Mitochondrial Ca Uniporter-Dependent Energetic Dysfunction Drives Hypertrophy in Heart Failure.

The role of the mitochondrial calcium uniporter (MCU) in energy dysfunction and hypertrophy in heart failure (HF) remains unknown. In angiotensin II (ANGII)-induced hypertrophic cardiac cells we have shown that hypertrophic cells overexpress MCU and present bioenergetic dysfunction. However, by silencing MCU, cell hypertrophy and mitochondrial dysfunction are prevented by blocking mitochondrial calcium overload, increase mitochondrial reactive oxygen species, and activation of nuclear factor kappa B-dependent hypertrophic and proinflammatory signaling.

Amyloid β-Oligomers Inhibit the Nuclear Ca Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons.

Hippocampal neuronal activity generates dendritic and somatic Ca signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca signals and on the Ca-dependent expression of neuroprotective genes.

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Neuronal Ca signals generated through the activation of Ca-induced Ca release in response to activity-generated Ca influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca release channels in rat hippocampal slices.

Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.

Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons.

Hippocampal dendritic spines express the RyR3 but not the RyR2 ryanodine receptor isoform.

The hippocampus is a brain region implicated in synaptic plasticity and memory formation; both processes require neuronal Ca signals generated by Ca entry via plasma membrane Ca channels and Ca release from the endoplasmic reticulum (ER). Through Ca-induced Ca release, the ER-resident ryanodine receptor (RyR) Ca channels amplify and propagate Ca entry signals, leading to activation of cytoplasmic and nuclear Ca-dependent signaling pathways required for synaptic plasticity and memory processes. Earlier reports have shown that mice and rat hippocampus expresses mainly the RyR2 isoform, with lower expression levels of the RyR3 isoform and almost undetectable levels of the RyR1 isoform; both the RyR2 and RyR3 isoforms have central roles in synaptic plasticity and hippocampal-dependent memory processes.

RyR-mediated Ca release elicited by neuronal activity induces nuclear Ca signals, CREB phosphorylation, and Npas4/RyR2 expression.

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca signals to the nucleus. Here, we present evidence showing that Ca release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons.

Ryanodine receptor-mediated Ca release and atlastin-2 GTPase activity contribute to IP-induced dendritic Ca signals in primary hippocampal neurons.

Neuronal Ca signals are fundamental for synaptic transmission and activity-dependent changes in gene expression. Voltage-gated Ca channels and N-methyl-d-aspartate receptors play major roles in mediating external Ca entry during action potential firing and glutamatergic activity. Additionally, the inositol-1,4,5-trisphosphate receptor (IPR) and the ryanodine receptor (RyR) channels expressed in the endoplasmic reticulum (ER) also contribute to the generation of Ca signals in response to neuronal activity.

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation.

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca dysregulation.

The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca signals, ERK and PI3K.

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca entry via N-methyl-D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca-induced Ca release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up-regulation.

Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory.

Aims: Previous studies indicate that hippocampal synaptic plasticity and spatial memory processes entail calcium release from intracellular stores mediated by ryanodine receptor (RyR) channels. In particular, RyR-mediated Ca release is central for the dendritic spine remodeling induced by brain-derived neurotrophic factor (BDNF), a neurotrophin that stimulates complex signaling pathways leading to memory-associated protein synthesis and structural plasticity. To examine if upregulation of ryanodine receptor type-2 (RyR2) channels and the spine remodeling induced by BDNF entail reactive oxygen species (ROS) generation, and to test if RyR2 downregulation affects BDNF-induced spine remodeling and spatial memory.

RyR2-Mediated Ca Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers.

Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca signals in neurons. We reported previously that these Ca signals, which arise from Ca entry and subsequent amplification by Ca release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca release, stimulate mitochondrial Ca-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant -acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction.

Astaxanthin Protects Primary Hippocampal Neurons against Noxious Effects of Aβ-Oligomers.

Increased reactive oxygen species (ROS) generation and the ensuing oxidative stress contribute to Alzheimer's disease pathology. We reported previously that amyloid-β peptide oligomers (AβOs) produce aberrant Ca(2+) signals at sublethal concentrations and decrease the expression of type-2 ryanodine receptors (RyR2), which are crucial for hippocampal synaptic plasticity and memory. Here, we investigated whether the antioxidant agent astaxanthin (ATX) protects neurons from AβOs-induced excessive mitochondrial ROS generation, NFATc4 activation, and RyR2 mRNA downregulation.

In vivo reflectance confocal microscopy of halo nevus.

Background: RCM (reflectance confocal microscopy) is a noninvasive, high-resolution technology that has been proven to improve the diagnostic accuracy over clinical examination in several skin diseases.

Objective: The aim of this article is to describe the morphologic features of halo nevi (HN) observed with RCM and correlate them with their dermoscopic characteristics.

Method: Nine patients with the clinical diagnosis of HN were assessed with RCM.

[Glucagonoma: evolution and treatment].

Glucagonomas are alpha pancreatic islet cell tumors that, when they are active, produce a syndrome characterized by necrolytic migratory erythema, diabetes mellitus, weight loss, anemia, glossitis, thromboembolism, neuropsychiatric disturbances and hyperglucagonemia. We report a 43 years old male presenting with a five years history of dermatological lesions, associated with weight loss, glossitis and onicodystrophy. Serum glucagon was 2200 pg/ml and a CAT scan showed a tumor in the tail of the pancreas.