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1.
Nat Genet ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

2.
Nat Commun ; 10(1): 4130, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.

3.
Int J Cardiol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31521439

RESUMO

BACKGROUND: Electro-anatomical remodeling in atrial fibrillation (AF) is associated with disease initiation and progression. Troponin T (TropT) - a specific biomarker for myocardial damage - is associated with AF incidence. However, its association with AF progression is understudied. The aim of the current analysis was to investigate the association between TropT and AF progression phenotypes: persistent AF and left atrial low voltage areas (LVAs). METHODS: Patients undergoing first AF ablation were included into analyses. LVAs were determined using high-density maps and defined as <0.5 mV. Blood samples from femoral vein were collected before catheter ablation. The analysis of TropT serum concentrations was performed using a high-sensitive assay from Roche Diagnostics. Biomarkers, clinical, anthropometric and echocardiographic data were compared with healthy individuals from the epidemiological cohort. RESULTS: The study included 824 healthy individuals without overt cardiovascular disease (54 ±â€¯10 years, 40% males) from epidemiological cohort and 241 AF patients (64 ±â€¯11 years, 59% males, 59% persistent AF, 27% LVAs). Patients with AF had higher TropT levels and larger left atrium (LA), while healthy individuals had better renal function and ejection fraction (all p < 0.001). In clinical cohort, there were significant differences between TropT levels according to AF progression groups: paroxysmal AF without/with LVAs (n = 86/12), persistent AF without/with LVAs (n = 90/53): means 7.3, 12.9, 8.4, 11.3 pg/ml, p < 0.001, respectively. Similar findings were observed for LA and renal function (all p < 0.001). On ROC analysis, TropT significantly predicted LVAs (AUC 0.675, 95%CI 0.598-0.752, p < 0.001) in AF patients. CONCLUSIONS: TropT may be useful to differentiate AF progression phenotypes.

4.
Analyst ; 144(18): 5558-5570, 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31408068

RESUMO

Obesity is a known risk factor for breast cancer and a negative prognostic factor for cancer recurrence and survival. Several studies demonstrated that aggressive breast tumor cells contain higher numbers of intracellular lipid droplets (LDs). Here we applied simultaneous visualization, identification and quantification of the lipid accumulation in lipid droplets (LDs) of aggressive, human triple-negative MDA-MB-231 breast cancer cells treated with adipose tissue-conditioned medium (ACM) derived from overweight and obese patients. In addition to Oil Red O and AdipoRed fluorescent staining, label-free confocal Raman microspectroscopy (CRM) has been applied. CRM enables imaging of cell compartments as well as quantification and monitoring of specific biomolecules and metabolic processes on a single cell level. Interestingly, breast cancer cells incubated with ACM showed a significantly higher number of intracellular LDs. Cultivation of breast tumor cells with ACM of obese patients induced the formation of LDs with a 20-fold higher lipid concentration than cultivation with basal medium. This is in line with the significantly higher levels of NEFAs (non-esterified fatty acids) detected in the ACM obtained from obese patient compared to ACM obtained from overweight patients or basal medium. Further, by principal component analysis, we identified a significant increase in unsaturation, esterification and lipid to protein ratio in LDs in breast cancer cells incubated with ACM. CRM analyses might function as a valuable diagnostic tool to identify metabolic alterations in biological samples which in turn could provide more detailed insights in the pathogenesis of breast cancer in association with obesity.

