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Pesquisa : D02.092.668 [Categoria DeCS]
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[PMID]:29184921
[Au] Autor:Jaworek MW; Schuabb V; Winter R
[Ad] Endereço:Physical Chemistry I - Biophysical Chemistry, Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany. roland.winter@tu-dortmund.de.
[Ti] Título:The effects of glycine, TMAO and osmolyte mixtures on the pressure dependent enzymatic activity of α-chymotrypsin.
[So] Source:Phys Chem Chem Phys;20(3):1347-1354, 2018 Jan 17.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:High pressure is an important feature of certain natural environments, such as the deep sea where pressures up to about 1000 bar are encountered. Further, pressure effects on biosystems are of increasing interest for biotechnological applications, such as baroenzymology. We studied the effect of two different natural osmolyte mixtures, with major components being glycine and trimethylamine-N-oxide (TMAO), on the activity of α-chymotrypsin, using high-pressure stopped-flow methodology in combination with fast UV/Vis detection. We show that pressure is not only able to drastically enhance the catalytic activity and efficiency of the enzyme, but also that glycine has a significant and diverse effect on the enzymatic activity and volumetric properties of the reaction compared to TMAO. The results might not only help to understand the modulation of enzymatic reactions by natural osmolytes, but also elucidate ways to optimize enzymatic processes in biotechnological applications.
[Mh] Termos MeSH primário: Quimotripsina/metabolismo
Glicina/química
Metilaminas/química
[Mh] Termos MeSH secundário: Quimotripsina/química
Glicina/metabolismo
Hidrólise
Cinética
Metilaminas/metabolismo
Concentração Osmolar
Pressão
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Methylamines); EC 3.4.21.1 (Chymotrypsin); EC 3.4.21.1 (alpha-chymotrypsin); FLD0K1SJ1A (trimethyloxamine); TE7660XO1C (Glycine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp06042d


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[PMID]:29247650
[Au] Autor:Li T; Gua C; Wu B; Chen Y
[Ad] Endereço:Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang 110004, Liaoning, China. Electronic address: li-tiejun-cmu@outlook.com.
[Ti] Título:Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease.
[So] Source:Biochem Biophys Res Commun;495(2):2071-2077, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chronic kidney disease (CKD) is strongly associated with increased cardiovascular risk. Impaired endothelial function, a key initiating step in the pathogenesis of cardiovascular disease, has been reported in patients with CKD, but the mechanisms responsible for endothelial dysfunction in CKD remain elusive. Emerging evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota-generated metabolite, is involved in the pathogenesis of many cardiovascular diseases. Circulating TMAO is elevated in CKD. Here we tested the hypothesis that elevated TMAO plays a contributory role in the pathogenesis of endothelial dysfunction in CKD. Rats underwent 5/6 nephrectomy to induce CKD or sham operation, and were treated with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) or vehicle. Eight weeks after nephrectomy and DMB treatment, circulating TMAO levels were markedly elevated in CKD-vehicle rats compared with sham-vehicle rats, but were reduced in CKD-DMB rats. Acetylcholine-induced endothelium-dependent vasodilation was impaired in CKD-vehicle rats compared with sham-vehicle rats as indicated by reduced maximal relaxation (E ) and decreased area under the curve (AUC). E and AUC were both normalized in CKD-DMB rats. No difference in sodium nitroprusside-induced endothelial-independent vasodilation was observed across groups. Molecular studies revealed that endothelial nitric-oxide synthase activity was decreased, while superoxide production and proinflammatory cytokine expression were increased in the aorta of CKD-vehicle rats compared with sham-vehicle rats. Of note, the abnormalities in above molecular parameters were completely restored in CKD-DMB rats. These results suggest that CKD elevates circulating TMAO levels, which may reduce eNOS-derived NO production by increasing vascular oxidative stress and inflammation, contributing to CKD-associated endothelial dysfunction and cardiovascular disease.
