The Replacement Rate: An Imperfect Indicator of Pension Adequacy in Cross-Country Analyses.

Pension systems are usually evaluated from the perspective of two basic criteria: pension adequacy and financial sustainability. The first criterion concerns the level of pension benefits and protection of the elderly from poverty. The second criterion applies to financial liquidity.

Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder.

The proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g.

A novel mouse model of Alzheimer's disease with chronic estrogen deficiency leads to glial cell activation and hypertrophy.

The role of estrogens in Alzheimer's disease (AD) involving β-amyloid (Aβ) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the β-amyloid precursor protein (APPsw, Swedish mutation) and the other expressing presenilin-1 lacking exon 9 (PS1Δ9).

Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor.

Although the processing profile of the membrane-bound epidermal growth factor precursor (pro-EGF) is tissue-specific, it has not been investigated at the cellular level nor have the cognate proteinases been defined. Among the proprotein convertases (PCs), only the membrane-bound PC7, the most ancient and conserved basic amino acid-specific PC family member, induces the processing of pro-EGF into an ∼115-kDa transmembrane form (EGF-115) at an unusual VHPR(290)↓A motif. Because site-directed mutagenesis revealed that Arg(290) is not critical, the generation of EGF-115 by PC7 is likely indirect.

The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates.

The proprotein convertases are synthesized as zymogens that acquire activity upon autocatalytic removal of their NH(2)-terminal prosegment. Based on the convertase furin, to fold properly and gain activity, the convertases PC5A, PACE4, and PC7 are presumed to undergo two sequential prosegment cleavages in the endoplasmic reticulum and then in the trans-Golgi network. However, biochemical and immunocytochemical experiments revealed that mouse PC5A is complexed to its prosegment at the plasma membrane.

Respiratory distress and neonatal lethality in mice lacking Golgi alpha1,2-mannosidase IB involved in N-glycan maturation.

There are three mammalian Golgi alpha1,2-mannosidases, encoded by different genes, that form Man5GlcNAc2 from Man(8-9)GlcNAc2 for the biosynthesis of hybrid and complex N-glycans. Northern blot analysis and in situ hybridization indicate that the three paralogs display distinct developmental and tissue-specific expression. The physiological role of Golgi alpha1,2-mannosidase IB was investigated by targeted gene ablation.

Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system.

Neural apoptosis-regulated convertase-1/proprotein convertase subtilisin-kexin like-9 (NARC-1/PCSK9) is a proprotein convertase recently described to play a major role in cholesterol homeostasis through enhanced degradation of the low-density lipoprotein receptor (LDLR) and possibly in neural development. Herein, we investigated the potential involvement of this proteinase in the development of the CNS using mouse embryonal pluripotent P19 cells and the zebrafish as models. Time course quantitative RT-PCR analyses were performed following retinoic acid (RA)-induced neuroectodermal differentiation of P19 cells.

Carbon monoxide released by CORM-3 inhibits human platelets by a mechanism independent of soluble guanylate cyclase.

Objective: Carbon monoxide (CO) modulates several physiological functions through activation of a cGMP-dependent pathway similar to that of nitric oxide (NO). Here we investigated the possible involvement of soluble guanylate cyclase in the anti-aggregatory effect of micromolar concentrations of CO released by a novel, water-soluble, CO releasing molecule (CORM) in human platelets.

Methods: Human platelet aggregation was induced by collagen or thrombin, and the effects of CO releasing molecule (CORM-3) and an NO donor on platelet aggregation were compared.

Beta-amyloid protein converting enzyme 1 and brain-specific type II membrane protein BRI3: binding partners processed by furin.

Using a yeast two-hybrid system, we screened a human brain cDNA library for possible interacting proteins with the C-terminal cytosolic tail of the beta-secretase beta-amyloid protein converting enzyme (BACE)1. This identified seven potential candidates, including the brain-specific type II membrane protein BRI3. Co-localization and co-immunoprecipitation experiments confirmed that BACE1 and BRI3 co-localize and interact with each other via the cytosolic tail of BACE1.

