1,721,089 research outputs found
Rapid Quantitative Prediction of Ionization Energies and Electron Affinities of Polycyclic Aromatic Hydrocarbons.
No full textQuantitative structure activity relationship (QSAR) studies of polycyclic aromatic hydrocarbons (PAHs) often employ rapid semiempirical calculations to evaluate ionization energy (IE) and electron affinity (EA) values, assuming they are equal (but of opposite sign) to the energies of the highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), respectively. However, regardless of the assumption of validity of Koopmans’ theorem, the reliability of this simple theoretical approach for reproducing the experimental IE and EA trends has not been tested, except for a few linear PAHs. Here the measured IEs and EAs of 17 PAHs are plotted vs. the HOMO and LUMO energies obtained with semiempirical AM1 calculations and, for comparison, HF/6-31G calculations. Good linear relationships are obtained with both methods, with correlation coefficients r >0.98 for the IEs and r >0.96 for the EAs. The IEs and EAs predicted by scaling the corresponding MO energies with the appropriate empirical linear equation are compared with experimental values available in the literature for PAHs (28 IEs and 22 EAs). The average (absolute) difference between evaluated and measured IEs is found to be 0.07 eV (s.d.=0.05 eV), while for the EAs the average difference is slightly larger. The accuracy of both AM1 and HF/6-31G methods are essentially equal, the former having the significant advantage of being 60 times faster. The present study demonstrates the ability of rapid semiempirical calculations carried out on the neutral molecules to parallel the experimental IE and EA values of PAHs, and provides simple linear equations which can be routinely employed for their quantitative prediction in this class of compounds
PAI-1, the primary plasmatic inhibitor of fibrinolysis. Physiopathologic role and molecular mechanisms
No full textPlasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in blood. PAI-1 is known to contribute to thrombus formation and to the development and the clinical course of acute and chronic cardiovascular diseases. Plasma levels of PAI-1 are regulated on a genetic basis but, more important, is the dependence on a series of other atherosclerotic risk factors like hypertriglyceridemia, diabetes and insulin resistance. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. At least in vitro, insulin is a potent inducer of PAI-1 synthesis by human hepatic cells, and, we have recently disentangled the molecular mechanisms responsible for enhanced PAI-1 gene expression by insulin. However, clinical data fail to support a direct acute contribution of insulin in regulating circulating PAI-1 levels. Recently, it has been proposed that adipose tissue could be responsible for the elevated plasma PAI-1 level observed in insulin resistance. It now seems reasonable to view PAI-1 as one of the factors contributing to the complex gene-environment interactions involved in the formation and dissolution of thrombi
Electron affinities of polycyclic aromatic hydrocarbons by means of B3LYP/6-31+G* calculations.
No full textThe gas-phase experimental adiabatic electron affinities (AEAs) of the polycyclic aromatic hydrocarbons (PAHs) anthracene, tetracene, pentacene, chrysene, pyrene, benzo[a]pyrene, benzo[e]pyrene and fluoranthene are well reproduced using the hybrid density functional method B3LYP with the 6-31+G* basis set, indicating that the smallest addition of diffuse functions to the basis set is suitable for a correct description of the stable PAH anion states. The calculated AEAs also give a very good linear correlation with available reduction potentials measured in solution.
The AEAs (not experimentally available) of the isomeric benzo[ghi]fluoranthene and cyclopenta[cd]pyrene, commonly found in the environment, are predicted to be 0.817 and 1.108 eV, respectively, confirming the enhancement of the electron-acceptor properties associated with fusion of a peripheral cyclopenta ring. The calculated localization properties of the lowest unoccupied MO of cyclopenta[cd]pyrene, together with its relatively high electron affinity, account for a high reactivity at the ethene double bond of this PAH in reductive processes
Oxidized LDLs influence thrombotic response and cyclooxygenase 2
No full textOxidative modification of low-density lipoproteins (LDLs) plays a key role in the development of atherosclerosis and the onset of coronary artery disease. LDL oxidation alters the antithrombotic balance of human endothelial cells inducing surface tissue factor (TF) pathway activity, which results in enhanced fibrin deposition. Fibrinolysis, which is strictly regulated by plasminogen activator inhibitor-1 (PAL-1) and tissue-type plasminogen activator (tPA). Is also dysregulated by LDL oxidation with a net increase in the inhibitory rate. Oxidized LDLs (oxLDLs) also affect many aspects of macrophage function linked to the inflammatory response of these cells, In particular, oxLDLs downregulate inducible cyclooxigenase (Cox-2) in human monocyte-derived macrophages exposed to bacterial lipopolysaccharide. This observation may support the hypothesis that, within atheromata, the transformation macrophages into foam cells results in the attenuation of the inflammatory response, thus contributing to the progression of athrogenesis. Among lipid constituents of oxLDLs, Ox-PAPC, a mixture of oxidized arachidonic acid-containing phospholipids, prevents Cox-2 expression, suggesting that it could be considered responsible for the biological activity of oxLDLs