[Mh] Termos MeSH primário: Endotélio Vascular/metabolismo
Endotélio Vascular/patologia
Metilaminas/sangue
Insuficiência Renal Crônica/sangue
Insuficiência Renal Crônica/patologia
Doenças Vasculares/sangue
Doenças Vasculares/patologia
[Mh] Termos MeSH secundário: Animais
Biomarcadores/sangue
Citocinas/sangue
Masculino
Ratos
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (Cytokines); 0 (Methylamines); 0 (Reactive Oxygen Species); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171217
[St] Status:MEDLINE


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[PMID]:29236735
[Au] Autor:Jaworska K; Huc T; Samborowska E; Dobrowolski L; Bielinska K; Gawlak M; Ufnal M
[Ad] Endereço:Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.
[Ti] Título:Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite.
[So] Source:PLoS One;12(12):e0189310, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:An increased blood trimethylamine N-oxide (TMAO) has emerged as a marker of cardiovascular mortality, however, the mechanisms of the increase are not clear. We evaluated if hypertension was associated with changes in the colon permeability to trimethylamine (TMA), a TMAO precursor. We did experiments on male, 24-26-week-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and SHR treated with enalapril, an antihypertensive drug (SHR-E). To check the colon permeability and liver TMA clearance, blood was collected from the portal vein and hepatic veins confluence, at baseline and after the intracolonic administration of TMA. Arterial blood pressure (BP) and intestinal blood flow (IBF) recordings and histological assessment of the colon were performed. SHR showed an increased gut-blood barrier permeability to TMA. Namely, at baseline SHR had a higher BP and portal blood TMA, but a lower IBF than WKY. After the intracolonic administration of TMA, SHR had a significantly higher portal blood TMA and higher TMA liver clearance than WKY. In SHR the arteriolar walls of the colon mucosa were significantly thicker than in WKY. Furthermore, SHR showed a significant decrease in the height of the mucosa. In contrast, SHR-E had lower portal blood TMA, lower BP and smaller thickness of arteriolar walls, but higher IBF than SHR, which indicates improved function of the gut-blood barrier in SHR-E. All groups had similar immunostaining of occludin and zonula occludens-1, markers of tight junctions. In conclusion, hypertensive rats show an increased permeability of the colon to TMA, which is accompanied by morphological and hemodynamic alterations in the colon. Therefore, cardiovascular diseases may be characterized by an increased permeability of the gut-blood barrier to bacterial metabolites such as TMA.
[Mh] Termos MeSH primário: Colo/metabolismo
Hipertensão/etiologia
Mucosa Intestinal/metabolismo
Metilaminas/metabolismo
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea
Colo/irrigação sanguínea
Masculino
Ratos
Ratos Endogâmicos SHR
Ratos Endogâmicos WKY
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Methylamines); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189310


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[PMID]:27779357
[Au] Autor:Venturato A; MacFarlane G; Geng J; Bradley M
[Ad] Endereço:School of Chemistry, University of Edinburgh, The King's Buildings, West Mains Road, Edinburgh, EH9 3KJ, UK.
[Ti] Título:Understanding Polymer-Cell Attachment.
[So] Source:Macromol Biosci;16(12):1864-1872, 2016 12.
[Is] ISSN:1616-5195
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The development of polymeric materials with cell adhesion abilities requires an understanding of cell-surface interactions which vary with cell type. To investigate the correlation between cell attachment and the nature of the polymer, a series of random and block copolymers composed of 2-(dimethylamino)ethyl acrylate and ethyl acrylate are synthesized through single electron transfer living radical polymerization. The polymers are synthesized with highly defined and controlled monomer compositions and exhibited narrow polydispersity indices. These polymers are examined for their performance in the attachment and growth of HeLa and HEK cells, with attachment successfully modeled on monomer composition and polymer chain length, with both cell lines found to preferentially attach to moderately hydrophobic functional materials. The understanding of the biological-material interactions assessed in this study will underpin further investigations of engineered polymer scaffolds with predictable cell binding performance.
