in the nine maize varieties and Early-Thaï, DMR-ES and Tzee-Yellow varieties were the least favourable host. To assess the relationship between grains physicochemical characteristics and varietal susceptibility, moisture, total phenolics, palmitic acid, proteins, amylose, density and grain hardness were evaluated according to standardized methods. Palmitic acid, SI, insects emerged and grain damage were significantly and positively correlated with each other, and negatively correlated with grains hardness, phenolics and amylose contents. Maize susceptibility index was significantly and negatively correlated to amylose, and phenolics contents and positively correlated to palmitic acid content. This study identified three resistant maize varieties to P. tuncatus and revealed that the major factors involved in this resistance were hardness, phenolic and amylose contents of grains.


Assuntos
Besouros/patogenicidade , Zea mays/crescimento & desenvolvimento , Zea mays/parasitologia , África , Amilose/metabolismo , Animais , Grão Comestível/crescimento & desenvolvimento , Grão Comestível/metabolismo , Ácido Palmítico/metabolismo , Fenol/metabolismo , Estruturas Vegetais/crescimento & desenvolvimento , Estruturas Vegetais/metabolismo , Estruturas Vegetais/parasitologia , Zea mays/metabolismo
3.
Am J Physiol Endocrinol Metab ; 318(3): E430-E439, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961705

RESUMO

Chronic exposure to high concentrations of stearic acid (C18:0) can result in ß-cell dysfunction, leading to development of type 2 diabetes. However, the molecular mechanisms underlying the destructive effects of stearic acid on ß-cells remain largely unknown. In this study, we aimed to investigate the role of miR-297b-5p on stearic acid-induced ß-cell apoptosis. Differential expression of microRNAs (miRNAs) was assessed in a ß-TC6 cell line exposed to stearic acid, palmitic acid, or a normal culture medium by high-throughput sequencing. The apoptosis rate was measured by flow cytometry after miR-297b-5p mimic/inhibitor transfection, and large-tumor suppressor kinase 2 (LATS2) was identified as a target of miR-297b-5p using a luciferase activity assay. In vivo, C57BL/6 mice were fed with normal and high-stearic-acid diet, respectively. Mouse islets were used for similar identification of miR-297b-5p and Lats2 in ß-TC6 cell. We selected two differentially expressed miRNAs in stearic acid compared with those in the palmitic acid and control groups. miR-297b-5p expression was significantly lower in ß-TC6 cells and mouse islets in stearic acid than in control group. Upregulation of miR-297b-5p alleviated the stearic acid-induced cell apoptosis and reduction in insulin secretion by inhibiting Lats2 expression in vitro. Meanwhile, silencing Lats2 significantly reversed the stearic acid-stimulated ß-cell dysfunction in both ß-TC6 cells and islets. Our findings indicate a suppressive role for miR-297b-5p in stearic acid-induced ß-cell apoptosis, which may reveal a potential target for the treatment of ß-cell dysfunction in the pathogenesis of type 2 diabetes.


Assuntos
Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Ácidos Esteáricos/farmacologia , Proteínas Supressoras de Tumor/genética , Animais , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/sangue , Citometria de Fluxo , Humanos , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácido Palmítico/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
World J Microbiol Biotechnol ; 36(1): 17, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912247

RESUMO

In this study, the effects of limited and excess nitrate on biomass, lipid production, and fatty acid profile in Messastrum gracile SE-MC4 were determined. The expression of fatty acid desaturase genes, namely stearoyl-ACP desaturase (SAD), omega-6 fatty acid desaturase (ω-6 FAD), omega-3 fatty acid desaturase isoform 1 (ω-3 FADi1), and omega-3 fatty acid desaturase isoform 2 (ω-3 FADi2) was also assessed. It was found that nitrate limitation generally increased the total oil, α-linolenic acid (C18:3n3) and total polyunsaturated fatty acid (PUFA) contents in M. gracile. The reduction of nitrate concentration from 1.76 to 0.11 mM increased the total oil content significantly from 32.5 to 41.85% (dry weight). Palmitic (C16:0) and oleic (C18:1) acids as the predominant fatty acids in this microalgae constituted between 82 and 87% of the total oil content and were relatively consistent throughout all nitrate concentrations tested. The expression of SAD, ω-6 FAD, and ω-3 FADi2 genes increased under nitrate limitation, especially at 0.11 mM nitrate. The ω-3 FADi1 demonstrated a binary up-regulation pattern of expression under both nitrate-deficient (0.11 mM) and -excess (3.55 mM) conditions. Thus, findings from this study suggested that limited or excess nitrate could be used as part of a cultivation strategy to increase oil and PUFA content following media optimisation and more efficient culture methodology. Data obtained from the expression of desaturase genes would provide valuable insights into their roles under excess and limited nitrate conditions in M. gracile, potentially paving the way for future genetic modifications.