5.
Thromb Res ; 180: 98-104, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31276978

RESUMO

INTRODUCTION: Little is known about peril constellations in primary hemostasis contributing to an acute myocardial infarction (MI) in patients with already manifest atherosclerosis. The study aimed to establish a predicting model based on six biomarkers of primary hemostasis: platelet count, mean platelet volume, hematocrit, soluble glycoprotein VI, fibrinogen and von Willebrand factor ratio. MATERIALS AND METHODS: The biomarkers were measured in 1.491 patients with manifest atherosclerosis of the Leipzig (LIFE) heart study. Three groups were divided: patients with coronary artery disease (900 patients) and patients with atherosclerosis and either ST-elevated MI (404 patients) or Non-ST-elevated MI (187 patients). Correlations were analyzed by non-linear analysis with Self Organizing Maps. Classification and discriminant analysis was performed using Learning Vector Quantization. RESULTS AND CONCLUSIONS: The combination of hemostatic biomarkers is regarded as valuable tool for identifying patients with atherosclerosis at risk for MI. Nevertheless, our study contradicts this belief. The biomarkers did not allow to establish a predicting model usable in daily patient care. Good specificity and sensitivity for the detection of MI was only reached in models including acute phase parameters (specificity 0,9036, sensitivity 0,7937 in men; 0,8977 and 0,8133 in women). In detail, hematocrit and soluble glycoprotein VI were significantly different between the groups. Significant dissimilarities were also found for fibrinogen (in men) and von Willebrand factor ratio. In contrast, the most promising parameters mean platelet volume and platelet count showed no difference, which is an important contribution to the controversy concerning them as new risk and therapy targets for MI.

6.
Cells ; 8(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349725

RESUMO

Aging is a risk factor for adipose tissue dysfunction, which is associated with inflammatory innate immune mechanisms. Since the adipose tissue/liver axis contributes to hepatosteatosis, we sought to determine age-related adipose tissue dysfunction in the context of the activation of the innate immune system fostering fatty liver phenotypes. Using wildtype and immune-deficient mice, we compared visceral adipose tissue and liver mass as well as hepatic lipid storage in young (ca. 14 weeks) and adult (ca. 30 weeks) mice. Adipocyte size was determined as an indicator of adipocyte function and liver steatosis was quantified by hepatic lipid content. Further, lipid storage was investigated under normal and steatosis-inducing culture conditions in isolated hepatocytes. The physiological age-related increase in body weight was associated with a disproportionate increase in adipose tissue mass in immune-deficient mice, which coincided with higher triglyceride storage in the liver. Lipid storage was similar in isolated hepatocytes from wildtype and immune-deficient mice under normal culture conditions but was significantly higher in immune-deficient than in wildtype hepatocytes under steatosis-inducing culture conditions. Immune-deficient mice also displayed increased inflammatory, adipogenic, and lipogenic markers in serum and adipose tissue. Thus, the age-related increase in body weight coincided with an increase in adipose tissue mass and hepatic steatosis. In association with a (pro-)inflammatory milieu, aging thus promotes hepatosteatosis, especially in immune-deficient mice.

7.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
8.
Curr Opin Lipidol ; 30(3): 260-261, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31045609
9.
PLoS One ; 14(2): e0212627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818393

RESUMO

BACKGROUND: PR interval prolongation is associated with increased risk for atrial fibrillation (AF). Different biomarkers are used to predict AF incidence and its outcomes. The aim of this study was to investigate the association between echocardiographic parameters and blood biomarkers in PR interval groups and AF. METHODS: The LIFE-Adult-Study is a population-based cohort study of randomly selected participants from Leipzig, Germany. In this cross-sectional analysis, individuals ≥40 years with available echocardiographic (LA diameter, EF) and laboratory data (creatinine, Troponin, NT-proBNP) were included. RESULTS: The study population comprised 1.429 individuals (median age 56 (IQR 48-66) years, 40% males) with complete ECG, echocardiographic and laboratory data. There were 48 (3.4%) individuals with AF, 177 (12.4%) with short, 138 (9.7%) with prolonged and 1.066 (74.5%) with normal PR interval. Individuals with PR interval prolongation had larger LA diameter, higher Troponin and NT-proBNP levels than individuals with normal PR interval, but lower than AF group (p<0.001). In contrast, eGFR was significantly higher in the group with PR interval prolongation than in AF, but lower than in individuals with normal PR interval (p<0.001). In the multivariate analysis, PR interval prolongation and AF shared similar characteristics, the only parameter different between both groups was NT-proBNP. CONCLUSIONS: Individuals with PR interval prolongation and AF showed similarities in echocardiographic parameters, renal function and blood biomarker levels. Longitudinal studies are necessary to prove whether the PR interval prolongation may be considered as preliminary stage for AF.

