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INTRODUCTION: Plasma D-lactate levels can be considered a surrogate indicator of MG flux. There are commercial methods specifically designed to cover pathological ranges (mmol/l in sepsis or leaky gut) that are not suitable to encompass the metabolically relevant ranges. MATERIAL AND METHODS: We modified and optimized the D-lactate Colorimetric Assay kit MAK058 from Sigma adding an ultracentrifugation step, kinetic reading and increasing reaction temperature. RESULTS AND CONCLUSIONS: We present a modified, optimized and validated method to measure serum D-lactate using a commercial kit to increase the sensitivity of the method to 2 orders of magnitude lower as well as minimizing interferences so that it may be used by researchers to explore the D-lactate pathway in metabolic disorders at a low cost (colorimetric method and a plate reader) and with a much higher specificity.
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Aldeído Pirúvico , Sepse , Biomarcadores , Colorimetria , Humanos , Ácido Láctico/metabolismo , Aldeído Pirúvico/metabolismoRESUMO
Obesity can lead children and adolescents to an increased cardiovascular disease (CVD) risk. A diet supplemented with Plantago psyllium has been shown to be effective in reducing LDL-C and IL-6 in adolescents. However, there are no studies that have explored small-dense LDL (sdLDL) or HDL subclasses. The aim of this study was to evaluate the impact of a fiber dietary intervention on LDL and HDL subclasses in adolescents with obesity. In this parallel, double blind, randomized clinical trial, the participants were assigned to Plantago psyllium or placebo (10g/day for 7 weeks). We randomized 113 participants, and evaluated and analyzed 100 adolescents (50 in each group), 15 to 19 years with a body mass index of 29-34. We measured biochemical markers LDL and HDL subclasses using the Lipoprint system (Quantimetrix) and IL-6 by ELISA. Post-treatment there was a decrease in sdLDL between the groups 2.0 (0-5.0) vs 1 (0-3.0) mg/dl (p = 0.004), IL-6 median 3.32 (1.24-5.96) vs 1.76 (0.54-3.28) pg/ml, p <0.0001. There were no differences in HDL subclasses and no adverse effects were reported in either group.Conclusions: Small dense LDL and IL-6 reduced in adolescents with obesity when consuming Plantago psyllium. This may be an early good strategy for the reduction of cardiovascular disease risk in this vulnerable population.Trial registration: ISRCTN # 14180431. Date assigned 24/08/2020 What is Known: ⢠Supplementing the diet with Plantago psyllium lowers LDL-C levels. What is New: ⢠First evidence that soluble fiber supplementation like Plantago psyllium decreases small dense LDL particles in association with lowered IL-6, reducing the risk of cardiovascular disease in obese adolescents.
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Plantago , Psyllium , Adolescente , Criança , Método Duplo-Cego , Humanos , Interleucina-6 , ObesidadeRESUMO
Oxidative stress is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, reliable biomarkers of NAFLD in relation to oxidative stress are not available. While paraoxonase 1 (PON1) is an antioxidant biomarker, there appears to be mixed data on PON-1 in patients with NAFLD. The aim of this meta-analysis was to assess the current data on PON1 activity (i.e., paraoxonase and arylesterase) in patients with NAFLD. A PubMed, CENTRAL, and Embase search identified 12 eligible articles. In the meta-analysis, the paraoxonase activity was low in patients with NAFLD (mean difference (MD) -27.17 U/L; 95% confidence interval (CI) -37.31 to -17.03). No difference was noted in the arylesterase activity (MD 2.45 U/L; 95% CI -39.83 to 44.74). In a subgroup analysis, the paraoxonase activity was low in biopsy-proven nonalcoholic steatohepatitis (MD -92.11 U/L; 95% CI -115.11 to -69.11), while the activity in NAFLD as diagnosed by ultrasonography or laboratory data was similar (MD -2.91 U/L; 95% CI -11.63 to 5.80) to that of non-NAFLD. In summary, the PON1, especially paraoxonase, activity could be a useful biomarker of NAFLD. Further studies are warranted to ascertain the relevance of PON1 measurements in patients with NAFLD.
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Arildialquilfosfatase/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Arildialquilfosfatase/genética , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologiaRESUMO
Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90-94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m2; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-13C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.
