279 research outputs found
Molecular and pharmacological modulation of CALHM1 promote neuroprotection against oxygen and glucose deprivation in a model of hippocampal slices
Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation
of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not
only on voltage but also on the extracellular concentration of calcium ([Ca2+]) ions. At low [Ca2+]e
or depolarization, the channel is opened, allowing Ca2+ influx; however, high extracellular [Ca2+]e
or hyperpolarization promote its resting state. The unique Ca2+ permeation of CALHM1 relates
to the molecular events that take place in brain ischemia, such as depolarization and extracellular
changes in [Ca2+]e, particularly during the reperfusion phase after the ischemic insult. In this study,
we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose
deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type
Calhm1+/+, Calhm1+/-, and Calhm1-/- mice were subjected to OGD/Reox. Our results point out to a
neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of
CALHM1 with CGP37157 reduced cell death in Calhm1+/+ slices but not in that of Calhm1-/- mice
after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring
reactive oxygen species production upon OGD/Reox in Calhm1+/+ and Calhm1-/- mice, resulting in
a downregulation of ROS production in Calhm1-/- hippocampal slices and increased expression of
HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1
results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium
overload and downregulation of oxygen reactive species productionThis research was funded by the Spanish Ministry of Science, Innovation and Universities Ref
RTI2018-095793-B-I00 and Comunidad Autónoma de Madrid Ref. B2017/BMD-3827 to MGL. ETN PURINESDX
Research and Innovation Agreement Nº 766124. Program under the Marie Sklodowska-Curie and Proyectos
Santander-Universidad Autónoma de Madrid 2017, to MFC
Central activation of alpha7 nicotinic signaling attenuates lps-induced neuroinflammation and sickness behavior in adult but not in aged animals
We previously reported that lipopolysaccharide (LPS) challenge caused microglial-mediated neuroinflammation and sickness behavior that was amplified in aged mice. As α7 nAChRs are im-plicated in the “Cholinergic anti-inflammatory pathway”, we aimed to determine how α7 nAChR stimulation modulates microglial phenotype in an LPS-induced neuroinflammation model in adult and aged mice. For this, BALB/c mice were injected intraperitoneally with LPS (0.33 mg/kg) and treated with the α7 nAChR agonist PNU282987, using different administration protocols. LPS challenge reduced body weight and induced lethargy and social withdrawal in adult mice. Peripheral (intraperitoneal) co-administration of the α7 nAChR agonist PNU282987 with LPS, attenuated body weight loss and sickness behavior associated with LPS challenge in adult mice, and reduced microglial activation with suppression of IL-1β and TNFα mRNA levels. Furthermore, central (intracerebroven-tricular) administration of the α7 nAChR agonist, even 2 h after LPS injection, attenuated the decrease in social exploratory behavior and microglial activation induced by peripheral administration of LPS, although this recovery was not achieved if activation of α7 nAChRs was performed peripherally. Finally, we observed that the positive results of central activation of α7 nAChRs were lost in aged mice. In conclusion, we provide evidence that stimulation of α7 nAChR signaling reduces microglial activation in an in vivo LPS-based model, but this cholinergic-dependent regulation seems to be dysfunctional in microglia of aged mice.This work was supported by the Spanish Ministry of Science, innovation and Universities
Ref. SAF2015-63935-R and Ref. RTI2018-095793-B-I00 and General Council for Research and Innovation of the Community of Madrid and European Structural Funds Ref. B2017/BMD–3827–NRF24ADCM to M.G.L. Aging studies were supported by an NIA grant (R01-AG-033028) to J.P.G
Synthesis and pharmacology of alkanediguanidinium compounds that block the neuronal nicotinic acetylcholine receptor