10.
Biomolecules ; 9(4)2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925749

RESUMO

Short chain fatty acids (SCFAs) are generated by the degradation and fermentation of complex carbohydrates, (i.e., dietary fiber) by the gut microbiota relevant for microbe⁻host communication. Here, we present a method for the quantification of SCFAs in fecal samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) upon derivatization to 3-nitrophenylhydrazones (3NPH). The method includes acetate, propionate, butyrate, and isobutyrate with a run time of 4 min. The reproducible (coefficients of variation (CV) below 10%) quantification of SCFAs in human fecal samples was achieved by the application of stable isotope labelled internal standards. The specificity was demonstrated by the introduction of a quantifier and qualifier ions. The method was applied to investigate the pre-analytic stability of SCFAs in human feces. Concentrations of SCFA may change substantially within hours; the degree and kinetics of these changes revealed huge differences between the donors. The fecal SCFA level could be preserved by the addition of organic solvents like isopropanol. An analysis of the colon content of mice either treated with antibiotics or fed with a diet containing a non-degradable and -fermentable fiber source showed decreased SCFA concentrations. In summary, this fast and reproducible method for the quantification of SCFA in fecal samples provides a valuable tool for both basic research and large-scale studies.


Assuntos
Ácidos Graxos Voláteis/análise , Animais , Cromatografia Líquida , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Controle de Qualidade , Espectrometria de Massas em Tandem
12.
J Lipid Res ; 60(4): 900-908, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30723096

RESUMO

Apolipoproteins are major structural and functional constituents of lipoprotein particles. As modulators of lipid metabolism, adipose tissue biology, and energy homeostasis, apolipoproteins may serve as biomarkers or potential therapeutic targets for cardiometabolic diseases. Mice are the preferred model to study metabolic disease and CVD, but a comprehensive method to quantify circulating apolipoproteins in mice is lacking. We developed and validated a targeted proteomics assay to quantify eight apolipoproteins in mice via proteotypic signature peptides and corresponding stable isotope-labeled analogs. The LC/MS/MS method requires only a 3 µl sample volume to simultaneously determine mouse apoA-I, apoA-II, apoA-IV, apoB-100, total apoB, apoC-I, apoE, and apoJ concentrations. ApoB-48 concentrations can be calculated by subtracting apoB-100 from total apoB. After we established the analytic performance (sensitivity, linearity, and imprecision) and compared results for selected apolipoproteins against immunoassays, we applied the method to profile apolipoprotein levels in plasma and isolated HDL from normocholesterolemic C57BL/6 mice and from hypercholesterolemic Ldl-receptor- and Apoe-deficient mice. In conclusion, we present a robust, quantitative LC/MS/MS method for the multiplexed analysis of eight apolipoproteins in mice. This assay can be applied to investigate the effects of genetic manipulation or dietary interventions on apolipoprotein levels in plasma and isolated lipoprotein fractions.

13.
Atherosclerosis ; 281: 17-24, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594773

RESUMO

BACKGROUND AND AIMS: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment. METHODS: ApoA-I, apoA-II, apoA-IV, apoB-100, apoC-I, apoC-III, apoE, and apoJ were simultaneously quantified in 3 µL EDTA-plasma by LC-MS/MS in a case-control subgroup of the Leipziger LIFE-Heart Study (N = 911). Confounder analysis with demographic, clinical covariates and serum lipids, cardiac, inflammatory, and hepatic markers were performed. Apos were associated with CAD, CAP, and PAD in a multivariate regression model. RESULTS: Fasting and statin therapy showed strongest effects on apo concentrations. Inverse correlations of HDL-related apos A-I, A-II, A-IV, and C-I were observed for troponin T and interleukin 6. Concentrations of apos A-II, B-100, C-I, and E were decreased under statin therapy. After adjustment for influencing factors and related lipids, only apoB-100 (odds ratio per one SD [OR], 1.39; 95% confidence interval [CI], 1.05-1.84) was independently associated with CAD while apoA-IV (OR, 0.74; 95% CI 0.58-0.95) indicated PAD. ApoB-100 (OR, 1.55; 95% CI, 1.18-2.04), apoC-III (OR, 1.30; 95% CI, 1.06-1.58), and apoE (OR, 1.34; 95% CI, 1.13-1.58) were associated with CAP. CONCLUSIONS: Triglyceride rich lipoproteins (TRLs) associated apos A-IV, B-100, C-III, and E are independently associated with stable ASCVD, providing further evidence for a potential role of TRLs in atherogenesis.