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Apolipoproteína B-100/química , Quilomícrons/isolamento & purificação , Lipoproteínas/isolamento & purificação , Triglicerídeos/isolamento & purificação , Cromatografia de Afinidade , Quilomícrons/química , Feminino , Voluntários Saudáveis , Humanos , Imunoprecipitação , Lipoproteínas/química , Masculino , Período Pós-Prandial , Triglicerídeos/químicaRESUMO
BACKGROUND & AIMS: Consumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d). METHODS: Children (9-18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child. RESULTS: Compared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%-14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm3 (IQR, 85-145 cm3) to 110 cm3 (IQR, 84-134 cm3) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat. CONCLUSIONS: Short-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043.
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Carboidratos da Dieta/administração & dosagem , Frutose/administração & dosagem , Insulina/metabolismo , Gordura Intra-Abdominal , Lipogênese , Obesidade Infantil/fisiopatologia , Adolescente , Negro ou Afro-Americano , Criança , Feminino , Teste de Tolerância a Glucose , Hispânico ou Latino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Fígado/diagnóstico por imagem , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Obesidade Infantil/complicações , Gordura Subcutânea/diagnóstico por imagemRESUMO
BACKGROUND: Childhood obesity is associated with insulin resistance (IR), increased levels of small dense low-density lipoprotein (sd-LDL) as well as with augmented hepatic de novo lipogenesis, which implies increased triose phosphate fluxes that may lead to increased methylglyoxal (MG) and its catabolic end product D-lactate. We hypothesized that obese adolescents have increased D-lactate serum levels associated with high incidence of sd-LDL. METHODS: This is a cross-sectional study where the anthropometric characteristics, atherogenic dyslipidemia complex, sd-LDL (Lipoprint, Quantimetrix) and D-lactate (kinetic enzymatic analysis) were explored in 30 lean vs. 30 obese adolescents (16 females and 14 males per group) without metabolic syndrome (MetS). Endothelial function by flow-mediated dilation (FMD, by ultrasound) and arterial lesion by carotid intima media thickness (CIMT, by ultrasound) were also measured. RESULTS: The mean age of participants was 16.8 ± 1.4 years. Obese adolescents had a body mass index of 32.7 ± 3.8 vs. 21.8 ± 2.1 in lean participants. The obesity group showed higher D-lactate levels: 6.2 ± 3.0 vs. 4.5 ± 2.5 µmol/L, higher levels of insulin: 15 (9.6-23.5) vs. 7.9 (6.5-10.5) µIU/mL; triglyceride (TG): 1.46 (1.1-1.8) vs. 0.84 (0.6-1.2) mmol/L; non-high-density lipoprotein-cholesterol (NON-HDL-C): 2.8 ± 0.9 vs. 2.3 ± 0.7 mmol/L; total cholesterol (TC)/HDL-C) index: 2.9 ± 0.7 vs. 2.4 ± 0.5; TG/HDL-C index: 2.2 (1.5-2.8) vs. 1.1 (0.8-1.8); %LDL-3: 4.2 ± 4.07 vs. 1.9 ± 2.7; smaller LDL size: 270.6 ± 3 vs. 272.2 ± 1.1 Å. D-lactate correlated positively with LDL-2: r = 0.44 and LDL-3 (sd-LDL): r = 0.49 and negatively with large LDL-1: r = -0.48 and LDL size: r = -0.46; (p<0.05, p<0.01, p<0.001 and p<0.0001, respectively). Obese adolescents showed higher CIMT: 0.51 ± 0.08 vs. 0.46 ± 0.08 mm and lower FMD: 20.3% ± 6.7% vs. 26.0% ± 9.3%. CONCLUSIONS: Obese adolescents display subclinical signs of IR and endothelial dysfunction. Higher serum sd-LDL levels correlated positively with D-lactate levels. These findings suggest an association between atherogenic dyslipoproteinemia and whole body MG fluxes already detectable in apparently healthy obese adolescents.