Taking as models the polyamine toxin fraction FTX from the funnel-web spider venom, and the guanidinium moiety of guanethidine, a series of azaalkane-1,omega-diguanidinium salts were obtained. Some of them blocked ion fluxes through the neuronal nicotinic receptors for acetylcholine (nAChR). The blockade was exerted at submicromolar concentrations, suggesting a highly selective interaction with the nAChR. In fact, the active compounds on the nAChR ion channel did not recognize the voltage-dependent Na+ or Ca2+ channels of bovine adrenal chromaffin cells. Therefore, these compounds may be useful tools to clarify the functions of nAChR receptors in the central and peripheral nervous systems.Fundación Ramón Arece
CALHM1 and its polymorphism P86L differentially control Ca<sup>2+</sup> homeostasis, mitogen-activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β
The mutated form of the Ca2+ channel CALHM1 (Ca2+ homeostasis
modulator 1), P86L-CALHM1, has been correlated with early onset
of Alzheimer’s disease (AD). P86L-CALHM1 increases production
of amyloid beta (Ab) upon extracellular Ca2+ removal and its
subsequent addback. The aim of this study was to investigate the
effect of the overexpression of CALHM1 and P86L-CALHM, upon
Ab treatment, on the following: (i) the intracellular Ca2+ signal
pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP
response element binding (CREB); and (iii) cell vulnerability after
treatment with Ab. Using aequorins to measure the effect of
nuclear Ca2+ concentrations ([Ca2+]n) and cytosolic Ca2+ concentrations
([Ca2+]c) on Ca2+ entry conditions, we observed that
baseline [Ca2+]n was higher in CALHM1 and P86L-CALHM1 cells
than in control cells. Moreover, exposure to Ab affected [Ca2+]c
levels in HeLa cells overexpressing CALHM1 and P86L-CALHM1
compared with control cells. Treatment with Ab elicited a
significant decrease in the cell survival proteins p-ERK and
p-CREB, an increase in the activity of caspases 3 and 7, and more
frequent cell death by inducing early apoptosis in P86L-CALHM1-
overexpressing cells than in CALHM1 or control cells. These
results suggest that in the presence of Ab, P86L-CALHM1 shifts
the balance between neurodegeneration and neuronal survival
toward the stimulation of pro-cytotoxic pathways, thus potentially
contributing to its deleterious effects in AD.This work was partly supported by the following grants: Ministerio de
Economía y Competitividad, FPU Program, Refs. AP2009/0343 (AJMO)
and AP2010/1219 (IB). ARN: FIS PI10/01426. MGL: Ministerio de
Economía y Competitividad, Ref. SAF2012-23332. MFCA: Consolidación
de grupos de investigación UAM-CAM 1004040047. We also thank
Fundación Teófilo Hernando, Madrid, Spain, for their continued suppor
Calcium signalling mediated through a7 and non-a7 nAChR stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release
Producción CientíficaCa2+ signalling and exocytosis mediated by nicotinic receptor (nAChR) subtypes, especially the a7 nAChR, in bovine
chromaffin cells are still matters of debate.We have used chromaffin cell cultures loaded with Fluo-4 or transfected with aequorins directed to the cytosol or
mitochondria, several nAChR agonists (nicotine, 5-iodo-A-85380, PNU282987 and choline), and the a7 nAChR allosteric
modulator PNU120596. Minimal [Ca2+]c transients, induced by low concentrations of selective a7 nAChR agonists and nicotine, were markedly
increased by the a7 nAChR allosteric modulator PNU120596. These potentiated responses were completely blocked by the
a7 nAChR antagonist a-bungarotoxin (a7-modulated-response). Conversely, high concentrations of the a7 nAChR agonists,
nicotine or 5-iodo-A-85380 induced larger [Ca2+]c transients, that were blocked by mecamylamine but were unaffected by
a-bungarotoxin (non-a7 response). [Ca2+]c increases mediated by a7 nAChR were related to Ca2+ entry through non-L-type
Ca2+ channels, whereas non-a7 nAChR-mediated signals were related to L-type Ca2+ channels; Ca2+-induced Ca2+-release
contributed to both responses. Mitochondrial involvement in the control of [Ca2+]c transients, mediated by either receptor,
was minimal. Catecholamine release coupled to a7 nAChRs was more efficient in terms of catecholamine released/[Ca2+]c.2015-09-1
Probing the phase transition to a coherent 2D Kondo Lattice
Kondo lattices are systems with unusual electronic properties that stem from
strong electron correlation, typically studied in intermetallic 3D compounds
containing lanthanides or actinides. Lowering the dimensionality of the
system enhances the role of electron correlations providing a new tuning
knob for the search of novel properties in strongly correlated quantum matter.