Assuntos
Ácidos Graxos Dessaturases/genética , Ácidos Graxos/análise , Microalgas/crescimento & desenvolvimento , Nitrogênio/metabolismo , Biomassa , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Regulação Enzimológica da Expressão Gênica , Metabolismo dos Lipídeos , Microalgas/genética , Microalgas/metabolismo , Ácido Oleico/metabolismo , Ácido Palmítico/metabolismo , Ácido alfa-Linoleico/metabolismo
5.
Cancer Immunol Immunother ; 69(1): 115-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802182

RESUMO

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.


Assuntos
Adipócitos/imunologia , Interleucina-17/metabolismo , Neoplasias Ovarianas/imunologia , Ácido Palmítico/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Fosforilação , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-31740387

RESUMO

Adverse effects of aging can be delayed with life-style interventions. We examined how exercise training (ET) alone or combined with omega-3 polyunsaturated fatty acid (PUFA) affects serum and adipose tissue (AT) lipidome in older women. Fifty-five sedentary older women were included in the physical activity program and given either sunflower (Placebo) or wax esters-rich (Calanus) oil capsules for 4 months. Serum and subcutaneous abdominal AT samples were acquired while maximum rates of oxygen consumption (VO2 max), insulin sensitivity (hyperinsulinemic-euglycemic clamps) and comprehensive lipidome profiles were determined before and after the study. ET increased VO2 max in both groups. Lipidomics profiling revealed unusual serum triacylglycerols and phospholipids with ether-bound alkyls in the Calanus group, while ET generally induced shorter-chain triacylglycerols in AT, suggesting increased de novo lipogenesis. The latter was positively associated with whole-body insulin sensitivity. Unexpectedly, insulin-sensitizing lipokines from the family of branched palmitic acid esters of hydroxy stearic acid (PAHSAs) were elevated in both serum and AT after ET, while PAHSAs-containing triacylglycerols were detected in AT. ET stimulated beneficial changes in AT, including PAHSAs synthesis. Although the added value of omega-3 PUFA supplementation was not proven, our discovery can help understand the nature of the metabolic benefits of exercise.


Assuntos
Tecido Adiposo/metabolismo , Exercício Físico/fisiologia , Ácidos Graxos Ômega-3/administração & dosagem , Insulina/metabolismo , Síndrome Metabólica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Terapia Combinada , Suplementos Nutricionais , Ésteres/metabolismo , Feminino , Humanos , Lipidômica , Lipogênese/fisiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Ácido Palmítico/metabolismo , Ácidos Esteáricos/metabolismo , Resultado do Tratamento
7.
Biochim Biophys Acta Gen Subj ; 1864(1): 129422, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491457

RESUMO

BACKGROUND: Previous studies suggested that fibrillar human IAPP (hIAPP) is more likely to deposit in ß-cells, resulting in ß-cell injury. However, the changes in the conformation of hIAPP in lipid environment and the mechanism involved in ß-cell damage are unclear. METHODS: Synthetic hIAPP was incubated with five types of free fatty acids and phospholipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS), which constitute the cell membrane. Thioflavin-T fluorescence assay was conducted to analyze the degree of hIAPP fibrosis, and circular dichroism spectroscopy was performed to detect the ß-fold formation of hIAPP. Furthermore, INS-1 cells were infected with human IAPP delivered by a GV230-EGFP plasmid. The effects of endogenous hIAPP overexpression induced by sodium palmitate on the survival, endoplasmic reticulum (ER) stress, and apoptosis of INS-1 cells were evaluated. RESULTS: The five types of free fatty acids can accelerate the fibrosis of hIAPP. Sodium palmitate also maintained the stability of fibrillar hIAPP. POPS, not POPC, accelerated hIAPP fibrosis. Treatment of INS-1 cells with sodium palmitate increased the expression of hIAPP, activated ER stress and ER stress-dependent apoptosis signaling pathways, and increased the apoptotic rate. CONCLUSION: Free fatty acids and anionic phospholipid can promote ß-fold formation and fibrosis in hIAPP. High lipid induced the overexpression of hIAPP and aggravated ER stress and apoptosis in INS-1 cells, which caused ß-cell death in high lipid environment. GENERAL SIGNIFICANCE: Our study reveals free fatty acids and hIAPP synergistically implicated in endoplasmic reticulum stress and apoptosis of islet ß-cells.


