Impact of metabolic syndrome on the outcome of patients with stable coronary artery disease: 2-year follow-up of the MASS II study

Objective We characterized the impact of the metabolic syndrome (MetS) and its components on cardiovascular adverse events in patients with symptomatic chronic multivessel coronary artery disease, which have been followed prospectively for 2 years. Methods Patients enrolled in the MASS II study were evaluated for each component of the MetS, as well as the full syndrome. Results The criteria for MetS were fulfilled in 52% of patients. The presence of MetS (P < 0.05), glucose intolerance (P=0.007), and diabetes (P=0.04) was associated with an increased mortality in our studied population. Moreover, despite a clear tendency for each of its components to increase the mortality risk, only the presence of the MetS significantly increased the risk of mortality among nondiabetic study participants in a multivariate model (P=0.03, relative risk 3.5, 95% confidence interval 1.1-6). Finally, MetS was still associated with increased mortality even after adjustment for diabetes status. These results indicate a strong and consistent relationship of the MetS with mortality in patients with stable coronary artery disease. Conclusion Although glucose homeostasis seems to be the major force driving the increased risk of MetS, the operational diagnosis of MetS still has information for stratifying patients when diabetes information is taken into account.

In Vivo Effects of Bothrops jararaca Venom on Metabolic Profile and on Muscle Protein Metabolism in Rats

This study investigated the in vivo effects of the Bothrops Jararaca venom (BjV) on general metabolic profile and, specifically. oil muscle protein metabolism in rats. The crude venom (0.4 mg/kg body weight, IV) was infused in awake rats, and plasma activity of enzymes and metabolites levels were determined after 1, 2, 3, and 4 hours. BjV increased urea, lactate, and activities of creatine kinase. lactate dehydrogenase. and aspartate aminotransferase after 4 hours. The content of liver glycogen was reduced by BjV. Protein metabolism was evaluated by means of microdialysis technique and in isolated muscles. BjV induced increase in the muscle interstitial-arterial tyrosine concentration difference. indicating a high protein catabolism. The myotoxicity induced by this venom is associated with reduction of protein synthesis and increase in rates of overall proteolysis, which was accompanied by activation of lysosomal and ubiquitin-proteasome systems without changes in protein levels of cathepsins and ubiquitin-protein conjugates.

Upper trunk fat assessment and its relationship with metabolic and biochemical variables and body fat in polycystic ovary syndrome

Background: Fat accumulation in the upper region of the body is common in polycystic ovary syndrome (PCOS) and is associated with metabolic complications. The present study aimed to assess the relationship between trunk circumference, metabolic indicators, and abdominal and visceral fat in obese PCOS women. Methods: The weight, fat mass, and subcutaneous arm fat (SAF) of 30 obese PCOS women and 15 healthy controls matched for age and body mass index were evaluated by bioelectrical impedance analysis. Trunk (TrC), neck (NC) and hip circumferences were measured, and the trunk/hip (Tr/H) ratio was determined. Total abdominal fat (TAF), visceral fat (VF) and trunk fat (TrF) were determined by computed tomography. Biochemical evaluation included glycaemia, insulinaemia, testosterone and lipid profile, insulin resistance (IR) was assessed by the QUICKI index. Results: In the PCOS group, there were positive correlations between NC and TAF (r = 0.49, P < 0.0006), TrC and VF (r = 0.62, P = 0.01), and NC and VF (r = 0.70, P < 0.0002). There was good correlation between TrC and TrF (r = 0.69, P = 0.003). TrF correlated with triglycerides levels positively (r = 0.44, P = 0.02). Women with PCOS and IR had a larger quantity of VF and TrF, but a smaller amount of SAF. Within the PCOS group, women with Tr/H ratio above the median had higher basal insulin levels and lower QUICKI indices compared to women presenting a Tr/H ratio below the median. Conclusions: TrC is associated with important metabolic variables in PCOS, proving to be a valuable and innovative tool for assessment of body adiposity distribution in obese PCOS women.