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Ácido Láctico/sangue , Lipoproteínas LDL/sangue , Obesidade/fisiopatologia , Adolescente , Biomarcadores/sangue , Biomarcadores/química , Índice de Massa Corporal , Espessura Intima-Media Carotídea , Estudos Transversais , Dislipidemias/fisiopatologia , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Ácido Láctico/química , Masculino , México , Aldeído Pirúvico/metabolismo , Estereoisomerismo , Adulto JovemRESUMO
BACKGROUND: The receptor for AGE (RAGE) is a key mediator in cerebral ischemia. Based on the evidence from animal studies and the presence of increased high mobility group box 1 protein (HMGB1, a RAGE ligand) in the serum of stroke patients, we hypothesized that soluble RAGE (sRAGE) increase in serum after ischemic and hemorrhagic stroke and that the levels decrease with patient improvement. METHODS: We performed a longitudinal study of the acute changes of sRAGE levels in a series of 15 ischemic and hemorrhagic stroke patients at admission and over a period averaging 1 week and extending for up to more than a month in some of the cases. Serum sRAGE was measured by an enzyme-linked immunosorbent assay (R&D Systems Inc., Minneapolis, MN, USA). RESULTS: Serum sRAGE at admission were not significantly different between patients and healthy controls, p=0.17. Over the following days after the event, stroke patients displayed an increase of the serum levels of sRAGE, which at peak ranged between 26% and 296%, p>0.001. Similar changes are seen for both types of events, hemorrhagic and ischemic. sRAGE changes paralleled recovery and recurrence or aggravation of the episodes. Biological variability of sRAGE as measured daily in healthy subjects over 21 days showed a CV of only 8.9%. CONCLUSIONS: Our results provide for the first time a proof of principle that circulating sRAGE increase after ischemic and hemorrhagic stroke and may become candidate biomarkers to consider in larger studies exploring prognostic or follow-up value.
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Isquemia Encefálica/sangue , Receptores Imunológicos/sangue , Acidente Vascular Cerebral/sangue , Idoso , Isquemia Encefálica/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Proteína HMGB1/sangue , Humanos , Estudos Longitudinais , Masculino , Receptor para Produtos Finais de Glicação Avançada , Acidente Vascular Cerebral/patologiaRESUMO
Chronic kidney disease (CKD) has been shown to be associated with high oxidative stress and cardiovascular disease. In this chapter our focus will be on the role of advanced glycation end products (AGE) and their receptor, RAGE in CKD progression and their role on cardiovascular complications. We provide a succinct, yet comprehensive summary of the current knowledge, the challenges and the future therapeutic avenues that are stemming out from novel recent findings. We first briefly review glycation and AGE formation and the role of the kidney in their metabolism. Next, we focus on the RAGE, its signaling and role in oxidative stress. We address the possible role of soluble RAGEs as decoys and the controversy regarding this issue. We then provide the latest information on the specific role of both AGE and RAGE in inflammation and perpetuation of kidney damage in diabetes and in CKD without diabetes, which is the main purpose of the review. Finally, we offer an update on new avenues to target the AGE-RAGE axis in CKD.
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Doenças Cardiovasculares/metabolismo , Nefropatias Diabéticas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Rim/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Doenças Cardiovasculares/patologia , Nefropatias Diabéticas/patologia , Humanos , Rim/patologia , Insuficiência Renal Crônica/patologiaRESUMO
PURPOSE: Critical illnesses are assessed according to the sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II. Circulating ischemia-modified albumin (IMA) is a biomarker generated under ischemic and oxidative conditions and may reflect disease severity in preoperative patients. This study investigated the correlations of IMA with SOFA and APACHE II scores in inpatients admitted for colorectal surgery. METHODS: We examined 27 patients with advanced colorectal cancers (mean age 69 years, men/women=15/12). Correlations between SOFA and APACHE II scores in addition to preoperative serum IMA and C-reactive protein (CRP) levels were analyzed. RESULTS: The mean IMA level was 0.5 AU, and the median CRP level was 0.6 mg/dL. Median scores for SOFA and APACHE II were 2 and 12 points, respectively. Significant positive correlations between IMA and SOFA (r=0.45, P<0.05) and IMA and APACHE II (r=0.45, P<0.05) were identified which remained significant in confounder-adjusted analyses. In contrast, weak correlations were observed between CRP and the SOFA and APACHE II scores. CONCLUSIONS: The positive correlations between IMA and both SOFA and APACHE II scores suggest that serum IMA measurements reflect the severity of systemic failure in patients admitted for colorectal surgery in the preoperative phase.