Assuntos
Apoptose/genética , Fibrose/genética , Células Secretoras de Insulina/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Amiloide/genética , Amiloide/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Estresse do Retículo Endoplasmático/genética , Ácidos Graxos não Esterificados/genética , Ácidos Graxos não Esterificados/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Ácido Palmítico/metabolismo , Fosfatidilcolinas/genética , Fosfatidilcolinas/metabolismo , Fosfatidilserinas/genética , Fosfatidilserinas/metabolismo , Conformação Proteica em Folha beta , Dobramento de Proteína
8.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L429-L441, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31850803

RESUMO

Insulin resistance and right ventricular (RV) dysfunction are associated with lipotoxicity in heritable forms of pulmonary arterial hypertension (PAH), commonly due to mutations in bone morphogenetic protein receptor type 2 (BMPR2). How BMPR2 dysfunction in cardiomyocytes alters glucose metabolism and the response of these cells to insulin are unknown. We hypothesized that BMPR2 mutation in cardiomyocytes alters glucose-supported mitochondrial respiration and impairs cellular responses to insulin, including glucose and lipid uptake. We performed metabolic assays, immunofluorescence and Western analysis, RNA profiling, and radioactive isotope uptake studies in H9c2 cardiomyocyte cell lines with and without patient-derived BMPR2 mutations (mutant cells), with and without insulin. Unlike control cells, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity as indicated by reduced mitochondrial respiration with increased mitochondrial superoxide production. These mutant cells show enhanced baseline phosphorylation of insulin-signaling protein as indicated by increased Akt, AMPK, and acetyl-CoA carboxylase phosphorylation that may negatively influence fatty acid oxidation and enhance lipid uptake, and are insulin insensitive. Furthermore, mutant cells demonstrate an increase in milk fat globule-EGF factor-8 protein (MFGE8), which influences the insulin-signaling pathway by phosphorylating AktSer473 via phosphatidylinositol 3-kinase and mammalian target of rapamycin. In conclusion, BMPR2 mutant cardiomyocytes have reduced metabolic plasticity and fail to respond to glucose. These cells have enhanced baseline insulin-signaling pattern favoring insulin resistance with failure to augment this pattern in response to insulin. BMPR2 mutation possibly blunts glucose uptake and enhances lipid uptake in these cardiomyocytes. The MFGE8-driven signaling pathway may suggest a new mechanism underlying RV lipotoxicity in PAH.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Animais , Antígenos de Superfície/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Antígenos CD36/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Resistência à Insulina , Camundongos , Proteínas do Leite/metabolismo , Mitocôndrias/metabolismo , Mutação/genética , Consumo de Oxigênio , Ácido Palmítico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Ratos , Superóxidos/metabolismo , Serina-Treonina Quinases TOR/metabolismo
9.
Food Funct ; 10(12): 7634-7644, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31728459