14.
J Emerg Med ; 56(2): 135-144, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30538084

RESUMO

BACKGROUND: Management of critically ill non-trauma patients in the resuscitation room of an emergency department (ED) is very challenging, and it is difficult to identify patients with a higher risk of death. Previous studies have shown that lactate indices can predict survival for selected diseases and syndromes. OBJECTIVE: As reported for other patient populations, we set out to determine whether admission lactate or lactate dynamics (LD) within 24 h can predict 30-day mortality in unselected critically ill non-traumatic patients. METHODS: In this retrospective study over a 1-year period, admission lactate, time weighted average lactate (LacTW) and LD of all critically ill adult patients admitted from ED to intensive care unit were analyzed. A linear regression model was implemented to estimate lactate data 1 h after admission. RESULTS: The admission lactate, LacTW, and LD within 24 h were analyzed from 392 critically ill patients. The overall 30-day mortality rate was around 29%. Admission lactate (4.1 ± 4.0 mmol/L vs. 6.6 ± 6.1 mmol/L; p < 0.01) and LacTW (1.8 ± 1.7 mmol/L vs. 4.1 ± 4.8 mmol/L; p < 0.01) were different between survivors and non-survivors. LD between survivors and non-survivors did not differ at 1 h, 6 h, 12 h, or 24 h. After excluding patients with out-of-hospital or in-hospital cardiac arrest during resuscitation room management, admission lactate and LD between survivors and non-survivors did not differ at 1 h, 12 h, and 24 h. LD at 6 h (44% ± 42% vs. 33% ± 58%; p = 0.042) and LacTW (1.7 ± 1.6 mmol/L vs. 2.6 ± 3.0 mmol/L; p < 0.01) did differ. CONCLUSIONS: In critically ill ED patients initially requiring treatment in a resuscitation room setting, LD at 6 h and LacTW may predict their survival beyond 30 days. These findings need to be confirmed in a prospective study design.


Assuntos
Estado Terminal/classificação , Ácido Láctico/análise , Ressuscitação/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Estado Terminal/epidemiologia , Estado Terminal/terapia , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Ácido Láctico/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ressuscitação/métodos , Ressuscitação/normas , Estudos Retrospectivos
15.
Int J Cardiol ; 274: 319-325, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30077532

RESUMO

BACKGROUND: A significant proportion of patients develop left ventricular (LV) remodeling leading to heart failure after acute myocardial infarction (AMI). Being able to identify these patients would represent a step forward towards personalized medicine. The present study aimed to determine the ability of cyclin dependent kinase inhibitor 1C (CDKN1C) to risk stratify AMI patients, in a sex-specific manner. METHODS: CDKN1C expression was measured in blood samples obtained at admission in a test cohort of 447 AMI patients and a validation cohort of 294 patients. The study end-point was LV function assessed by the ejection fraction (EF) at follow-up. RESULTS: In the test cohort, CDKN1C was lower in patients with a reduced EF (<40%) compared to patients with preserved EF (≥50%). This observation was specific to women. CDKN1C was a significant univariate predictor of LV function in women only. In multivariable analysis including demographic and clinical parameters, CDKN1C predicted LV function in women (odds ratio [95% confidence interval] 0.44 [0.23-0.82]) but not in men (0.90 [0.70-1.16]). Addition of CDKN1C to a multivariable clinical model reduced the Akaike information criterion, attesting for an incremental predictive value, in women (p = 0.006) but not in men (p = 0.41). Bootstrap internal validation confirmed the added value of CDKN1C in women. The female-specific predictive value of CDKN1C was validated in the independent cohort. CONCLUSION: CDKN1C is a novel female-specific biomarker of LV function after AMI.


