Influence of Obesity and Metabolic Disease on Carotid Atherosclerosis in Patients with Coronary Artery Disease (CordioPrev Study)

BackgroundRecent data suggest that the presence of associated metabolic abnormalities may be important modifiers of the association of obesity with a poorer prognosis in coronary heart disease. We determined the influence of isolated overweight and obesity on carotid intima media thickness (IMT-CC), and also assessed whether this influence was determined by the presence of metabolic abnormalities.Methods1002 participants from the CordioPrev study were studied at entry. We determined their metabolic phenotypes and performed carotid ultrasound assessment. We evaluated the influence of obesity, overweight and metabolic phenotypes on the IMT-CC.ResultsMetabolically sick participants (defined by the presence of two or more metabolic abnormalities) showed a greater IMT-CC than metabolically healthy individuals (p = 4 * 10⁻⁶). Overweight and normal weight patients who were metabolically healthy showed a lower IMT-CC than the metabolically abnormal groups (all p<0.05). When we evaluated only body weight (without considering metabolic phenotypes), overweight or obese patients did not differ significantly from normal-weight patients in their IMT-CC (p = 0.077). However, obesity was a determinant of IMT-CC when compared to the composite group of normal weight and overweight patients (all not obese).ConclusionsIn coronary patients, a metabolically abnormal phenotype is associated with a greater IMT-CC, and may be linked to a higher risk of suffering new cardiovascular events. The protection conferred in the IMT-CC by the absence of metabolic abnormality may be blunted by the presence of obesity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00924937","term_id":"NCT00924937"}}NCT00924937     

Altered longevity‐assurance activity of p53:p44 in the mouse causes memory loss,neurodegeneration and premature death

The longevity‐assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44^+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin‐like growth factor 1 receptor (IGF‐1R) signaling and altered metabolism of the microtubule‐binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ‘humanized’ form of the amyloid precursor protein (APP), p44^+/+ animals developed a selective degeneration of memory‐forming and ‐retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis‐ and autophagy‐like cell deaths. These results indicate that altered longevity‐assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF‐1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP_695/swe mice, a model of Alzheimer’s disease.     

Identification of in vivo HSP90-interacting proteins reveals modularity of HSP90 complexes is dependent on the environment in psychrophilic bacteria

Heat shock protein 90 (HSP90) is a conserved molecular chaperone that functions as part of complexes in which different client proteins target it to diverse sets of substrates. In this paper, HSP90 complexes were investigated in γ-proteobacteria from mild (Shewanella oneidensis) and cold environments (Shewanella frigidimarina and Psychrobacter frigidicola), to determine changes in HSP90 interactions with client proteins in response to the adaptation to cold environments. HSP90 participation in cold adaptation was determined using the specific inhibitor 17-allylamino-geldanamycin. Then, HSP90 was immunoprecipitated from bacterial cultures, and the proteins in HSP90 complexes were analyzed by two-dimensional gel electrophoresis and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. According to HSP90-associated protein analysis, only 15 common proteins were found in both species from the same genus, S. oneidensis and S. frigidimarina, whereas a significant higher number of common proteins were found in both psychrophilic species S. frigidimarina and P. frigidicola 21 (p < 0.001). Only two HSP90-interacting proteins, the chaperone proteins DnaK and GroEL, were common to the three species. Interestingly, some proteins related to energy metabolism (isocitrate lyase, succinyl-CoA synthetase, alcohol dehydrogenase, NAD(+) synthase, and malate dehydrogenase) and some translation factors only interacted with HSP90 in psychrophilic bacteria. We can conclude that HSP90 and HSP90-associated proteins might take part in the mechanism of adaptation to cold environments, and interestingly, organisms living in similar environments conserve similar potential HSP90 interactors in opposition to phylogenetically closely related organisms of the same genus but from different environments.     

Major digestive carbohydrase during larval development of meal moth, Plodia interpunctella (Lepidoptera: pyralidae)

The digestive system of P. interpunctella was characterized during its larval development to determination of carbohydrases using disaccharides (sucrose and maltose) and polysaccharides (starch and inulin) as substrate. At 6(th) instar larval, Invertase>alpha-amylase> maltase activities peaks were observed. Invertase was fractionated with acetone and isolated. The Invertase was 485.5 fold purified by Sephacryl S-200 and DEAE-Sephadex. Its kinetic parameters were K(m) of 6.6 mM, V(max) of 0.48, pH optimum of 5.5 and temperature optimum of 30 degrees C. This enzyme was activated by CaCl(2) and inhibited by EDTA. When analyzed by SDS-PAGE it showed one band of M(r) 34 kDa. The understanding of the digestive system of P. interpunctella could be a key step in the design of bioinsecticides.     