[Mh] Termos MeSH primário: Acrilatos/química
Adesão Celular/fisiologia
Metilaminas/química
Polímeros/química
Polímeros/metabolismo
[Mh] Termos MeSH secundário: Materiais Biocompatíveis/química
Materiais Biocompatíveis/metabolismo
Células HEK293
Células HeLa
Seres Humanos
Polimerização
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(dimethylamino ethyl)acrylate); 0 (Acrylates); 0 (Biocompatible Materials); 0 (Methylamines); 0 (Polymers); 71E6178C9T (ethyl acrylate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180117
[Lr] Data última revisão:
180117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE
[do] DOI:10.1002/mabi.201600253


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[PMID]:29240800
[Au] Autor:Chung RWS; Wang Z; Bursill CA; Wu BJ; Barter PJ; Rye KA
[Ad] Endereço:Lipid Research Group, Heart Research Institute, Sydney, NSW, Australia.
[Ti] Título:Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice.
[So] Source:PLoS One;12(12):e0189523, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat-fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice.
[Mh] Termos MeSH primário: Aterosclerose/patologia
Suplementos Nutricionais
Esfingomielinas/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas E/genética
Aterosclerose/sangue
Dieta Hiperlipídica
Metilaminas/sangue
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Esfingomielinas/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Methylamines); 0 (Sphingomyelins); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189523


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[PMID]:29054581
[Au] Autor:Eronina TB; Mikhaylova VV; Chebotareva NA; Borzova VA; Yudin IK; Kurganov BI
[Ad] Endereço:Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 33, bld. 2, Leninsky Ave., Moscow 119071, Russia. Electronic address: eronina@inbi.ras.ru.
[Ti] Título:Mechanism of aggregation of UV-irradiated glycogen phosphorylase b at a low temperature in the presence of crowders and trimethylamine N-oxide.
[So] Source:Biophys Chem;232:12-21, 2018 01.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:To characterize the initial stages of protein aggregation, the kinetics of aggregation of UV-irradiated glycogen phosphorylase b (UV-Phb) was studied under conditions when the aggregation proceeded at a low rate (10°C, 0.03M Hepes buffer, pH6.8, containing 0.1M NaCl). Aggregation of UV-Phb was induced by polyethylene glycol and Ficoll-70, acting as crowders, or a natural osmolyte trimethylamine N-oxide (TMAO). It has been shown that the initial rate of the stage of aggregate growth is proportional to the protein concentration squared, suggesting that the order of aggregation with respect to the protein is equal to two. It has been concluded that the aggregation mechanism of UV-Phb at 10°C in the presence of crowders includes the nucleation stage and stages of protein aggregate growth (the basic aggregation pathway). The aggregation mechanism is complicated in the presence of TMAO, and the stage of aggregate-aggregate assembly induced by TMAO should be added to the basic aggregation pathway. It has been shown that the ability of TMAO at a low concentration (0.05M) to induce aggregation of UV-Phb is due to the decrease in the absolute value of zeta potential of the protein in the presence of TMAO.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Ficoll/farmacologia
Glicogênio Fosforilase Muscular/antagonistas & inibidores
Metilaminas/farmacologia
Polietilenoglicóis/farmacologia
Temperatura Ambiente
[Mh] Termos MeSH secundário: Animais
Difusão Dinâmica da Luz
Inibidores Enzimáticos/química
Ficoll/química
Glicogênio Fosforilase Muscular/isolamento & purificação
Glicogênio Fosforilase Muscular/metabolismo
Cinética
Metilaminas/química
Polietilenoglicóis/química
Agregados Proteicos/efeitos dos fármacos
Coelhos
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Methylamines); 0 (Protein Aggregates); 25702-74-3 (Ficoll); 30IQX730WE (Polyethylene Glycols); EC 2.4.1.- (Glycogen Phosphorylase, Muscle Form); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171022
[St] Status:MEDLINE


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[PMID]:29017075
[Au] Autor:Li XS; Li S; Kellermann G
[Ad] Endereço:Pharmasan Labs, Inc., 373 280th Street, Osceola, WI 54020, USA. Electronic address: xiaoguang.li@pharmasan.com.