Relationship between fibrinolytic and metabolic variables: a study in patients attending a lipid clinic
No full textWe investigated the relationship between plasma levels of metabolic and fibrinolytic variables in 163 fasted patients attending a lipid clinic. Of these patients, 118 had hypertriglyceridaemia (HTG) and 45 had normotriglyceridaemia (NTG). In HTG, basal fibrinolytic activity, ie tissue plasminogen activator (t-PA) activity, was impaired as a result of high plasminogen activator inhibitor type 1 (PAI-1) antigen and activity. Multiple stepwise regression analysis identified insulin and triglyceride levels as independent determinants of plasma PAI-1 levels (R2 = 0.18; P = 0.0001). When the patients were stratified into tertiles according to their levels of triglyceride and insulin, PAI-1 antigen levels were found to increase with rising levels of triglyceride in each insulin tertile. In contrast, the increase of PAI-1 with rising insulin levels was evident in the highest triglyceride tertile. In addition, subjects in the lowest tertile of both triglyceride and insulin had the lowest PAI-1 antigen levels, and subjects in the highest tertile of both triglyceride and insulin had the highest levels of PAI-1. Both basal and stimulated levels of t-PA antigen were significantly higher in HTG than in NTG. Multiple stepwise regression analysis identified triglyceride level as the sole major determinant of t-PA antigen levels (R2 = 0.13; P = 0.00003). The observation that both insulin and triglycerides correlate with PAI-1, whereas triglycerides were involved only in the increased secretion of t-PA, suggests that these two proteins are regulated by different mechanisms
Signaling pathways involved in the induction of PAI-1 by VLDL in HEPG2 cells
No full textWe have previously shown that very low density lipoproteins (VLDL) enhance the biosynthesis of plasminogen activator inhibitor type 1 (PAl-1) in HepG2 cells. In this study we have investigated the mechanism(s) responsible for the induction of PAI-1 biosynthesis by this lipoprotein fraction. To this end subconfluent HepG2 cells were incubated for 16 h with 100 μg/ml VLDL in the presence of different inhibitors of signalling pathways. Mepacrine (15μM), a phospholipase inhibitor, completely prevented the enhancing effect of VLDL on PAI-I secretion. Protein kinase C involvement was investigated using a specific inhibitor (H7, 50μM) or by enzyme downregulation by cell pretreatment with PMA (100nM). In these conditions VLDL induced PAI-1 biosynthesis was reduced by 80% and 40%, respectively. The role of calcium was investigated by the use of specific inhibitors added to cell cultures before VLDL. TMB8 (20 μM), which prevents Ca2+ release from intracellular stores, reduced PAI-1 secretion by 30%, whereas EGTA (1mM) plus thapsigargin (1-2μM), which induce Ca2+ depletion from internal membrane stores, inhibited it by 50%. In contrast, removal of calcium from the cell culture medium with EGTA (1mM), or blocking ions influx with Nifedipine (50μM) did not not prevent P AI-1 induction by VLDL. Overall the data indicate that several secondary messenger-generating pathways, as the phospholipases, protein kinase C and the release of calcium from internal membrane stores form networks of coregulation which result in the induction of PAI-1 biosynthesis by VLDL
LDL-acetilate e sintesi di PAI-1 da parte di cellule endoteliali: ruolo del recettore scavenger
No full textIn studi precedenti abbiamo dimostrato che le LDL chimicamente modificate (acetil-LDL) erano in grado di stimolare la "de novo" sintesi di PAI-1 da parte di cellule endoteliali in coltura. L'effetto, dose-dipendente (10-100 μg proteina/ml), si accompagnava all'aumento dell'espressione di RNA messaggero per il PAI-1. Scopo di questo studio è stato quello di valutare un possibile coinvolgimento del recettore per le lipoproteine modificate "scavenger receptor" nel mediare tale effetto. Cellule endoteliali sono state quindi incubate con concentrazioni crescenti di acetil-LDL (10-100 μg proteina/ml) in presenza di composti in grado di competere con le acetil-LDL per l'uptake e la degradazione attraverso tale recettore. Coincubazione delle cellule endoteliali con concentrazioni scalari di acetil-LDL e di un inibitore competitivo quale il Fucoidano (50-100 μg/ml) era in grado di ridurre del 50% la stimolazione del PAI-1 indotta da acetil-LDL. Tale effetto era anche accompagnato da una uguale (50%) riduzione dei livelli di colesterolo intracellulare. Esperimenti condotti in presenza di un inibitore non competitivo per il legame con il recettore "scavenger" quale il condroitin solfato (100 μg/ml) non modificava né la sintesi di PAI-1 né i livelli di colesterolo intracellulare incrementati dalle acetil-LDL. Tali dati indicano come l'effetto delle acetil-LDL sulla stimolazione della sintesi di PAI-l sia mediata dalla interazione di tali lipoproteine con il recettore "scavenger" presente sulle cellule endoteliali
Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway
No full textImpairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation. In this study we have analyzed the effects of agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARalpha agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation. In contrast, the synthetic PPARgamma agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct. In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARalpha activation and requires signaling through the ERK1/2 signaling pathway
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