Localization of eukaryotic initiation factor 2 in neuron primary cultures and established cell lines

Eukaryotic initiation factor 2 (eIF-2) is a heterotrimeric protein with subunits α, β and γ that forms a ternary complex with Met-tRNA and GTP. It promotes the binding of Met-tRNA to ribosomes and controls translational rates via phosphorylation/dephosphorylation mechanisms. By means of immunofluorescence and post-embedding immunocytochemistry of intact cells and quantitative immunoblotting of cell extracts, the cellular distribution of the initiation factor has been examined in primary neuronal cultures as well as in two established cell lines: PC12 phaeochromocytoma cells and rat pituitary GH4C1 cells. Our results indicated that the initiation factor is located not only in the cytoplasm but also in the nuclei of the cultured neurons and cell lines. In the cytoplasm, immunocytochemical studies reveal that the factor is present mainly in those areas that are rich in ribosomes. In the nucleus, the immunolabelling of eukaryotic initiation factor 2 verified the presence of gold particles in both nucleolar and extranucleolar areas. The specific distribution of this factor on both sides of the nuclear envelope suggests that it might have some nuclear-related function(s) besides its already known role in the control of translation     

Isolation and synthesis of two coumarins from melampodium divaricatum

Two new coumarin isomers have been isolated from Melampodium divaricatum and identified by spectral procedures as 8-hydroxy-7-(3′-methyl-2′-butenyloxy)coumarin (1) and 7-hydroxy-8-(3′-methyl-2′-butenyloxy)coumarin (2). The regioselective synthesis of each isomer was made by two different alkylation pathways confirming their structures.     

Hypertriglyceridemia Influences the Degree of Postprandial Lipemic Response in Patients with Metabolic Syndrome and Coronary Artery Disease: From the Cordioprev Study

Objective

To determine whether metabolic syndrome traits influence the postprandial lipemia response of coronary patients, and whether this influence depends on the number of MetS criteria.

Materials and Methods

1002 coronary artery disease patients from the CORDIOPREV study were submitted to an oral fat load test meal with 0.7 g fat/kg body weight (12% saturated fatty acids, 10% polyunsaturated fatty acids, 43% monounsaturated fatty acids), 10% protein and 25% carbohydrates. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 hours during the postprandial state. Total and incremental area under the curves of the different postprandial parameters were calculated following the trapezoid rule to assess the magnitude of change during the postprandial state

Results

Postprandial lipemia response was directly related to the presence of metabolic syndrome. We found a positive association between the number of metabolic syndrome criteria and the response of postprandial plasma triglycerides (p<0.001), area under the curve of triglycerides (p<0.001) and incremental area under the curve of triglycerides (p<0.001). However, the influence of them on postprandial triglycerides remained statistically significant only in those patients without basal hypertriglyceridemia. Interestingly, in stepwise multiple linear regression analysis with the AUC of triglycerides as the dependent variable, only fasting triglycerides, fasting glucose and waist circumference appeared as significant independent (P<0.05) contributors. The multiple lineal regression (R) was 0.77, and fasting triglycerides showed the greatest effect on AUC of triglycerides with a standardized coefficient of 0.75.

Conclusions

Fasting triglycerides are the major contributors to the postprandial triglycerides levels. MetS influences the postprandial response of lipids in patients with coronary heart disease, particularly in non-hypertriglyceridemic patients.     

Brain proteomics identifies potential simvastatin targets in acute phase of stroke in a rat embolic model

Finding an efficient neuroprotectant is of urgent need in the field of stroke research. The goal of this study was to test the effect of acute simvastatin administration after stroke in a rat embolic model and to explore its mechanism of action through brain proteomics. To that end, male Wistar rats were subjected to a Middle Cerebral Arteria Occlusion and simvastatin (20 mg/kg s.c) (n = 11) or vehicle (n = 9) were administered 15 min after. To evaluate the neuroprotective mechanisms of simvastatin, brain homogenates after 48 h were analyzed by two‐dimensional fluorescence Difference in Gel Electrophoresis (DIGE) technology. We confirmed that simvastatin reduced the infarct volume and improved neurological impairment at 48 h after the stroke in this model. Considering our proteomics analysis, 66 spots, which revealed significant differences between groups, were analyzed by matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry allowing the identification of 27 proteins. From these results, we suggest that simvastatin protective effect can be partly explained by the attenuation of the oxidative and stress response at blood–brain barrier level after cerebral ischemia. Interestingly, analyzing one of the proteins (HSP75) in plasma from stroke patients who had received simvastatin during the acute phase, we confirmed the results found in the pre‐clinical model.