Assuntos
Inibidor de Quinase Dependente de Ciclina p57/genética , Regulação da Expressão Gênica , Infarto do Miocárdio/genética , RNA/genética , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Inibidor de Quinase Dependente de Ciclina p57/biossíntese , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fatores Sexuais
16.
Clin Nutr ; 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30591380

RESUMO

BACKGROUND & AIMS: While the world is extensively looking for alternatives to animal protein sources, it is not clear which plant sources can provide the requisite full complement of essential amino acids (EAAs). Wolffia globosa is an aquatic, edible duckweed, the smallest plant on earth, and it offers all nine EAAs, dietary fibers, polyphenols, iron, zinc and B12 vitamin. This work was designed to evaluate Mankai (a newly developed high-protein strain of W. globosa) as an optional bioavailable source of EAAs for humans (primary outcome), and of further nutrients such as vitamin B12, in comparison to well-established animal and plant protein sources; cheese and peas, respectively. METHODS: 36 men, subjected for 3 days to a stable diet and subsequent overnight (12 h) fast, were randomized to consume one of three iso-protein (30 g) based test-meals (soft cheese, green peas, Mankai). Blood samples were collected at 0, 30, 90 and 180 min. RESULTS: The 3 h blood concentrations of the EAAs: histidine, phenylalanine, threonine, lysine, and tryptophan, triggered by intake of Mankai, was essentially significant as compared to baseline (p < 0.05) and similar to that of soft cheese and pea changes (p > 0.05 between groups). Although branched-chain-amino-acids (leucine/isoleucine, valine) increased significantly by Mankai within 3 h (p < 0.05 vs. baseline), the change was relatively higher for cheese as compared to Mankai or peas (p < 0.05 between groups). The increase in vitamin B12 by Mankai was higher as compared to changes induced by either cheese (p=0.007) or peas (p=0.047, between groups). CONCLUSIONS: Mankai may provide a high-quality substitute source for animal protein, and a potential bioavailable source of vitamin B12.

17.
Biofactors ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30496627

RESUMO

Leptin influences inflammation and immune response. Dose-dependent effects of leptin on biomarkers of inflammation have not been studied in vivo, so far. Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR-/- ;ob/ob) female mice were treated with three different leptin doses or saline for 12 weeks. The effect of leptin on plasma interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 concentrations and Il-6 and Mcp-1 mRNA expression in vivo were assessed. Macrophage infiltration in epididymal adipose tissue (epiAT) after leptin treatment was determined by quantitative immunohistochemical analysis. Aortic root atherosclerotic lesions were analyzed by oil red O staining. Mean plasma IL-6 and MCP-1 decreased significantly in the 3.0 mg/kg BW/day group as compared to control mice (both P < 0.01). Messenger RNA expression of Il-6 and Mcp-1 was significantly down-regulated by leptin treatment in different adipose tissues in vivo. Characteristic crown-like structures formed by adipose tissue macrophages were significantly reduced by leptin treatment in epiAT. Recombinant leptin dose-dependently diminished plaque area in the aortic root. Leptin administration within the subphysiological to physiological range diminishes circulating pro-inflammatory IL-6 and MCP-1. Reduction of Il-6 and Mcp-1 gene expression in adipose tissue, as well as decreased adipose tissue macrophage infiltration might contribute. © 2018 BioFactors, 2018.