Statins rise cytoplasmic calcium level [Ca2+]i in cultured endothelial cells.

Recently, we have shown that some HMG-CoA reductase inhibitors (statins) induce immediate pleiotropic effects in vascular endothelium both in vivo and in vitro, to mention only PGI2-mediated thrombolysis in rats and NO-mediated endothelium-dependent vasodilation in guinea pig coronary circulation. Here we look whether immediate endothelial effect of statins is associated with mobilization of intracellular calcium ions [Ca2+]i in cultured bovine aortic endothelial cells (BAEC). We analyzed the effects of various statins (atorvastatin, cerivastatin, simvastatin, lovastatin and pravastatin at concentration of 10-30 microM) on [Ca2+]i in BAEC in comparison to responses induced by bradykinin (Bk) (10 nM), adenosine diphosphate (1 microM), acetylcholine (100 nM), adrenaline (10 microM), serotonin (10 microM) or calcium ionophore A 23187 (0.

Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats.

Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3-30 microg kg(-1) (captopril View Article and Find Full Text PDF

Bradykinin as a major endogenous regulator of endothelial function.

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls.

Mesoionic oxatriazoles (MOTA): NO-donating characteristics and pharmacology.

Biological role of nitric oxide (NO), functioning of isoforms of NO synthetases (NOS) and pharmacology of principle NO-donors were reviewed. NO donating characteristics and pharmacology of 23 mesoionic oxatriazoles (MOTA) were compared with those of 5-morpholinosydnonimine (SIN-1), S-nitroso-N-acetylpenicillamine (SNAP), sodium nitroprusside (NaNP) and glyceryl trinitrate (GTN). It is concluded that in vitro NO donating profile of MOTA hardly can be used as a predicting measure for their pharmacological activities either in vitro or in vivo.

Comparison of endothelial pleiotropic actions of angiotensin converting enzyme inhibitors and statins.

Two in vitro and one in vivo assay were performed to study the endothelial pleiotropic actions of "tissue type" angiotensin converting enzyme inhibitors (ACE-Is) such as perindopril and quinapril, their active forms, that is, quinaprilat and peridoprilat, or of statins belonging to natural (lovastatin), semisynthetic (simvastatin), and synthetic enantiomeric (atorvastatin, cerivastatin) classes. Cytoplasmic [Ca2+]i levels in cultured bovine aortic endothelial cells and endothelium-dependent nitric oxide-mediated coronary vasodilatation in the Langendorff preparation of guinea pig heart constituted our in vitro assays. The in vivo assay consisted of study of PGI2-mediated thrombolytic response in arterial blood of rats after intravenous administration of drugs.

Significance of endothelial prostacyclin and nitric oxide in peripheral and pulmonary circulation.

Background: Vasoprotective function of endothelial cells is associated, among others, with biosynthesis and release of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), carbon monoxide (CO) and plasminogen activator (t-PA). These endothelial mediators calm down activated platelets and leukocytes, prevent the occurrence of parietal thrombotic events, promote thrombolysis, maintain tissue perfusion and protect vascular wall against acute damage and against chronic remodeling. Endothelial dysfunction in patients suffering from atherosclerosis or diabetes type 2 is associated not only with suppression in release of the above mediators but also with deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion (O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1).

Thienopyridines: effects on cultured endothelial cells.

In cultured endothelial cells harvested from human umbilical vein (HUVEC) or bovine aorta (BAEC) the 30 min incubation with calcium ionophore A 23187 (1 microM) or ticlopidine (100 microM) caused an increase in nitrite generation in HUVEC from basal 227 +/- 37 to 372 +/- 60 or to 325 +/- 33 pmoles per 10(6) cells, respectively, and in BAEC from basal 182 +/- 17 to 378 +/- 18 or to 423 +/- 66 pmoles per 106 cells (n = 6), respectively. Calcium ionophore A 23187 (1 microM) or ticlopidine (100 microM) next to 30 min incubation with BAEC increased release of 6-keto-PGF 1alpha from basal level of 9.4 +/- 1.