RESUMO

Chemotherapy is currently used to treat colorectal cancer (CRC), the most common cancer worldwide. However, chemotherapeutic drugs are limited by severe side effects or drug resistance. In this study, bioactive compound(s), a mixture of palmitic acid, stearic acid, and glyceryl 1,3-dipalmitate (PSG), in Lactobacillus paracasei subsp. paracasei NTU 101-fermented reconstituted skimmed milk ethanol extract (NTU 101-FMEE) were isolated and identified. PSG (1 : 1.5 : 6.3) at 125 µg mL-1 could significantly decrease CRC cell viability at dosages that were not cytotoxic to healthy colon epithelial cells or macrophages. Moreover, the inhibitory effect of the combination of 62.5 µg mL-1 PSG (1 : 1.5 : 6.3) and 5-fluorouracil (5-FU) was significantly higher than that of 5-FU alone (p < 0.05). PSG up-regulated the activities of apoptosis-related proteins and down-regulated the nuclear factor-κB signaling pathway compared to the levels in the control group. Overall, PSG purified from NTU 101-FMEE possesses the potential to ameliorate CRC by improving the effects of adjuvant chemotherapy drugs and reducing side effects.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Produtos Fermentados do Leite/análise , Fluoruracila/farmacologia , Lactobacillus paracasei/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/fisiopatologia , Produtos Fermentados do Leite/microbiologia , Fermentação , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Ácidos Esteáricos/metabolismo , Ácidos Esteáricos/farmacologia
10.
Molecules ; 24(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703459

RESUMO

This study describes the chemical constituents of Albiziae Cortex and their ability to ameliorate steatosis and promote proliferation and anti-oxidation in vitro. Together, five known lignan glycosides, (7S,8R)-erythro-syringylglycerol-ß-O-4'-sinapyl ether 9-O-ß-D-glucopyranoside (1), (+)-lyoniresinol-9'-O-gluco-side (2), (-)-lyoniresinol-9'-O-glucoside (3), picraquassioside C (4), and icariside E5 (5), were isolated from the Albiziae Cortex. Their structures were elucidated by extensive NMR and high-resolution mass spectrometry analysis and compared with reported data. Oil Red O staining results revealed that compounds 1, 2, and 3 attenuated lipid accumulation and lipid metabolic disorders in FFAs (oleate/palmitate, 2:1 ratio, 0.3 mM)-exposed HepG2 cells. The Cell Counting Kit 8 (CCK-8) assay results revealed that compounds 1 and 5 can significantly promote human umbilical vein endothelial cell (HUVEC) proliferation; meanwhile, these compounds did not exhibit significant cytotoxicity against HUVECs. In addition, 2',7'-dichlorofluorescein diacetate (DCFH-DA) staining results revealed that high glucose (HG)-induced reactive oxygen species (ROS) production was abolished by compounds 1, 2, and 3. This is the first report of the isolation of lignan skeletons from the genus Albizzia julibrissin with the ability to ameliorate steatosis and promote proliferation and anti-oxidation activities.


Assuntos
Albizzia/química , Antioxidantes , Proliferação de Células/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Lignanas/química , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Espectrometria de Massas , Ressonância Magnética Nuclear Biomolecular , Ácido Oleico/metabolismo , Oxirredução , Ácido Palmítico/metabolismo
11.
Eur J Med Chem ; 184: 111767, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622854

RESUMO

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ±â€¯19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.


Assuntos
Descoberta de Drogas , Ácido Palmítico/antagonistas & inibidores , Sulfonamidas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Compostos de Vinila/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Células HEK293 , Humanos , Estrutura Molecular , Ácido Palmítico/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Fatores de Transcrição/metabolismo , Compostos de Vinila/síntese química , Compostos de Vinila/química
12.
J Oleo Sci ; 68(11): 1149-1155, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31611519

RESUMO

The absorption efficacies and catabolic rates of fatty acids are affected by their binding position on triacylglycerol (TAG). However, the kind of effect calcium treatment has on the catabolism of fatty acids is unclear. In this study, the catabolic rates of 13C-labeled palmitic acid, oleic acid, and linoleic acid bound to sn-1, 3 (α) and sn-2 (ß) position of TAG in the presence of calcium were compared using isotope ratio mass spectrometry. The catabolic rates of 13C-labeled fatty acids were evaluated using the ratio of 13C to 12C in the carbon dioxide expired by mice. The catabolic rate of palmitic acid bound to the α position was significantly lower than that of palmitic acid bound to the ß position of TAG. The rates of 13CO2 formation from palmitic acid at the ß position remained higher for a long time. In contrast, oleic and linoleic acids at the α position were as well catabolized as those at the ß position. These results indicate that in the presence of calcium, the saturated fatty acid bound to the ß position is highly catabolized, whereas that bound to the α position is not well catabolized. Saturated fatty acid at the α position is hydrolyzed by pancreatic lipase to promptly form insoluble complexes with calcium, which are excreted from the body, and thereby reducing the catabolic rate of these fatty acids.