[Ti] Título:A simple dilute and shoot approach incorporated with pentafluorophenyl (PFP) column based LC-MS/MS assay for the simultaneous determination of trimethylamine N-oxide and trimethylamine in spot urine samples with high throughput.
[So] Source:J Chromatogr B Analyt Technol Biomed Life Sci;1067:61-70, 2017 Nov 01.
[Is] ISSN:1873-376X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Determination of trimethylamine N-oxide (TMAO) and trimethylamine (TMA) in biological and environmental samples has drawn great attention recently due to their increasing association with human health and disease. It remains a challenge to simultaneously quantify TMAO and TMA in a simple, fast and cost-effective manner due to pre-analytical and analytical constraints. For the first time, we describe a dilute and shoot approach combined with LC-MS/MS detection for the simultaneous measurement of the analytes in spot urine samples with high throughput. Compared to the existing methods, the merits of the proposed assay include the use of a simple dilute and shoot approach (100-fold), small sample volume (10µL), short LC run on a PFP column (4.0min) and multi-analyte MS detection without sample cleanup, derivatization, evaporation and a HILIC column. Dilution, LC and MS parameters were optimized in detail. Method validation yielded a wide linearity for TMAO (1.0-400µg/mL) and TMA (0.025-10µg/mL) with a respective limit of quantitation of 1.0 and 0.025µg/mL. The quantitation was not affected by 41 major urinary components, structurally-related drugs and metabolites. The intra- and inter-day assay precisions were ≤3.6% and recoveries were 93.3%-103.3% for spiked quality control samples. The clinical utility of the alternative spot urine sampling approach compared to conventional 24h urine collection was supported by a significant correlation between the two sampling strategies (n=20, p<0.0001, r=0.757-0.862; slope=0.687-1.170) and no statistical difference in day-to-day biological variability (n=20). The applicability and reliability of the assay was verified by the assessment of reference intervals in a cohort of 118 healthy people. The proposed assay would be beneficial for the rapid and accurate determination of the increasingly important TMAO and TMA demanded in clinical, environmental, pharmaceutical and nutritional fields.
[Mh] Termos MeSH primário: Cromatografia Líquida/métodos
Ensaios de Triagem em Larga Escala/métodos
Metilaminas/urina
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Adulto
Feminino
Fluorbenzenos
Seres Humanos
Limite de Detecção
Modelos Lineares
Masculino
Meia-Idade
Fenóis
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorobenzenes); 0 (Methylamines); 0 (Phenols); A2YCF0YUHA (2,3,4,5,6-pentafluorophenol); FLD0K1SJ1A (trimethyloxamine); LHH7G8O305 (trimethylamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE


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[PMID]:28986254
[Au] Autor:Chase K; Doval F; Vershinin M
[Ad] Endereço:Department of Physics, Oregon State University, 301 Weniger Hall, Corvallis, OR 97331-6507, United States.
[Ti] Título:Enhanced stability of kinesin-1 as a function of temperature.