Thrombolytic activity of beta-adrenolytic drug, sotalol.

Sotalol is a beta-adrenoreceptor blocking drug, the clinical efficacy of which has been linked up to its negative chrono- and inotropic effects and its hypotensive action. In addition, beta-adrenolytic drugs are known to inhibit platelet aggregation in vitro possibly through lowering of calcium ions level. Here, we report that in rats sotalol at a dose of 10-20 mg/kg i.

Nitric oxide donation and nitrite assays in the presence of thiols and albumin as determined by Griess' and Werringloer's methods.

Nitric oxide (NO) or nitrite (NO2-) were assayed using the Werringloer's method or the Griess' method, respectively, in the presence or absence of various thiols, amino acids, or albumin. This has been done because both methods are used to determine the generation of endogenous NO from L-arginine or exogenous NO from drugs in vivo, paying little attention to biological constituents which may affect results of these assays. Albumin, reduced glutathione (GSH), cysteine and N-acetylcysteine, but not other amino acids lowered the amount of NO2- as detected by Griess' method no matter whether sodium nitrite or 3-morpholinosydnonimine (SIN-1) were used as a source of NO2-.

Scavenging of reactive oxygen species as the mechanism of drug action.

Reactive oxygen species (ROS) are generated when oxygen is supplied in excess and/or its reduction is insufficient. The best explored ROS are superoxide anions, hydroxyl radicals and hydrogen peroxide. The first two are free radicals.

The effect of nitric oxide donors on the release of plasminogen activator inhibitor (PAI) from rabbit platelets in vitro.

Here we describe effects of four nitric oxide (NO) donors, 4-arylsubstituted oxatriazol derivatives and 3-morpholino-sydnonimine (SIN-1) at concentrations of 30-1000 microM on the release of plasminogen activator inhibitor (PAI) from rabbit platelets in vitro. At 37 degrees C, pH of 7.4 and a concentration of 30 microM, all compounds released NO as measured by the Werringloer's technique.

Mesoionic oxatriazole derivatives--a new group of NO-donors.

A number of new 3-aryl-1,2,3,4-oxatriazole-5-imine derivatives (GEA Compounds--GEAC) were synthetized. GEAC are NO-releasers as evidenced by direct measurement of NO in headspace/NO-analyzer, by cooxygenation of oxyhaemoglobin to methaemoglobin in the Werringloer's test and by generation of nitrite in the Griess' reaction. During the release of NO from GEAC the consumption of O2 could be detected only when high concentrations of GEAC were used.

Prostacyclin and the mechanism of action of defibrotide.

Defibrotide (DEF) is a product of the controlled hydrolysis of DNA from mammalian lungs. In vitro DEF (1-2000 micrograms/ml) neither inhibited the aggregation of human, rabbit and cat platelets nor released PGI2 from cultured porcine aortic endothelial cells. Preincubated with platelet preparations, DEF (10 micrograms/ml) lowered the IC50 for the anti-aggregatory action of PGI2 from 2.

An abnormality of arachidonic acid metabolism is not a generalized phenomenon in patients with aspirin-induced asthma.

Aspirin (ASA)-induced asthma is a distinct clinical syndrome in which bronchoconstrictive response to nonsteroidal anti-inflammatory drugs can be predicted on the basis of their in vitro activity as inhibitors of cyclooxygenase. In ten ASA-sensitive asthmatics and ten matched healthy controls we measured 12-hydroxy-eicosatetraenoic acid (12-HETE) production by platelets and 5-hydroxy-eicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4) production by polymorphonuclear leucocytes. The blood cells were obtained before administration of the threshold doses of ASA and during the ASA-induced reactions.