Assuntos
Cálcio/farmacologia , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Triglicerídeos/metabolismo , Animais , Sítios de Ligação , Cálcio/administração & dosagem , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Marcação por Isótopo , Ácido Linoleico/química , Ácido Linoleico/metabolismo , Masculino , Camundongos Endogâmicos , Ácido Oleico/química , Ácido Oleico/metabolismo , Ácido Palmítico/química , Ácido Palmítico/metabolismo
13.
Int J Mol Sci ; 20(20)2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31614951

RESUMO

Obesity is closely associated with neuroinflammation in the hypothalamus, which is characterized by over-activated microglia and excessive production of pro-inflammatory cytokines. The present study was aimed at elucidating the effects of (-)-epigallocatechin gallate (EGCG) on palmitic acid-stimulated BV-2 microglia and high-fat-diet-induced obese mice. The results indicated the suppressive effect of EGCG on lipid accumulation, pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release, and microglial activation in both cellular and high-fat-diet rodent models. These results were associated with lower phosphorylated levels of the janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway. In conclusion, EGCG can attenuate high-fat-induced hypothalamic inflammation via inhibiting the JAK2/STAT3 signaling pathways in microglia.


Assuntos
Fármacos Antiobesidade/farmacologia , Catequina/análogos & derivados , Microglia/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/uso terapêutico , Catequina/farmacologia , Catequina/uso terapêutico , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Hipotálamo/efeitos dos fármacos , Hipotálamo/imunologia , Hipotálamo/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Microglia/metabolismo , Obesidade/metabolismo , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Polifenóis/farmacologia , Fator de Transcrição STAT3/metabolismo , Chá/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
J Dairy Sci ; 102(11): 9842-9856, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495626

RESUMO

The objective of our study was to evaluate the effects of altering the dietary ratio of palmitic (C16:0) and oleic (cis-9 C18:1) acids on nutrient digestibility, energy partitioning, and production responses of lactating dairy cows. Cows were blocked by milk yield and assigned to 3 groups (12 cows per group) in a main plot: low (45.2 ± 1.7 kg/d), medium (53.0 ± 1.6 kg/d), and high (60.0 ± 1.9 kg/d). Within each production group, a truncated Latin square arrangement of fatty acid (FA) treatments was used in 2 consecutive 35-d periods. The FA treatments supplemented at 1.5% of diet dry matter were (1) 80:10 (80% C16:0 + 10% cis-9 C18:1), (2) 73:17 (73% C16:0 + 17% cis-9 C18:1), (3) 66:24 (66% C16:0 + 24% cis-9 C18:1), and (4) 60:30 (60% C16:0 + 30% cis-9 C18:1). Treatment × production group interactions were observed for yields of milk, fat-corrected milk, energy-corrected milk, milk fat, milk protein, and milk lactose and energy partitioned to milk. Increasing cis-9 C18:1 in FA treatments reduced fat-corrected milk, energy-corrected milk, and milk energy output in low-producing cows but increased these in high-producing cows. Increasing cis-9 C18:1 in FA treatments did not affect milk yield, milk protein yield, and milk lactose yield in low- and medium-producing cows but increased these in high-producing cows. Regardless of production level, there was no effect of treatments on dry matter intake; however, increasing cis-9 C18:1 in FA treatments increased body weight change and body condition score change. Increasing cis-9 C18:1 in FA treatments increased total FA digestibility due to a linear increase in 16- and 18-carbon FA digestibilities. Interactions between FA treatments and production level were observed for the yield of milk fat and milk FA sources. In low-producing cows, increasing cis-9 C18:1 in FA treatments decreased milk fat yield due to a decrease in de novo and mixed milk FA without changes in preformed milk FA. In contrast, in high-producing cows, increasing cis-9 C18:1 in FA treatments increased milk fat yield due to an increase in de novo and preformed milk FA. Our results indicate that high-producing dairy cows (averaging 60 kg/d) responded better to a fat supplement containing more cis-9 C18:1, whereas low-producing cows (averaging 45 kg/d) responded better to a supplement containing more C16:0.