[So] Source:Biochem Biophys Res Commun;493(3):1318-1321, 2017 Nov 25.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kinesin-1 is a mechanochemical enzyme which mediates long distance intracellular cargo transport along microtubules in a wide variety of eukaryotic cells. Kinesin is also relatively easy to purify and shows robust function in vitro, leading to numerous proposals for using the kinesin-1/microtubule system for nanoscale transport in engineered devices. However, kinesin in vitro shows signs of degradation at ∼30 °C which severely limits its usability in biomimetic engineering. Notably, kinesin-1 functions robustly in animal cells at body temperatures as high as 40 °C which suggests that kinesin functioning can be stabilized beyond what is observed in vitro. The present study investigated the effect of trimethylamine N-oxide (TMAO) as a potential heat-protecting agent for kinesin function and microtubule stability. We show that at a concentration of 200 mM, TMAO can indeed stabilize kinesin-based motility up to a little over 50 °C and that such motility can be sustained for extended periods of time. Our results suggest that intracellular crowding (mimicked in vitro by TMAO) can indeed stabilize kinesin-1 at high temperatures and helps resolve a long standing discrepancy between thermal stability of kinesin-1 observed in vivo and in vitro. Moreover, when considered together with our previous report that kinesin-1 can function well down to near-freezing conditions, this study establishes kinesin-1/microtubule motility as a thermally viable engineering platform.
[Mh] Termos MeSH primário: Cinesina/química
Metilaminas/química
[Mh] Termos MeSH secundário: Animais
Cinesina/metabolismo
Microtúbulos/metabolismo
Estabilidade Proteica
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Methylamines); EC 3.6.4.4 (Kinesin); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE


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[PMID]:28942145
[Au] Autor:Sun G; Yin Z; Liu N; Bian X; Yu R; Su X; Zhang B; Wang Y
[Ad] Endereço:Department of Nephrology, Shengjing Hospital, China Medical University, China. Electronic address: sun-guangping@hotmail.com.
[Ti] Título:Gut microbial metabolite TMAO contributes to renal dysfunction in a mouse model of diet-induced obesity.
[So] Source:Biochem Biophys Res Commun;493(2):964-970, 2017 Nov 18.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Emerging evidence shows that obesity induces renal injury and is an independent risk factor for the development of chronic kidney disease (CKD), even without diabetes or hyperglycemia. Although multiple metabolic factors have been suggested to account for obesity-associated renal injury, the precious underlying mechanisms are not completely understood. Recent study shows that increased trimethylamine N-Oxide (TMAO), a gut microbiota-generated metabolite, directly contributes to renal interstitial fibrosis and dysfunction. Circulating TMAO is elevated in high-fat diets (HFD)-induced obese animals. Here we tested the hypothesis that elevated TMAO might play a contributory role in the development of renal dysfunction in a mouse model of HFD-induced obesity that mimics human obesity syndrome. Male C57BL/6 mice received either a low-fat diet (LFD) or a HFD, without or with 3,3-Dimethyl-1-butanol (DMB, a trimethylamine formation inhibitor) for 16 weeks. Compared with mice fed a LFD, mice fed a HFD developed obesity and metabolic disorders, and exhibited significantly elevated plasma TMAO levels at the end of the experiment. Molecular and morphological studies revealed that renal interstitial fibrosis, phosphorylation of SMAD3 (a key regulator of renal fibrosis), expression of kidney injury molecule-1 and plasma cystatin C were significantly increased in mice fed a HFD, compared with mice fed a LFD. Additionally, expression of NADPH oxidase-4 and pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1 ß was also augmented in mice fed a HFD as compared to mice fed a LFD. These molecular and morphological alterations observed in mice fed a HFD were prevented by concomitant treatment with DMB, which reduced plasma TMAO levels. Furthermore, elevated circulating TMAO levels were positively correlated with increased renal interstitial fibrosis and expression of kidney injury molecule-1. Notable, there was no difference in blood pressure among groups, and DMB treatment had no effects on body weight and metabolic parameters. These data suggest that HFD-induced obesity leads to elevations in gut microbiota-generated metabolite TMAO in the circulation, which contributes to renal interstitial fibrosis and dysfunction by promoting renal oxidative stress and inflammation. These findings may provide new insights into the mechanisms underlying obesity-associated CKD. Targeting TMAO may be a novel strategy for prevention and treatment of CKD in patients with obesity.