The realization of a 2D Kondo lattice by stacking a single-layer Mott insulator
on a metallic surface is reported. The temperature of the system is steadily
lowered and by using high-resolution scanning tunneling spectroscopy, the
phase transition leading to the Kondo lattice is followed. Above 27 K the
interaction between the Mott insulator and the metal is negligible and both
keep their original electronic properties intact. Below 27 K the Kondo
screening of the localized electrons in the Mott insulator begins and below
11 K the formation of a coherent quantum electronic state extended to the
entire sample, i.e., the Kondo lattice, takes place. By means of density
functional theory, the electronic properties of the system and its evolution
with temperature are explained. The findings contribute to the exploration of
unconventional states in 2D correlated materialsThis work was supported by Ministerio de Ciencia, Innovación y Universidades through grants, PID2021-128011NB-I00 and PID2019-105458RBI00. Ministerio de Ciencia e Innovación and Comunidad de Madrid
through grants “Materiales Disruptivos Bidimensionales (2D)” (MAD2DCM)-UAM and “Materiales Disruptivos Bidimensionales (2D)” (MAD2DCM)-IMDEA-NC funded by the Recovery, Transformation and Resilience
Plan, and by NextGenerationEU from the European Union. Comunidad de
Madrid through grants NMAT2D-CM P20128/NMT-4511 and NanoMagCost. IMDEA Nanoscience acknowledges support from the “‘Severo
Ochoa”’ Programme for Centres of Excellence in R&D CEX2020-001039-S.
IFIMAC acknowledges support from the “‘María de Maeztu”’ Programme
for Units of Excellence in R&D CEX2018-000805-M. M.G. thanks Ministerio de Ciencia, Innovación y Universidades “Ramón y Cajal” Fellowship RYC2020-029317-I. Allocation of computing time at the Centro de Computación Científica at the Universidad Autónoma de Madrid, the CINECA
Consortium INF16_npqcd Project, and Newton HPCC Computing Facility
at the University of Calabria (MP
Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease
Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age-related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood–brain barrier to reach the target areas in the brain or to regulate the function of the blood–brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood–brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential.Funding for open access charge; Universidad de Málaga / CBU
Reactive oxygen-related diseases: therapeutic targets and emerging clinical indications
SIGNIFICANCE
Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear.
RECENT ADVANCES
We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach.
CRITICAL ISSUES
Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired.
FUTURE DIRECTIONS
Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171-1185
Metastable polymorphic phases in monolayer TaTe2
Polymorphic phases and collective phenomena—such as charge density waves (CDWs)—in transition metal dichalcogenides (TMDs) dictate the physical and electronic properties of the material. Most TMDs naturally occur in a single given phase, but the fine-tuning of growth conditions via methods such as molecular beam epitaxy (MBE) allows to unlock otherwise inaccessible polymorphic structures. Exploring and understanding the morphological and electronic properties of new phases of TMDs is an essential step to enable their exploitation in technological applications. Here, scanning tunneling microscopy (STM) is used to map MBE-grown monolayer (ML) TaTe2. This work reports the first observation of the 1H polymorphic phase, coexisting with the 1T, and demonstrates that their relative coverage can be controlled by adjusting synthesis parameters. Several superperiodic structures, compatible with CDWs, are observed to coexist on the 1T phase. Finally, this work provides theoretical insight on the delicate balance between Te…Te and Ta–Ta interactions that dictates the stability of the different phases. The findings demonstrate that TaTe2 is an ideal platform to investigate competing interactions, and indicate that accurate tuning of growth conditions is key to accessing metastable states in TMD
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