Assuntos
Ração Animal/análise , Bovinos/fisiologia , Suplementos Nutricionais/análise , Metabolismo Energético , Ácidos Graxos/administração & dosagem , Leite/metabolismo , Animais , Dieta/veterinária , Digestão/efeitos dos fármacos , Feminino , Lactação , Lactose/análise , Leite/química , Proteínas do Leite/análise , Ácido Palmítico/metabolismo
15.
BMC Vet Res ; 15(1): 324, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492181

RESUMO

BACKGROUND: Obesity in cats has been associated with alterations in adipokines including: adiponectin, interleukin-6 (IL6), and tumor necrosis factor-α (TNFα). Omega-3 polyunsaturated fatty acids have multiple beneficial effects on obesity-associated disorders, and therefore may alleviate these alterations. This study aimed to determine the effects of body condition, fat depot, troglitazone, and different fatty acids on secretion of adiponectin, IL6 and TNFα from adipose tissue of healthy cats. Subcutaneous and visceral adipose tissue samples were collected from 18 healthy intact female cats, and body condition score (Range 3-7/9) was determined. Concentrations of adiponectin were measured in mature adipocytes cultures and concentrations of IL6 and TNFα were measured in stromovascular cells cultures following treatment with control medium, troglitazone at 10 µM, eicosapentaenoic acid, arachidonic acid, or palmitic acid, at 25, 50, or 100 µM. RESULTS: Stromovascular cells of visceral origin secreted higher concentrations of IL6 than corresponding cells of subcutaneous origin (P = 0.003). Arachidonic acid treatment at 25, 50, and 100 µM increased IL6 secretion in subcutaneous (P = 0.045, P = 0.002, and P < 0.001, respectively) and visceral (P = 0.034, P = 0.001, and P < 0.001, respectively) stromovascular cells. Eicosapentaenoic acid treatment increased TNFα secretion in subcutaneous stromovascular cells at 25, 50, and 100 µM (P = 0.002, P = 0.001, and P = 0.015, respectively) and in visceral stromovascular cells at 50 µM (P < 0.001). No significant effect on medium adiponectin concentration was observed following troglitazone treatment (P = 0.4) or fatty acids treatments at 25 (P = 0.2), 50 (P = 0.8), or 100 (P = 0.7) µM. Body condition score did not have significant effects on medium concentrations of adiponectin (P = 0.4), IL6 (P = 0.1), or TNFα (P = 0.8). CONCLUSIONS: This study demonstrated higher basal secretion of IL6 from visceral compared to subcutaneous adipose tissue, a stimulatory effect of arachidonic acid on secretion of IL6 and a stimulatory effect of eicosapentaenoic acid on TNFα from feline adipose tissue.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Tecido Adiposo/metabolismo , Animais , Ácido Araquidônico/metabolismo , Constituição Corporal , Gatos , Células Cultivadas , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Feminino , Interleucina-6/metabolismo , Ácido Palmítico/metabolismo , Troglitazona/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
16.
Inflamm Res ; 68(11): 915-932, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31363792

RESUMO

Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1ß and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.


Assuntos
Macrófagos/metabolismo , Ácido Palmítico/metabolismo , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Obesidade/metabolismo , PPAR gama/metabolismo , Receptores Toll-Like/metabolismo
18.
J Biol Chem ; 294(36): 13487-13501, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31337710