[Mh] Termos MeSH primário: Microbioma Gastrointestinal
Nefropatias/metabolismo
Metilaminas/metabolismo
Obesidade/metabolismo
[Mh] Termos MeSH secundário: Animais
Dieta Hiperlipídica/efeitos adversos
Modelos Animais de Doenças
Hemodinâmica
Inflamação/sangue
Inflamação/etiologia
Inflamação/metabolismo
Inflamação/microbiologia
Rim/patologia
Nefropatias/sangue
Nefropatias/etiologia
Nefropatias/microbiologia
Masculino
Metilaminas/sangue
Camundongos
Camundongos Endogâmicos C57BL
Obesidade/sangue
Obesidade/etiologia
Obesidade/microbiologia
Estresse Oxidativo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Methylamines); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170925
[St] Status:MEDLINE


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[PMID]:28935756
[Au] Autor:Trenteseaux C; Gaston AT; Aguesse A; Poupeau G; de Coppet P; Andriantsitohaina R; Laschet J; Amarger V; Krempf M; Nobecourt-Dupuy E; Ouguerram K
[Ad] Endereço:From the UMR 1280 Physiopathologie des Adaptations Nutritionnelles, INRA, Université de Nantes, France (C.T., G.P., P.d.C., V.A., M.K., E.N.-D., K.O.); Centre de Recherche en Nutrition Humaine Ouest, Nantes, France (C.T., A.A., M.K., K.O.); UMR1063 Stress Oxydant et Pathologies Métaboliques, INSERM,
[Ti] Título:Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids.
[So] Source:Arterioscler Thromb Vasc Biol;37(11):2053-2063, 2017 Nov.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. APPROACH AND RESULTS: Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic and but higher gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in and gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower gene expression compared with female born to normocholesterolemic mothers. DNA methylation of , and promoter regions was slightly modified and may explain the mRNA expression modulation. CONCLUSIONS: Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
[Mh] Termos MeSH primário: Doenças da Aorta/metabolismo
Aterosclerose/metabolismo
Ácidos e Sais Biliares/metabolismo
Hipercolesterolemia/metabolismo
Metilaminas/metabolismo
Efeitos Tardios da Exposição Pré-Natal
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Animais Recém-Nascidos
Aorta/metabolismo
Aorta/patologia
Doenças da Aorta/etiologia
Doenças da Aorta/genética
Doenças da Aorta/patologia
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Aterosclerose/etiologia
Aterosclerose/genética
Aterosclerose/patologia
Colesterol/metabolismo
Colesterol 7-alfa-Hidroxilase/genética
Colesterol 7-alfa-Hidroxilase/metabolismo
Metilação de DNA
Modelos Animais de Doenças
Feminino
Vesícula Biliar/metabolismo
Predisposição Genética para Doença
Hipercolesterolemia/complicações
Hipercolesterolemia/genética
Fígado/metabolismo
Masculino
Camundongos Knockout
Oxigenases/genética
Oxigenases/metabolismo
Fenótipo
Placa Aterosclerótica
Gravidez
Regiões Promotoras Genéticas
Receptores Citoplasmáticos e Nucleares/genética
Receptores Citoplasmáticos e Nucleares/metabolismo
Receptores de LDL/genética
Receptores de LDL/metabolismo
Receptores Depuradores Classe B/genética
Receptores Depuradores Classe B/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Bile Acids and Salts); 0 (Methylamines); 0 (Receptors, Cytoplasmic and Nuclear); 0 (Receptors, LDL); 0 (Scarb1 protein, mouse); 0 (Scavenger Receptors, Class B); 0 (farnesoid X-activated receptor); 97C5T2UQ7J (Cholesterol); EC 1.13.- (Oxygenases); EC 1.14.13.8 (dimethylaniline monooxygenase (N-oxide forming)); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); FLD0K1SJ1A (trimethyloxamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309923



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