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APACHE , Neoplasias Colorretais/sangue , Escores de Disfunção Orgânica , Cuidados Pré-Operatórios , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Albumina Sérica , Albumina Sérica HumanaRESUMO
For the past 30 years, statin therapy has been the cornerstone for the reduction in the risk of atherosclerotic cardiovascular disease (ASCVD) [...].
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The availability of sugar has expanded over the past 50 years, due to improved industrial processes and corn subsidies, particularly in the form of sweetened beverages. This correlates with a surge in the prevalence of cardiometabolic disorders, which has brought this issue back into the spotlight for public health. In this narrative review, we focus on the role of fructose in the genesis of cardiometabolic dyslipidemia (an increase in serum triglyceride-rich lipoproteins (TRL): VLDL, chylomicrons (CM), and their remnants) bringing together the most recent data on humans, which demonstrates the crucial interaction between glucose and fructose, increasing the synthesis while decreasing the catabolism of these particles in a synergistic downward spiral. After reviewing TRL metabolism, we discuss the fundamental principles governing the metabolism of fructose in the intestine and liver and the effects of dysregulated fructolysis, in conjunction with the activation of carbohydrate-responsive element-binding protein (ChREBP) by glucose and the resulting crosstalk. The first byproduct of fructose catabolism, fructose-1-P, is highlighted for its function as a signaling molecule that promotes fat synthesis. We emphasize the role of fructose/glucose interaction in the liver, which enhances de novo lipogenesis, triglyceride (TG) synthesis, and VLDL production. In addition, we draw attention to current research that demonstrates how fructose affects the activity of lipoprotein lipase by increasing the concentration of inhibitors such as apolipoprotein CIII (apoCIII) and angiopoietin-like protein 3 (ANGPTL3), which reduce the catabolism of VLDL and chylomicrons and cause the building up of their atherogenic remnants. The end outcome is a dual, synergistic, and harmful action that encourages atherogenesis. Thus, considering the growing concerns regarding the connection between sugar consumption and cardiometabolic disease, current research strongly supports the actions of public health organizations aimed at reducing sugar intake, including dietary guidance addressing "safe" limits for sugar consumption.
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The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as "remnants", is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.
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Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1-4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles' fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions.
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Aterosclerose , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Quilomícrons/metabolismo , Lipoproteínas VLDL/metabolismo , Período Pós-Prandial , Aterosclerose/metabolismoRESUMO
Oxidative stress is known to be associated with the pathophysiology of chronic kidney disease (CKD). Paraoxonase 1 (PON1) is an antioxidant enzyme that has been proposed as a biomarker for CKD. While several studies have reported an association between serum PON1 activity and CKD, consensus based on systematically analyzed data remains necessary. We set out to conduct a meta-analysis of literature on PON1 in CKD. Electronic databases, such as MEDLINE, Embase and CENTRAL, were searched for available studies on PON1 activity in patients with CKD (without dialysis) as published before December 2022. A random-effects meta-analysis was performed. In total, 24 studies (22 studies on paraoxonase and 11 on arylesterase activity) were eligibly identified. Patients with CKD showed a lower activity of paraoxonase (standard mean difference [SMD], -1.72; 95% confidence interval [CI], -2.15 to -1.29) and arylesterase (SMD, -2.60; 95%CI, -3.96 to -1.24) than healthy controls. In the subgroup analyses, paraoxonase activity was lower in chronic kidney failure (CKF), an advanced stage of CKD, than in non-CKF. In summary, PON1 activity is low in patients with CKD, suggesting that the antioxidant defense by PON1 is impaired in CKD. The decrease in enzyme activity is pronounced in advanced CKD showing some variability depending on the substrate employed to measure PON1 activity. Further studies are warranted.
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Chronic renal failure (CRF) is associated with the development of cardiovascular disease (CVD). Paraoxonase 1 (PON1), an antioxidant enzyme, shows cardioprotective properties and has been proposed as a therapeutic marker for CRF. A systematic analysis of the literature assessing the association between PON1 activity and renal replacement therapy (RRT) of CRF is currently lacking. Therefore, we set out to perform a meta-analysis of the available data on PON1 in RRT of CRF. We searched three electronic databases for studies on PON1 activity in CRF patients with RRT such as hemodialysis (HD), peritoneal dialysis (PD), or renal transplantation (RTx), published before June 2023. A random-effects and network meta-analysis were performed. A total of 53 studies were eligibly identified. Compared to CRF patients without RRT, RTx patients had higher paraoxonase activity (standard mean difference (SMD), 1.76, 95% confidence interval (CI), 0.76-2.75), followed by HD (SMD, 0.73; 95% CI, 0.02-1.45) and PD patients. Likewise, RTx patients had higher arylesterase activity (SMD, 1.84, 95% CI, 0.18-3.50), followed by HD and PD patients. Also, paraoxonase activity was increased after HD (SMD, 0.59, 95% CI, 0.16-1.03). In conclusion, the overall data demonstrated that PON1 activity is higher in CRF patients with RRT, particularly RTx, followed by that of HD and PD. Measuring PON1 activity can also be included to the paraclinical toolbox for the management of RRT, in addition to the understanding of CRF-related pathophysiology. Regarding the selection of RRT types and their potential to prevent CVD, more research is required.
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Glycation is implicated in neurological disorders. In some cases it plays a key role in the pathogenesis, in others it plays a co-adjuvant role or it appears as a consequence of degenerative changes and protein accumulation stemming from other pathways. In this work, we attempt to provide a concise, updated review of the major recent findings concerning glycation in neurological diseases. After a short introduction covering advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE), we will discuss the impact of glycation in central nervous system disorders including Alzheimer's, Parkinson's and Creutzfeldt-Jakob disease, as well as peripheral diabetic polyneuropathies. Therapies directed at lowering the concentrations of RAGE ligands including AGEs, blocking RAGE signaling, preventing oxidative stress or lowering methylglyoxal (MGO) levels may significantly decrease the development of AGE-related pathologies in patients with neurological disorders. Many drugs are on the pipeline and the future clinical trials will reveal if the promising results translate into clinical application.
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Produtos Finais de Glicação Avançada/metabolismo , Doenças do Sistema Nervoso/metabolismo , Animais , Glicosilação , Humanos , Doenças do Sistema Nervoso/patologia , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/metabolismo , Transdução de SinaisRESUMO
Dysfunctional visceral fat plays a key role in the initiation and maintenance of chronic inflammation, liver steatosis and subsequent systemic insulin resistance that primes the body for development of metabolic syndrome. These changes, occurring with or without obesity, lead to type 2 diabetes. In this chapter, we first provide a brief overview of the factors that lead to dysfunctional visceral fat and their relative importance. Adipose tissue has a great plasticity which allows for cell hypertrophy and, when needed, angiogenesis to sustain hypertrophy. Due to the prevalence of inexpensive and widely available "junk food," i.e., those enriched in fat, carbohydrate and sugar, this response becomes maladaptive. Hypertrophied adipocytes become hypoxic. Some undergo necrosis which induces macrophage recruitment forming crown structures wherein macrophages and leukocytes surround injured adipocytes. This leads to the ominous triad: inflammation, fibrosis (extracellular matrix hypertrophy) and impaired angiogenesis as well as consequent unresolved hypoxia. Adipokines and cytokines secreted by these crown structures as well as the palmitate fluxes due to excessive lipolysis are released from visceral adipose tissue to portal blood. They inundate the liver causing insulin resistance. In this review we explore the actions of adipokines, proteins and macrophage cytokines (adiponectin, leptin, FABP4, resistin, PAI-1, ANGPT3/4, IL-6 and TNFα) that normally intervene but whose action goes awry in the presence of inflammation and insulin resistance. We provide an assessment of their relative clinical utility as well as challenges associated with their use as biomarkers.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Adipocinas/metabolismo , Biomarcadores , Citocinas/metabolismo , Humanos , Hipertrofia , Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismoRESUMO
BACKGROUND: Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity. METHODS: This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42). RESULTS: As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C c, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant. CONCLUSION: Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).