RESUMO

Junctophilins (JPH1-JPH4) are expressed in excitable and nonexcitable cells, where they tether endoplasmic/sarcoplasmic reticulum (ER/SR) and plasma membranes (PM). These ER/SR-PM junctions bring Ca-release channels in the ER/SR and Ca as well as Ca-activated K channels in the PM to within 10-25 nm. Such proximity is critical for excitation-contraction coupling in muscles, Ca modulation of excitability in neurons, and Ca homeostasis in nonexcitable cells. JPHs are anchored in the ER/SR through the C-terminal transmembrane domain (TMD). Their N-terminal Membrane-Occupation-Recognition-Nexus (MORN) motifs can bind phospholipids. Whether MORN motifs alone are sufficient to stabilize JPH-PM binding is not clear. We investigate whether S-palmitoylation of cysteine (Cys), a critical mechanism controlling peripheral protein binding to PM, occurs in JPHs. We focus on JPH2 that has four Cys residues: three flanking the MORN motifs and one in the TMD. Using palmitate-alkyne labeling, Cu(I)-catalyzed alkyne-azide cycloaddition reaction with azide-conjugated biotin, immunoblotting, proximity-ligation-amplification, and various imaging techniques, we show that JPH2 is S-palmitoylatable, and palmitoylation is essential for its ER/SR-PM tether function. Palmitoylated JPH2 binds to lipid-raft domains in PM, whereas palmitoylation of TMD-located Cys stabilizes JPH2's anchor in the ER/SR membrane. Binding to lipid-raft domains protects JPH2 from depalmitoylation. Unpalmitoylated JPH2 is largely excluded from lipid rafts and loses the ability to form stable ER/SR-PM junctions. In adult ventricular myocytes, native JPH2 is S-palmitoylatable, and palmitoylated JPH2 forms distinct PM puncta. Sequence alignment reveals that the palmitoylatable Cys residues in JPH2 are conserved in other JPHs, suggesting that palmitoylation may also enhance ER/SR-PM tethering by these proteins.


Assuntos
Membrana Celular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Musculares/metabolismo , Ácido Palmítico/metabolismo , Retículo Sarcoplasmático/metabolismo , Animais , Células COS , Células Cultivadas , Chlorocebus aethiops , Humanos
19.
Fish Shellfish Immunol ; 92: 508-518, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31247319

RESUMO

Mechanisms by which vaccines enhance immunity to combat bacterial pathogens are not fully understood. Recently, we have found that live Edwardsiella tarda vaccine enhances ability against the bacterial challenge by metabolic modulation in zebrafish. Here we first explored the metabolic modulation promoted by inactivated E. tarda to eliminate the pathogen. Inactivated E. tarda vaccine modulated a similar metabolome to combat with the pathogen in zebrafish as live E. tarda vaccine did. Specifically, both vaccines promoted biosynthesis of unsaturated fatty acids and the TCA cycle. However, due to relatively higher activated TCA cycle in inactivated vaccine than live vaccine, live vaccine promoted higher abundance of palmitate than inactivated vaccine. Consistently, the protection against E. tarda challenge was palmitate dose-dependent. Live vaccine activated higher expression of IL-1ß, IL-8,Cox-2 genes and lower expression of IL-15, IL-21 genes than inactivated vaccine, which is similar to the results stimulated by high and low doses of palmitate, respectively. These findings indicate live and inactivated E. tarda vaccines stimulate differential abundances of palmitate that contribute to differential innate immunities against bacterial infection. Thus, metabolic environment contributes to immune response.


Assuntos
Ácido Palmítico/metabolismo , Animais , Vacinas Bacterianas , Edwardsiella tarda/fisiologia , Infecções por Enterobacteriaceae/imunologia , Doenças dos Peixes/imunologia , Distribuição Aleatória , Vacinas Atenuadas , Vacinas de Produtos Inativados , Peixe-Zebra
20.
Methods Mol Biol ; 2009: 13-33, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31152392

RESUMO

The use of synthetically synthesized azide and alkyne fatty acid analogs coupled with bioorthogonal Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction-based detection methods to study protein S-acylation reactions has replaced the traditional method of using in vivo metabolic radiolabeling with tritiated palmitic acid and has greatly facilitated our understanding of this essential cellular process. Here, we describe the chemical synthesis of myristic (C:14), palmitic (C16:0), and stearic (C18:0) acid-azide probes and detail how they may be utilized as chemical reporters for the analysis of S-acylation of exogenously expressed proteins in cells.


Assuntos
Ácido Mirístico/análise , Ácido Palmítico/análise , Proteína S/análise , Ácidos Esteáricos/análise , Acilação , Reação de Cicloadição , Células HEK293 , Humanos , Ácido Mirístico/metabolismo , Ácido Palmítico/metabolismo , Proteína S/metabolismo , Ácidos Esteáricos/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA