The knowledge of the pathogenesis of obesity and its metabolic sequelae has significantly advanced over the last few decades and adipose tissue is now considered a link between obesity and insulin ...resistance. Adiponectin, one of the major adipocyte-secreted proteins, has attracted scientific interest in recent years and has been extensively studied both in human and animal models. Adiponectin exerts insulin-sensitizing effects through binding to its receptors, leading to activation of AMPK, PPAR-α, and potentially other unknown molecular pathways. In obesity-linked insulin resistance, both adiponectin and adiponectin receptors are downregulated, leading to activation of signaling pathways involved in metabolism regulation. Up-regulation of adiponectin/adiponectin receptors or enhancing adiponectin receptor function may be an interesting therapeutic strategy for obesity-linked insulin resistance. In this review we will focus on the recent research related to the relationship between the adiponectin system and insulin resistance. The potential use of adiponectin or its receptor for therapeutic intervention will be also discussed.
•Adiponectin exerts insulin-sensitizing effects by binding to its receptors on target tissues.•Adiponectin system is downregulated in insulin resistance.•Up-regulation of adiponectin may represent a therapeutic strategy for insulin resistance.•Several strategies have been suggested for increasing the favorable effects of adiponectin.
We assessed whether high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, expressed by an increased TG/HDL-C ratio, predict coronary atherosclerotic disease (CAD) ...outcomes in patients with stable angina. We studied 355 patients (60 ± 9 years, 211 males) with stable angina who underwent coronary computed tomography angiography (CTA), were managed clinically and followed for 4.5 ± 0.9 years. The primary composite outcome was all-cause mortality and non-fatal myocardial infarction. At baseline, the proportion of males, patients with metabolic syndrome, diabetes and obstructive CAD increased across TG/HDL-C ratio quartiles, together with markers of insulin resistance, hepatic and adipose tissue dysfunction and myocardial damage, with no difference in total cholesterol or LDL-C. At follow-up, the global CTA risk score (HR 1.06, 95% confidence interval (CI) 1.03-1.09, P = 0.001) and the IV quartile of the TG/HDL-C ratio (HR 2.85, 95% CI 1.30-6.26, P < 0.01) were the only independent predictors of the primary outcome. The TG/HDL-C ratio and the CTA risk score progressed over time despite increased use of lipid-lowering drugs and reduction in LDL-C. In patients with stable angina, high TG and low HDL-C levels are associated with CAD related outcomes independently of LDL-C and treatments.Trial registration. EVINCI study: ClinicalTrials.gov NCT00979199, registered September 17, 2009; SMARTool study: ClinicalTrials.gov NCT04448691, registered June 26, 2020.
AIM:To determine the clinical effectiveness of intense psychological support to physical activity(PA)in nonalcoholic fatty liver disease(NAFLD),compared with cognitive-behavioral ...treatment(CBT).METHODS:Twenty-two NAFLD cases received support to exercise,tailored to their motivational needs(PA group).The effects on body weight,physical fitness6-min walk test,VO2max and the PA-rating(PA-R)questionnaireand body fat(fatty liver indices and visceral adiposity index)were compared with data obtained in 44 NAFLD subjects enrolled in a CBT program for weight loss,after adjustment for propensity score,calculated on baseline data.Measurements were performed at baseline,at 4-mo and one-year follow-up.Changes in anthropometric,biochemical and PA parameters were tested by repeated measurement ANOVA.Outcome results were tested by logistic regression analysis.RESULTS:At the end of the intensive program,BMI was less significantly reduced in the PA group(-1.09±1.68 kg/m2 vs-2.04±1.42 kg/m2 in the CBT group,P=0.019)and the difference was maintained at 1-year follow-up(-0.73±1.63 vs-1.95±1.88,P=0.012)(ANOVA,P=0.005).PA-R was similar at baseline,when only 14%of cases in PA and 36%in CBT(P=0.120)recorded values≥3.At 4 mo,a PA-R≥3 was registered in 91%of PA and 46%of CBT,respectively(P<0.001)and PA-R≥5(up to 3 h/wk of moderate-toheavy intensity physical activity)was registered in 41%of PA and only 9%of CBT group(P<0.007).The6-min walk test increased by 139±26 m in PA and by only 43±38 m in CBT(P<0.001)and VO2max by8.2±3.8 mL/kg per minute and 3.3±2.7 mL/kg per minute,respectively(P<0.002).After adjustment for propensity,weight loss>7%was significantly associated with CBT group at one year(OR=6.21;95%CI:1.23-31.30),whereas PA-R>3 was associated with PA group(10.31;2.02-52.63).Liver enzymes decreased to values within normal limits in 36%of PA cases and61%of CBT(P<0.070).Estimated liver fat(Kotronen index)fell below the fatty liver threshold in 36%of PA and 34%and CBT cases at one-year(not different).Also the fatty liver index and the visceral adiposity index improved to a similar extent.CONCLUSION:Intensive psychological counseling for PA produces hepatic effects not different from standard CBT,improving physical fitness and liver fat independent of weight loss.Strategies promoting exercise are worth and effective in motivated patients,particularly in lean NAFLD patients where large weight loss cannot be systematically pursued.
Recently osteopontin (OPN), a protein of the extracellular matrix, has generated in hepatocellular carcinoma (HCC) a significant interest as a prognostic factor. Aim of this study was to confirm, in ...liver tissues of subjects with HCV-positive HCC undergoing liver transplantation (RL, n=10) and of donors (DL, n=14), the increase of OPN plasma and tissue concentration, the OPN splicing isoforms expression profiling together with those of thrombin, and to evaluate a possible association between OPN measurements. Their association with Notch-1, IV-Collagen-7s domain, IL-6 and TNF-α were also evaluated. Real-Time PCR experiments and immunometric assay were performed. mRNA expression resulted higher in RL than in DL for all analyzed genes and several correlations were found between them. The more relevant association were between OPN-a and OPN-b (p<0.0001), between thrombin and OPN-a (p=0.007), between 7s-collagen and OPN isoforms (p<0.05) and between Notch-1 with OPN-c (p=0.004). Both OPN plasma and liver tissue extract concentrations were assessed confirming the trend observed at the mRNA level. An important association was found between OPN plasma and protein (p<0.0001, r=0.96) even splitting patients in DL (p<0.0001, r=0.93) and RL (p<0.0001, r=0.96). A reduction of OPN plasma levels was found at 6months after transplantation. Considering MELD score as liver disease severity, the mRNA expression of our markers as well as of OPN plasma and tissue concentrations resulted increased as a function of clinical severity. Our results might be considered a useful starting point to validate OPN as a prognostic and diagnostic marker of HCC.
Aim of this study was to evaluate the relationship of plasma PCSK9 with metabolic and inflammatory profile and coronary atherosclerotic burden in patients with suspected CAD enrolled in the EVINCI ...study.
PCSK9 was measured in 539 patients (60.3 ± 8.6 years, 256 males) with symptoms of CAD characterized by risk factors, bio-humoral profiles, and treatment. N = 412 patients underwent coronary computed tomography angiography (CTA) to assess the presence and characteristics of coronary atherosclerosis. A CTA score, combining extent, severity, composition, and location of plaques was computed.
Patients were divided according to PCSK9 quartiles: I (< 136 ng/mL), II-III (136-266 ng/mL), and IV quartile (> 266 ng/mL). Compared with patients in quartile IV, patients in quartile I had a higher prevalence of the metabolic syndrome and higher values of body mass index. LDL- and HDL-cholesterol were significantly lower in patients in the quartile I than in those in quartile IV. Coronary CTA documented normal vessels in 30% and obstructive CAD in 35% of cases without differences among PCSK9 quartiles. Compared with patients with the highest levels, patients with the lowest PCSK9 levels had a higher CTA score mainly due to higher number of mixed non-obstructive coronary plaques. At multivariable analysis including clinical, medications, and lipid variables, PCSK9 was an independent predictor of the CTA score (coefficient - 0.129, SE 0.03, P < 0.0001), together with age, male gender, statins, interleukin-6, and leptin.
In patients with stable CAD, low PCSK9 plasma levels are associated with a particular metabolic phenotype (low HDL cholesterol, the metabolic syndrome, obesity, insulin resistance and diabetes) and diffuse non-obstructive coronary atherosclerosis. Trial registration ClinicalTrials.gov NCT00979199. Registered September 17, 2009.
The endothelial nitric oxide synthase (eNOS) gene deficiency is known to cause impaired coronary vasodilating capability in animal models. In the general clinical population, the eNOS gene ...polymorphisms, able to affect eNOS activity, were associated with cardiometabolic risk features and prevalence of coronary artery disease (CAD).
To investigate the association of eNOS Glu298Asp gene polymorphism, cardiometabolic profile, obstructive CAD and inducible myocardial ischemia in patients with suspected stable CAD.
A total of 506 patients (314 males; mean age 62 ± 9 years) referred for suspected CAD was enrolled. Among these, 325 patients underwent stress ECG or cardiac imaging to assess the presence of inducible myocardial ischemia and 436 patients underwent non-invasive computerized tomography or invasive coronary angiography to assess the presence of obstructive CAD. Clinical characteristics and blood samples were collected for each patient.
In the whole population, 49.6% of patients were homozygous for the Glu298 genotype (Glu/Glu), 40.9% heterozygotes (Glu/Asp) and 9.5% homozygous for the 298Asp genotype (Asp/Asp). Obstructive CAD was documented in 178/436 (40.8%) patients undergoing coronary angiography while myocardial ischemia in 160/325 (49.2%) patients undergoing stress testing. Patients with eNOS Asp genotype (Glu/Asp + Asp/Asp) had no significant differences in clinical risk factors and in circulating markers. Independent predictors of obstructive CAD were age, gender, obesity, and low HDL-C. Independent predictors of myocardial ischemia were gender, obesity, low HDL-C and Asp genotype. In the subpopulation in which both stress tests and coronary angiography were performed, the Asp genotype remained associated with increased myocardial ischemia risk after adjustment for obstructive CAD.
In this population, low-HDL cholesterol was the only cardiometabolic risk determinant of obstructive CAD. The eNOS Glu298Asp gene polymorphism was significantly associated with inducible myocardial ischemia independently of other risk factors and presence of obstructive CAD.
ObjectiveExternally validated pretest probability models for risk stratification of subjects with chest pain and suspected stable coronary artery disease (CAD), determined through invasive coronary ...angiography or coronary CT angiography, are analysed to characterise the best validation procedures in terms of discriminatory ability, predictive variables and method completeness.DesignSystematic review and meta-analysis.Data sourcesGlobal Health (Ovid), Healthstar (Ovid) and MEDLINE (Ovid) searched on 22 April 2020.Eligibility criteriaWe included studies validating pretest models for the first-line assessment of patients with chest pain and suspected stable CAD. Reasons for exclusion: acute coronary syndrome, unstable chest pain, a history of myocardial infarction or previous revascularisation; models referring to diagnostic procedures different from the usual practices of the first-line assessment; univariable models; lack of quantitative discrimination capability.MethodsEligibility screening and review were performed independently by all the authors. Disagreements were resolved by consensus among all the authors. The quality assessment of studies conforms to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). A random effects meta-analysis of area under the receiver operating characteristic curve (AUC) values for each validated model was performed.Results27 studies were included for a total of 15 models. Besides age, sex and symptom typicality, other risk factors are smoking, hypertension, diabetes mellitus and dyslipidaemia. Only one model considers genetic profile. AUC values range from 0.51 to 0.81. Significant heterogeneity (p<0.003) was found in all but two cases (p>0.12). Values of I2 >90% for most analyses and not significant meta-regression results undermined relevant interpretations. A detailed discussion of individual results was then carried out.ConclusionsWe recommend a clearer statement of endpoints, their consistent measurement both in the derivation and validation phases, more comprehensive validation analyses and the enhancement of threshold validations to assess the effects of pretest models on clinical management.PROSPERO registration numberCRD42019139388.
Osteopontin (OPN) is a phosphoglycoprotein of cardiac extracellular matrix and it is still poorly defined whether its expression changes in failing heart of different origin. The full-length OPN-a ...and its isoforms (OPN-b, OPN-c) transcriptomic profile were evaluated in myocardium of patients with dilated or ischemic cardiomyopathy (DCM n = 8; LVEF% = 17.5±3; ICM n = 8; LVEF% = 19.5±5.2) and in auricle of valvular patients (VLP n = 5; LVEF%≥50), by Real-time PCR analysis. OPN-a and thrombin mRNA levels resulted significantly higher in DCM compared to ICM patients (DCM:31.3±7.4, ICM:2.7±1.1, p = 0.0002; DCM:19.1±4.9, ICM:5.4±2.2, p = 0.007, respectively). Although both genes' mRNA levels increased in patients with LVEF<50% (DCM+ICM) with respect to VLP with LVEF>50%, a significant increase in OPN (p = 0.0004) and thrombin (p = 0.001) expression was observed only in DCM. In addition, a correlation between OPN-a and thrombin was found in patients with LVEF<50% (r = 0.6; p = 0.003). The mRNA pattern was confirmed by OPN-a cardiac protein concentration (VLP:1.127±0.26; DCM:1.29±0.22; ICM:1.00±0.077 ng/ml). The OPN splice variants expression were detectable only in ICM (OPN-b: 0.357±0.273; OPN-c: 0.091±0.033) and not in DCM patients. A significant correlation was observed between collagen type I, evaluated by immunohistochemistry analysis, and both OPN-a mRNA expression (r = 0.87, p = 0.002) and OPN protein concentrations (r = 0.77, p = 0.016). Concluding, OPN-a and thrombin mRNA resulted dependent on the origin of heart failure while OPN-b and OPN-c highlighted a different expression for DCM and ICM patients, suggesting their correlation with different clinical-pathophysiological setting.
Circulating miRNAs (c-miRNAs) are promising biomarkers for HF diagnosis and prognosis. There are no studies on HF pediatric patients undergoing VAD-implantation. Aims of this study were: to examine ...the c-miRNAs profile in HF children; to evaluate the effects of VAD on c-miRNAs levels; to in vitro validate putative c-miRNA targets. c-miRNA profile was determined in serum of HF children by NGS before and one month after VAD-implant. The c-miRNA differentially expressed were analyzed by real time-PCR, before and at 4 hrs,1,3,7,14,30 days after VAD-implant. A miRNA mimic transfection study in HepG2 cells was performed to validate putative miRNA targets selected through miRWalk database. Thirteen c-miRNAs were modified at 30 days after VAD-implant compared to pre-VAD at NSG, and, among them, six c-miRNAs were confirmed by Real-TimePCR. Putative targets of the validated c-miRNAs are involved in the hemostatic process. The in vitro study confirmed a down-regulatory effect of hsa-miR-409-3p towards coagulation factor 7 (F7) and F2. Of note, all patients had thrombotic events requiring pump change. In conclusion, in HF children, the level of six c-miRNAs involved in the regulation of hemostatic events changed after 30 days of VAD-treatment. In particular, the lowering of c-miR-409-3p regulating both F7 and F2 could reflect a pro-thrombotic state after VAD-implant.
Obesity is a complex pathology with interacting and confounding causes due to the environment, hormonal signaling patterns, and genetic predisposition. At present, the Zucker rat is an eligible ...genetic model for research on obesity and metabolic syndrome, allowing scrutiny of gene expression profiles. Real-time PCR is the benchmark method for measuring mRNA expressions, but the accuracy and reproducibility of its data greatly depend on appropriate normalization strategies. In the Zucker rat model, no specific reference genes have been identified in myocardium, kidney, and lung, the main organs involved in this syndrome. The aim of this study was to select among ten candidates (Actb, Gapdh, Polr2a, Ywhag, Rpl13a, Sdha, Ppia, Tbp, Hprt1 and Tfrc) a set of reference genes that can be used for the normalization of mRNA expression data obtained by real-time PCR in obese and lean Zucker rats both at fasting and during acute hyperglycemia. The most stable genes in the heart were Sdha, Tbp, and Hprt1; in kidney, Tbp, Actb, and Gapdh were chosen, while Actb, Ywhag, and Sdha were selected as the most stably expressed set for pulmonary tissue. The normalization strategy was used to analyze mRNA expression of tumor necrosis factor α, the main inflammatory mediator in obesity, whose variations were more significant when normalized with the appropriately selected reference genes. The findings obtained in this study underline the importance of having three stably expressed reference gene sets for use in the cardiac, renal, and pulmonary tissues of an experimental model of obese and hyperglycemic Zucker rats.
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