Enhanced concentrations of relevant markers of nitric oxide formation after exercise training in patients with metabolic syndrome

Metabolic syndrome (MetS) denotes a clustering of risk factors that may affect nitric oxide (NO) bioavailability and predispose to cardiovascular diseases, which are delayed by exercise training. However, no previous study has examined how MetS affects markers of NO formation, and whether exercise training increases NO formation in MetS patients. Here, we tested these two hypotheses. We studied 48 sedentary individuals: 20 healthy controls and 28 MetS patients. Eighteen MetS patients were subjected to a 3-month exercise training (E+group), while the remaining 10 MetS patients remained sedentary (E-group). The plasma concentrations of nitrite, cGMP, and ADMA (asymmetrical dimethylarginine: an endogenous nitric oxide synthase inhibitor), and the whole blood nitrite concentrations were determined at baseline and after exercise training using an ozone-based chemiluminescence assay, and commercial enzyme immunoassays. Thiobarbituric acid reactive species (TBA-RS) were measured in the plasma to assess oxidative stress using a fluorometric method. We found that, compared with healthy subjects, patients with MetS have lower concentrations of markers of NO formation, including whole blood nitrite, plasma nitrite, and plasma cGMP, and increased oxidative stress (all P < 0.05). Exercise training increased the concentrations of whole blood nitrite and cGMP, and decreased both oxidative stress and the circulating concentrations of ADMA (both P < 0.05). These findings show clinical evidence for lower endogenous NO formation in patients with MetS, and for improvements in NO formation associated with exercise training in MetS patients. (C) 2008 Elsevier Inc. All rights reserved.

Prevalence and risk factors of metabolic syndrome in Brazilian and Italian obese adolescents: a comparison study

Background: Metabolic syndrome (MS) prevalence between different populations in obese adolescents is scanty to date. Objective: To compare the MS prevalence and related risk factors in Brazilian and Italian obese adolescents. Methods: A total of 509 adolescents (110 Brazilian, 399 Italian), aged 15-19 years. Anthropometric characteristics, triglycerides (TG), total, low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-cholesterol, fasting plasma glucose (FPG), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and blood pressure were measured. Results: Age, body mass index (BMI) and BMI z-score were not significantly different between the two subgroups. BMI z-score, TG, FPG, HOMA-IR and systolic blood pressure (SBP) were significantly higher in boys than in girls both in Brazilian and Italian adolescents, while HDL-cholesterol levels were lower in boys than in girls. No significant differences were observed in BMI, LDL and total-cholesterol and DBP in two genders and groups. Insulin, FPG, HOMA-IR and TG were significantly higher, while LDL-cholesterol and SBP were significantly lower in Brazilian than in Italian subjects, both in males and females. HDL and total-cholesterol and diastolic blood pressure (DBP) were not significantly different between the two subgroups and genders. MS prevalence was higher in Brazilian than in Italian obese boys (34.8 vs. 23.6%, p < 0.001) and girls (15.6 vs. 12.5%, p < 0.01). The most frequently altered parameter was HOMA-IR both in subjects with MS (100% in Brazilian and 81.8% in Italian) and without MS (42.9% and 11.7%). Conclusion: Metabolic syndrome represents a worldwide emerging health problem in different ethnical populations, the alterations of the risk factors related to MS (different in their prevalence between different subgroups) being strictly linked to the degree of obesity.

Non-coding transcript in T cells (NTT): Antisense transcript activates PKR and NF-kappa B in human lymphocytes

T cell activation is a complex process involving many steps and the role played by the non-protein-coding RNAs (ncRNAs) in this phenomenon is still unclear. The non-coding T cells transcript (NTT) is differentially expressed during human T cells activation, but its function is unknown. Here, we detected a 426 m NTT transcript by RT-PCR using RNA of human lymphocytes activated with a synthetic peptide of HIV-1. After cloning, the sense and antisense 426 nt NTT transcripts were obtained by in vitro transcription and were sequenced. We found that both transcripts are highly structured and are able to activate PKR. A striking observation was that the antisense 426 nt NTT transcript is significantly more effective in activating PKR than the corresponding sense transcript. The transcription factor NF-kappa B is activated by PKR through phosphorylation and subsequent degradation of its inhibitor I-kappa B beta. We also found that the antisense 426 nt NTT transcript induces more efficiently the degradation Of I-kappa B beta than the sense transcript. Thus, this study suggests that the role played by NTT in the activation of lymphocytes can be mediated by PKR through NF-kappa B activation. However, the physiological significance of the activity of the antisense 426 nt NTT transcript remains unknown. (c) 2007 Elsevier Inc. All rights reserved.