18.
Mol Metab ; 18: 15-24, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30348590

RESUMO

OBJECTIVE: The liver performs a central role in regulating energy homeostasis by increasing glucose output during fasting. Recent studies on Argonaute2 (Ago2), a key RNA-binding protein mediating the microRNA pathway, have illustrated its role in adaptive mechanisms according to changes in metabolic demand. Here we sought to characterize the functional role of Ago2 in the liver in the maintenance of systemic glucose homeostasis. METHODS: We first analyzed Ago2 expression in mouse primary hepatocyte cultures after modulating extracellular glucose concentrations and in the presence of activators or inhibitors of glucokinase activity. We then characterized a conditional loss-of-function mouse model of Ago2 in liver for alterations in systemic energy metabolism. RESULTS: Here we show that Ago2 expression in liver is directly correlated to extracellular glucose concentrations and that modulating glucokinase activity is adequate to affect hepatic Ago2 levels. Conditional deletion of Ago2 in liver resulted in decreased fasting glucose levels in addition to reducing hepatic glucose production. Moreover, loss of Ago2 promoted hepatic expression of AMP-activated protein kinase α1 (AMPKα1) by de-repressing its targeting by miR-148a, an abundant microRNA in the liver. Deletion of Ago2 from hyperglycemic, obese, and insulin-resistant Lepob/ob mice reduced both random and fasted blood glucose levels and body weight and improved insulin sensitivity. CONCLUSIONS: These data illustrate a central role for Ago2 in the adaptive response of the liver to fasting. Ago2 mediates the suppression of AMPKα1 by miR-148a, thereby identifying a regulatory link between non-coding RNAs and a key stress regulator in the hepatocyte.

19.
Sci Rep ; 8(1): 12811, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143737

RESUMO

Post-mortem biochemistry of serum markers has been the subject of numerous studies, but in-situ marker stability after death has not been sufficiently evaluated yet. Such laboratory analyses are especially necessary in the cases of functional deaths without morphological evidence of the death causes and also in cardiac death cases with only very short survival times. The aim of the study was to determine the post-mortem stability of commonly-used serum markers at predefined time points. In 20 cases, peripheral venous samples were taken starting immediately after circulatory arrest and ending 48 hours after death. Serum creatinine, urea, 3-ß-hydroxybutyrate, tryptase, myoglobin, troponin T, creatin kinase and creatin kinase-MB have been included. For all markers, we observed increasing marker levels for longer post-mortem intervals. Significant marker level changes began two hours after death. Excessive increases were observed for cardiac and muscle markers. Marker levels showed high intra-assay precision. Furthermore, the markers were robust enough to withstand freeze-thaw cycles. Potential contamination of arteriovenous blood did not influence the post-mortem marker levels. Post-mortem blood should be sampled as soon as possible, as increased post-mortem intervals may heavily change marker levels in-situ in individual cases, whereas the markers are mostly unaffected by laboratory conditions.

20.
Thromb Haemost ; 118(8): 1470-1480, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30060257

RESUMO

BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid and a constituent of high-density lipoprotein (HDL) exerting several atheroprotective effects in vitro. However, the few studies addressing anti-atherogenic effects of S1P in vivo have led to disparate results. We here examined atherosclerosis development in low-density lipoprotein receptor (LDL-R)-deficient (LDL-R-/-) mice with elevated endogenous S1P levels. METHODS AND RESULTS: Sub-lethally irradiated LDL-R-/- mice were transplanted with bone marrow deficient in sphingosine kinase 2 (SphK2), which led to the elevation of S1P concentrations in erythrocytes, plasma and HDL by approximately 1.5- to 2.0-fold in SphK2-/-/LDL-R-/- mice. Afterwards, mice were fed a Western diet for 14 weeks. Elevation of endogenous S1P significantly reduced atherosclerotic lesion formation by approximately half without affecting the plasma lipid profile. Furthermore, the macrophage content of atherosclerotic lesions and lipopolysaccharide-induced monocyte recruitment to the peritoneal cavity were reduced in SphK2-/-/LDL-R-/- mice. Studies using intra-vital microscopy revealed that endogenous S1P lowered leukocyte adhesion to capillary wall and decreased endothelial permeability to fluorescently labelled LDL. Moreover, SphK2-/-/LDL-R-/- mice displayed decreased levels of vascular cell adhesion molecule 1 in atherosclerotic lesions and in plasma. Studies in vitro demonstrated reduced monocyte adhesion and transport across an endothelial layer exposed to increasing S1P concentrations, murine plasma enriched in S1P or plasma obtained from SphK2-deficient animals. In addition, decreased permeability to fluorescence-labelled dextran beads or LDL was observed in S1P-treated endothelial cells. CONCLUSION: We conclude that raising endogenous S1P levels exerts anti-atherogenic effects in LDL-R-/- mice that are mediated by favourable modulation of endothelial function.

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