Assessment of short forms of recurrent atrial extra systoles by echocardiography with left atrial strain in ambulatory patients without organic cardiopathy.

Aim: To analyse the potential usefulness and clinical relevance of the assessment by echocardiography with left atrial strain, based on the myocardial atrial deformation curves with speckle-tracking velocity vector imaging (VVI), in the analysis of short-form recurrent atrial extra systoles in ambulatory patients not suffering from organic cardiopathy.

Methods: We designed a descriptive, prospective, and observational study including 270 patients between the ages of 18 and 75 assessed during an outpatient cardiology consultation attended due to palpitations over a period of two years. Using ambulatory electrocardiographic monitoring, we selected cases with short forms of repetitive atrial extrasystole, isolated or recurrentatrial fibrillation and a control group formed by those patients without repetitive ectopia.

Gossypol Treatment Restores Insufficient Apoptotic Function of DFF40/CAD in Human Glioblastoma Cells.

Glioblastoma (GBM) is a highly aggressive brain tumor and almost all patients die because of relapses. GBM-derived cells undergo cell death without nuclear fragmentation upon treatment with different apoptotic agents. Nuclear dismantling determines the point-of-no-return in the apoptotic process.

Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides.

The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease.

Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory.

Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels.

Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis.

Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer's disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.

Secretase-independent and RhoGTPase/PAK/ERK-dependent regulation of cytoskeleton dynamics in astrocytes by NSAIDs and derivatives.

Profens like ibuprofen, R-flurbiprofen, or CHF5074 are being considered for the treatment of Alzheimer's disease because epidemiological data indicates that non-steroidal anti-inflammatory drugs are protective against neurodegeneration. Rho-GTPases are small G proteins, including RhoA, Cdc42, and Rac1, which control cytoskeleton dynamics. Because ibuprofen promotes axon growth via RhoA in neurons, we examined whether profens modulate astrocyte plasticity via Rho-GTPases.

Glial cells as sources and targets of natriuretic peptides.

Natriuretic peptides and their receptors are widely expressed in mammalian CNS and increasing evidence implicates them in the regulation of neural development, synaptic transmission and processing of information, and neuroprotection. Although the peptides have been mainly localized in neuronal populations they are also produced in glial cells. Astroglia and microglia also express functional natriuretic peptide receptors that can regulate important physiological responses.

NO-sensitive guanylyl cyclase beta1 subunit is peripherally associated to chromosomes during mitosis. Novel role in chromatin condensation and cell cycle progression.

NO-sensitive guanylyl cyclase (GC(NO)), the major NO target, is involved in important regulatory functions in the cardiovascular, gastrointestinal and central nervous systems. GC(NO) exists as heterodimers of alpha(1/2) and beta1 subunits. Deletion of the obligate beta1 dimerizing partner abrogates NO/cGMP signaling and shortens the life span of KO mice.

Regulation and function of cyclic GMP-mediated pathways in glial cells.

A large body of evidence supports a role for the NO-cGMP-protein kinase G pathway in the regulation of synaptic transmission and plasticity, brain development and neuroprotection. Circumstantial evidence implicates natriuretic peptide-stimulated cGMP formation in the same CNS functions. In addition to neurons, both cGMP-mediated pathways are functional in glial cells and an increasing number of reports indicate that they may control important aspects of glial cell physiology relevant to neuronal function.

The ANP-cGMP-protein kinase G pathway induces a phagocytic phenotype but decreases inflammatory gene expression in microglial cells.

Reactive gliosis is a prominent feature of CNS injury that involves dramatic changes in glial cell morphology together with increased motility, phagocytic activity, and release of inflammatory mediators. We have recently demonstrated that stimulation of the cGMP-protein kinase G (PKG) pathway by NO or atrial natriuretic peptide (ANP) regulates cytoskeleton dynamics and motility in rat astrocytes in culture. In this work, we show that the cGMP-PKG pathway stimulated by ANP, but not by NO, regulates microglial cell morphology by inducing a dramatic reorganization in the actin cytoskeleton.

LPS-induced down-regulation of NO-sensitive guanylyl cyclase in astrocytes occurs by proteasomal degradation in clastosomes.

We previously showed that treatment with bacterial lipopolysaccharide (LPS) or pro-inflammatory cytokines decreases NO-sensitive guanylyl cyclase (GC(NO)) activity in astrocytes by decreasing the half-life of the obligate GC(NO) beta1 subunit in a NO-independent but transcription- and translation-dependent process. Here we show that LPS-induced beta1 degradation requires proteasome activity and is independent of NFkappaB activation or beta1 interaction with HSP90. Immunocytochemistry and confocal microscopy analysis revealed that LPS promotes colocalization of the predominantly soluble beta1 protein with ubiquitin and the 20S proteasome in nuclear aggregates that present characteristics of clastosomes, nuclear bodies involved in proteolysis via the ubiquitin-proteasome system.

Reduced expression of NO-sensitive guanylyl cyclase in reactive astrocytes of Alzheimer disease, Creutzfeldt-Jakob disease, and multiple sclerosis brains.

In Alzheimer's disease (AD) brains increased NO synthase (NOS) expression is found in reactive astrocytes surrounding amyloid plaques. We have recently shown that treatment with beta-amyloid peptides or IL-1beta down-regulates NO-sensitive soluble guanylyl cyclase (sGC) in cultured astrocytes and in adult rat brain. In this work, we have examined sGC activity and expression in postmortem brain tissue of AD patients and matched controls.