Diabetes induces metabolic alterations in dental pulp

Diabetes can interfere in tissue nutrition and can impair dental pulp metabolism. This disease causes oxidative stress in cells and tissues. However, little is known about the antioxidant system in the dental pulp of diabetics. Thus, it would be of importance to study this system in this tissue in order to verify possible alterations indicative of oxidative stress. The aim of this study was to evaluate some parameters of antioxidant system of the dental pulp of healthy (n = 8) and diabetic rats (n = 8). Diabetes was induced by streptozotocin in rats. Six weeks after diabetes induction, a pool of the dental pulp of the 4 incisors of each rat (healthy and diabetic) was used for the determination of total protein and sialic acid concentrations and catalase and peroxidase activities. Data were compared by a Student t test (p <= 0.05). Dental pulps from both groups presented similar total protein concentrations and peroxidase activity. Dental pulps of diabetic rats exhibited significantly lower free, conjugated, and total sialic acid concentrations than those of control tissues. Catalase activity in diabetic dental pulps was significantly enhanced in comparison with that of control pulps. The result of the present study is indicative of oxidative stress in the dental pulp caused by diabetes. The increase of catalase activity and the reduction of sialic acid could be resultant of reactive oxygen species production.

Increased circulating levels of matrix metalloproteinase (MMP)-8, MMP-9, and pro-inflammatory markers in patients with metabolic syndrome

Background: Metabolic syndrome (MetS) predisposes to cardiovascular complications. Increased concentrations of pro-inflammatory mediators and imbalanced concentrations of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) may reflect the pathophysiology of MetS. We compared the circulating levels of MMPs, TIMPs, and inflammatory mediators in MetS patients with those found in healthy controls. Methods: We studied 25 healthy subjects and 25 MetS patients. The plasma levels of pro-MMP-2 and pro-MMP-9 were determined by gelatin zymography. The plasma concentrations of MMP-8, MMP-3, TIMP-1, TIMP-2, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), intercellular adhesion molecule (sICAM-1), and sP-selectin were measured by ELISA kits. Results: We found higher sP-selectin, sICAM-1, MCP-1, and IL-6 (all P<0.05) concentrations in MetS patients compared with healthy controls. No differences in pro-MMP-2, MMP-3, and TIMP-2 levels were found (all P>0.05). However, we found higher pro-MMP-9, MMP-8. and TIMP-1 levels in MetS patients compared with healthy controls (all P<0.05). Conclusions: Patients with MetS have increased circulating concentrations of pro-MMP-9, MMP-8, and TIMP-1 that are associated with increased concentrations of pro-inflammatory mediators and adhesion molecules. These findings suggest that MMPs may have a role in the increased cardiovascular risk of MetS patients. Pharmacological interventions targeting MMPs, especially MMP-9 and MMP-8 deserve further investigation in MetS patients. (C) 2009 Elsevier B.V. All rights reserved.

Long-term metabolic and skeletal muscle adaptations to short-sprint training: Implications for sprint training and tapering

The adaptations of muscle to sprint training can be separated into metabolic and morphological changes. Enzyme adaptations represent a major metabolic adaptation to sprint training, with the enzymes of all three energy systems showing signs of adaptation to training and some evidence of a return to baseline levels with detraining. Myokinase and creatine phosphokinase have shown small increases as a result of short-sprint training in some studies and elite sprinters appear better able to rapidly breakdown phosphocreatine (PCr) than the sub-elite. No changes in these enzyme levels have been reported as a result of detraining. Similarly, glycolytic enzyme activity (notably lactate dehydrogenase, phosphofructokinase and glycogen phosphorylase) has been shown to increase after training consisting of either long (> 10-second) or short (< 10-second) sprints. Evidence suggests that these enzymes return to pre-training levels after somewhere between 7 weeks and 6 months of detraining. Mitochondrial enzyme activity also increases after sprint training, particularly when long sprints or short recovery between short sprints are used as the training stimulus. Morphological adaptations to sprint training include changes in muscle fibre type, sarcoplasmic reticulum, and fibre cross-sectional area. An appropriate sprint training programme could be expected to induce a shift toward type Ha muscle, increase muscle cross-sectional area and increase the sarcoplasmic reticulum volume to aid release of Ca2+. Training volume and/or frequency of sprint training in excess of what is optimal for an individual, however, will induce a shift toward slower muscle contractile characteristics. In contrast, detraining appears to shift the contractile characteristics towards type IIb, although muscle atrophy is also likely to occur. Muscle conduction velocity appears to be a potential non-invasive method of monitoring contractile changes in response to sprint training and detraining. In summary, adaptation to sprint training is clearly dependent on the duration of sprinting, recovery between repetitions, total volume and frequency of training bouts. These variables have profound effects on the metabolic, structural and performance adaptations from a sprint-training programme and these changes take a considerable period of time to return to baseline after a period of detraining. However, the complexity of the interaction between the aforementioned variables and training adaptation combined with individual differences is clearly disruptive to the transfer of knowledge and advice from laboratory to coach to athlete.

Non-coding RNAs: the architects of eukaryotic complexity

Around 98% of all transcriptional output in humans is noncoding RNA. RNA-mediated gene regulation is widespread in higher eukaryotes and complex genetic phenomena like RNA interference, co-suppression, transgene silencing, imprinting, methylation, and possibly position-effect variegation and transvection, all involve intersecting pathways based on or connected to RNA signaling. I suggest that the central dogma is incomplete, and that intronic and other non-coding RNAs have evolved to comprise a second tier of gene expression in eukaryotes, which enables the integration and networking of complex suites of gene activity. Although proteins are the fundamental effectors of cellular function, the basis of eukaryotic complexity and phenotypic variation may lie primarily in a control architecture composed of a highly parallel system of trans-acting RNAs that relay state information required for the coordination and modulation of gene expression, via chromatin remodeling, RNA-DNA, RNA-RNA and RNA-protein interactions. This system has interesting and perhaps informative analogies with small world networks and dataflow computing.

Transcripts of the MHM region on the chicken Z chromosome accumulate as non-coding RNA in the nucleus of female cells adjacent to the DMRT1 locus

The male hypermethylated (MHM) region, located near the middle of the short arm of the Z chromosome of chickens, consists of approximately 210 tandem repeats of a BamHI 2.2-kb sequence unit. Cytosines of the CpG dinucleotides of this region are extensively methylated on the two Z chromosomes in the male but much less methylated on the single Z chromosome in the female. The state of methylation of the MHM region is established after fertilization by about the 1-day embryonic stage. The MHM region is transcribed only in the female from the particular strand into heterogeneous, high molecular-mass, non-coding RNA, which is accumulated at the site of transcription, adjacent to the DMRT1 locus, in the nucleus. The transcriptional silence of the MHM region in the male is most likely caused by the CpG methylation, since treatment of the male embryonic fibroblasts with 5-azacytidine results in hypo-methylation and active transcription of this region. In ZZW triploid chickens, MHM regions are hypomethylated and transcribed on the two Z chromosomes, whereas MHM regions are hypermethylated and transcriptionally inactive on the three Z chromosomes in ZZZ triploid chickens, suggesting a possible role of the W chromosome on the state of the MHM region.

Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P4501B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009

A variety of polycyclic aromatic hydrocarbons and their dihydrodiol derivatives, arylamines, heterocyclic amines, and nitroarenes, were incubated with cDNA-based recombinant (Escherichia coli or Trichoplusia ni) systems expressing different forms of human cytochrome P450 (P450 or CYP) and NADPH-P450 reductase using Salmonella typhimurium, tester strain NM2009, and the resultant DNA damage caused by the reactive metabolites was detected by measuring expression of umu gene in the cells. Recombinant (bacterial) CYP1A1 was slightly more active than any of four CYP1B1 allelic variants, CYP1B1*1, CYP1B1*2, CYP1B1*3, and CYP1B1*6, in catalyzing activation of chrysene-1,2-diol, benz[a]anthracene-trans-1,2-, 3,4-, 5,6-, and 8,9-diol, fluoranthene-2,3-diol, dibenzo[a]pyrene, benzo[c]phenanthrene, and dibenz[a,h]anthracene and several arylamines and heterocyclic amines, whereas CYP1A1 and CYP1B1 enzymes had essentially similar catalytic specificities toward other procarcinogens, such as (+)-, (-)-, and (+/-)-benzo[a]pyrene-7,8-diol, 5-methylchrysene-1,2-diol, 7,12-dimethylbenz[a]anthracene-3,4-diol, dibenzo[a,l]pyrene-11,12-diol, benzo[b]fluoranthene-9,10-diol, benzo[c]chrysene, 5,6-dimethylchrysene-1,2-diol, benzo[c]phenanthrene-3,4-diol, 7,12-dimethylbenz[a]anthracene, benzo[a]pyrene, 5-methylchrysene, and benz[a]anthracene. We also determined activation of these procarcinogens by recombinant (T. ni) human P450 enzymes in S. typhimurium NM2009. There were good correlations between activities of procarcinogen activation by CYP1A1 preparations expressed in E. coli and T. ni cells, although basal activities with three lots of CYP1B1 in T. ni cells were very high without substrates and NADPH in our assay system. Using 14 forms of human P450S (but not CYP1B1) (in T. ni cells), we found that CY1P1A2, 2C9, 3A4, and 2C19 catalyzed activation of several of polycyclic aromatic hydrocarbons at much slower rates than those catalyzed by CYP1A1 and that other enzymes, including CYP2A6, 2B6, 2C8, 2C18, 2D6, 2E1, 3A5, 3A7, and 4A11, were almost inactive in the activation of polycyclic aromatic hydrocarbons examined here.

Metabolic activation of heterocyclic amines and other procarcinogens in Salmonella typhimurium umu tester strains expressing human cytochrome P4501A1, 1A2, 1B1, 2C9, 2D6, 2E1, and 3A4 and human NADPH-P450 reductase and bacterial O-acetyltransferase

We investigated roles of different forms of cytochrome P450 (P450 or CYP) in the metabolic activation of heterocyclic amines (HCAs) and other procarcinogens to genotoxic metabolite(s) in the newly developed umu tester strains Salmonella typhimurium (S. typhimurium) OY1002/1A1, OY1002/1A2, OY1002/1B1, OY1002/2C9, OY1002/2D6, OY1002/2E1 and OY 1002/3A4. which express respective human P450 enzymes and NADPH-cytochrome P350 reductase (reductase) and bacterial O-acetyltransferase (O-AT). These strains were established by introducing two plasmids into S. typhimurium TA 1535, one carrying both P450 and the reductase cDNA in a bicistronic construct under control of an IPTG-inducible double me promoter and the other, pOA 102, carrying O-AT and umuClacZ fusion genes. Expression levels of CYP were found to range between 35 to 550 nmol/l cell culture in the strains tested. O-AT activities in different strains ranged from 52 to 135 nmol isoniazid acetylated/min/mg protein. All HCAs tested, and 2-aminoanthracene and 2-aminofluorene exhibited high genotoxicity in the OY1002/1A2 strain, and genotoxicity of 2-amino-3-methylimidazo [4,5-f]quinoline was detected in both the OY1002/1A1 and OY1002/1A2 strains. 1-Amino-1,4-dimethyl-5H-pyrido[4.3-b]-indole and 3-amino-1-methyl-5H-pyrido[4,3-b]-indole were activated in the OY1002/1A1, OY1002/1B1, OY1002/1A2, and OY1002/3A4 strains. Aflatoxin B-1 exhibited genotoxicity in the OY1002/1A2, OY1002/1A1, and OY1002/3A4 strains. beta -Naphthylamine and benzo[a]pyrene did not exhibit genotoxicity in any of the strains. These results suggest that CYP1A2 is the major cytochrom P450 enzyme involved in bioactivation of HCAs. (C) 2001 Elsevier Science B.V. All rights reserved.