HIV-1 coat protein gp120 decreases NO-dependent cyclic GMP accumulation in rat brain astroglia by increasing cyclic GMP phosphodiesterase activity.

The human immunodeficiency virus type-1 (HIV-1) coat glycoprotein gp120 has been proposed as a likely etiologic agent of HIV-associated dementia (HAD). The pathogenic mechanisms underlying HAD have not yet been fully elucidated, but different evidences indicate that glial cells play an essential role in the development and amplification of the disease. The NO/cyclic GMP (cGMP) system is a widespread signal transduction pathway in the CNS involved in numerous physiological and pathological functions.

Nitric oxide-dependent and independent down-regulation of NO-sensitive guanylyl cyclase in neural cells.

NO-sensitive guanylyl cyclase or soluble guanylyl cyclase (sGC) is the major target for NO and cyclic GMP the mediator of its vasodilating and neuromodulatory actions. Studies on the mechanism of nitrovasodilator-induced tolerance have shown that in smooth muscle cells sGC is down-regulated by prolonged exposure to exogenous or endogenous NO. Increased expression of NO synthase (NOS) in CNS glial cells is a landmark of acute and chronic neuroinflammation.

Interleukin-1 beta and lipopolysaccharide decrease soluble guanylyl cyclase in brain cells: NO-independent destabilization of protein and NO-dependent decrease of mRNA.

We previously showed that soluble guanylyl cyclase (sGC) is down-regulated in astroglial cells after exposure to LPS. Here, we show that this effect is not mediated by released IL-1beta but that this cytokine is also able to decrease NO-dependent cGMP accumulation in a time- and concentration-dependent manner. The effect of IL-1beta is receptor-mediated, mimicked by tumor necrosis factor-alpha and involves a decrease in sGC activity and protein.

Regulation of NO-dependent cyclic GMP formation by inflammatory agents in neural cells.

In the CNS, NO is an important physiological messenger involved in the modulation of brain development, synaptic plasticity, neuroendocrine secretion, sensory processing, and cerebral blood flow [Annu. Rev. Physiol.

Beta-amyloid peptides decrease soluble guanylyl cyclase expression in astroglial cells.

In astroglial cells beta-amyloid peptides (betaA) induce a reactive phenotype and increase expression of NO synthase. Here we show that treatment of rat brain astrocytes with betaA decreases their capacity to accumulate cyclic GMP (cGMP) in response to NO as a result of a decreased expression of soluble guanylyl cyclase (sGC) at the protein and mRNA levels. Potentiation of betaA-induced NO formation by interferon-gamma did not result in a larger decrease in cGMP formation and inhibition of NO synthase failed to reverse down-regulation of sGC, indicating that NO is not involved.

Interleukin-1beta stimulates cyclic GMP efflux in brain astrocytes.

In rat brain astroglia-enriched cultures long-term treatment with interleukin-1beta induces NO release and stimulation of soluble guanylyl cyclase. The cGMP formed is recovered in the extracellular medium but not in the cell monolayer. The interleukin-1beta effect is mediated by type I receptor and potentiated by interferon-gamma.

Nitric oxide-independent down-regulation of soluble guanylyl cyclase by bacterial endotoxin in astroglial cells.

Induction of nitric oxide (NO) synthase (NOS) type 2 (NOS-2) in glial cells after exposure to bacterial endotoxin [lipopolysaccharide (LPS)] or inflammatory cytokines has been repeatedly demonstrated both in vitro and in vivo. However, little is known about effects of these agents on NO-dependent cyclic GMP (cGMP) formation. In this work, we show that treatment of rat cerebellar astrocyte-enriched primary cultures with LPS decreases NO donor-stimulated cGMP formation with a similar initial time course (up to 9-12 h) and concentration dependency (0.

AMPA receptors are coupled to the nitric oxide/cyclic GMP pathway in cerebellar astroglial cells.

In cultured rat cerebellar astroglia kainate induces cGMP formation with low potency (EC50 310 microM). In the presence of cyclothiazide, a blocker of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor desensitization, the effect of kainate was potentiated and glutamate and AMPA elicited large increases (> 100-fold) in cGMP levels. The response to all three agonists was abolished by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine and required extracellular calcium.

Regulation by calcium of the nitric oxide/cyclic GMP system in cerebellar granule cells and astroglia in culture.

Ca2+ entry induced by N-methyl-D-aspartate (NMDA) in neurons and by noradrenaline (NA) in astrocytes is known to increase intracellular cyclic GMP (cGMP) levels through stimulation of the Ca2+-dependent nitric oxide synthase type I (NOS-I). The possibility that Ca2+ entry could also down-regulate intracellular cGMP by activating a Ca2+/calmodulin-dependent phosphodiesterase (CaM-PDE) has been investigated here in primary cultures enriched in granule neurons or in astroglia from rat cerebellum. We show that the same agonists that stimulate nitric oxide (NO) formation (NMDA and NA at 100 microM) and the Ca2+ ionophore A23187 (10 microM) decrease cGMP generated in response to direct stimulation of soluble guanylyl cyclase (sGC) by NO donors in both cell types.