Early PSA-NCAM reduction in the dentate gyrus and impaired plasticity in the Alzheimer´s disease 3xTg-mice model.

Neurodegenerative diseases such as Alzheimer´s (AD) and physiological ageing are characterized by a decline in neurogenesis and in the polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and specifically in the dentate gyrus (DG). In the 3xTG-AD mouse model, which mimics the human disease in both pathological and behavioral features, this decline in PSA-NCAM is associated with the presence of Aβ plaques at 9 months and Tau tangles at 12-15 months. In this work we studied the presence of PSA-NCAM at early ages (1-6 months) in the same model.

Entorhinal cortex astrocytic atrophy in human frontotemporal dementia.

The pathophysiology of Fronto Temporal Dementia (FTD) remains poorly understood, specifically the role of astroglia. Our aim was to explore the hypothesis of astrocytic alterations as a component for FTD pathophysiology. We performed an in-depth tri-dimensional (3-D) anatomical and morphometric study of glial fibrillary acidic protein (GFAP)-positive and glutamine synthetase (GS)-positive astrocytes in the human entorhinal cortex (EC) of FTD patients.

Astrocyte S100β expression and selective differentiation to GFAP and GS in the entorhinal cortex during ageing in the 3xTg-Alzheimer's disease mouse model.

The study of astrocytes and its role in the development and evolution of neurodegenerative diseases, including Alzheimer's disease (AD) is essential to fully understand their aetiology. The aim if this study is to deepen into the concept of the heterogeneity of astrocyte subpopulations in the EC and in particular the identification of differentially functioning astrocyte subpopulations that respond differently to AD progression. S100β protein belongs to group of small calcium regulators of cell membrane channels and pumps that are expressed by astrocytes and is hypothesised to play and have a relevant role in AD development.

Prominent and conspicuous astrocyte atrophy in human sporadic and familial Alzheimer's disease.

Pathophysiology of sporadic Alzheimer's disease (SAD) and familial Alzheimer's disease (FAD) remains poorly known, including the exact role of neuroglia and specifically astroglia, in part because studies of astrocytes in human Alzheimer's disease (AD) brain samples are scarce. As far as we know, this is the first study of a 3-D immunohistochemical and microstructural analysis of glial fibrillary acidic protein (GFAP)- and glutamine synthetase (GS)-positive astrocytes performed in the entorhinal cortex (EC) of human SAD and FAD samples. In this study, we report prominent atrophic changes in GFAP and GS astrocytes in the EC of both SAD and FAD characterised by a decrease in area and volume when compared with non-demented control samples (ND).

ABO blood group as a determinant of COVID-19 and Long COVID: An observational, longitudinal, large study.

Background: An association of ABO blood group and COVID-19 remains controversial.

Methods: Following STROBE guidance for observational research, we explored the distribution of ABO blood group in patients hospitalized for acute COVID-19 and in those with Long COVID. Contingency tables were made and risk factors were explored using crude and adjusted Mantle-Haentzel odds ratios (OR and 95% CI).

Neuroanatomical and morphometric study of S100β positive astrocytes in the entorhinal cortex during ageing in the 3xTg-Alzehimer's disease mouse model.

Astrocytes contribute to the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we report the neuroanatomical and morphometric analysis of astrocytes in the entorhinal cortex (EC) of the aged wild type (WT) and triple transgenic (3xTg-AD) mouse model of AD. Using 3D confocal microscopy, we determined the surface area and volume of positive astrocytic profiles in male mice (WT and 3xTg-AD) from 1 to 18 months of age.

A new serotonin 2A receptor antagonist with potential benefits in Non-Alcoholic Fatty Liver Disease.

Peripheral 5-hydroxytryptamine 2A receptor (5-HT2AR) could be a new pharmacological target for NASH, an evolution of NAFLD characterized by hepatic steatosis, cytoskeletal alterations, and hepatic inflammation that can arise with or without fibrosis. SJT4a is a synthetic β-carboline antagonist for 5-HT2AR developed by SJT molecular research to treat NASH. We performed a combined in silico/in vivo study on this potential drug to elucidate its activity and possible mechanism of action.

Tri-2-Hydroxyarachidonein Induces Cytocidal Autophagy in Pancreatic Ductal Adenocarcinoma Cancer Cell Models.

Cell proliferation in pancreatic cancer is determined by a complex network of signaling pathways. Despite the extensive understanding of these protein-mediated signaling processes, there are no significant drug discoveries that could considerably improve a patient's survival. However, the recent understanding of lipid-mediated signaling gives a new perspective on the control of the physiological state of pancreatic cells.

The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy.

Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor in adults, and the median survival of patients with GBM is 14.5 months. Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways.

2-Hydroxy-Docosahexaenoic Acid Is Converted Into Heneicosapentaenoic Acid via α-Oxidation: Implications for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a neurodegenerative disease with as yet no efficient therapies, the pathophysiology of which is still largely unclear. Many drugs and therapies have been designed and developed in the past decade to stop or slow down this neurodegenerative process, although none has successfully terminated a phase-III clinical trial in humans. Most therapies have been inspired by the amyloid cascade hypothesis, which has more recently come under question due to the almost complete failure of clinical trials of anti-amyloid/tau therapies to date.

The triacylglycerol, hydroxytriolein, inhibits triple negative mammary breast cancer cell proliferation through a mechanism dependent on dihydroceramide and Akt.

The plasma membrane is an attractive target for new anticancer drugs, not least because regulating its lipid structure can control multiple signaling pathways involved in cancer cell proliferation, differentiation and survival. Accordingly, the novel anticancer drug hydroxytriolein (HTO) was designed to interact with and regulate the composition and structure of the membrane, which in turn controls the interaction of amphitropic signaling membrane proteins with the lipid bilayer. Changes in signaling provoked by HTO impair the growth of triple negative breast cancer (TNBC) cells, aggressive breast tumor cells that have a worse prognosis than other types of breast cancers and for which there is as yet no effective targeted therapy.

The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA.

: 2-Hydroxyoleic acid (2OHOA) is particularly active against glioblastoma multiforme (GBM) and successfully finished a phase I/IIA trial in patients with glioma and other advanced solid tumors. However, its mechanism of action is not fully known. : The relationship between SMS1 and SMS2 expressions (mRNA) and overall survival in 329 glioma patients was investigated, and so was the correlation between SMS expression and 2OHOA's efficacy.

Treatment with albumin-hydroxyoleic acid complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation.

Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.

Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy.

Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions.

G protein-membrane interactions II: Effect of G protein-linked lipids on membrane structure and G protein-membrane interactions.

G proteins often bear myristoyl, palmitoyl and isoprenyl moieties, which favor their association with the membrane and their accumulation in G Protein Coupled Receptor-rich microdomains. These lipids influence the biophysical properties of membranes and thereby modulate G protein binding to bilayers. In this context, we showed here that geranylgeraniol, but neither myristate nor palmitate, increased the inverted hexagonal (H) phase propensity of phosphatidylethanolamine-containing membranes.

Neuroprotective effect of 2-hydroxy arachidonic acid in a rat model of transient middle cerebral artery occlusion.

Stroke modifies the composition of cell membranes by eliciting the breakdown of membrane phospholipids whose products, such as arachidonic acid (AA), are released in the cytosol. The action of enzymes such as cyclooxygenases on AA leads to inflammatory stimuli and increases the cell oxidative stress. We report here the neuroprotective effect of 2-hydroxyarachidonic acid (2OAA), a cyclooxygenase inhibitor derived from AA, as a promising neuroprotective therapy against stroke.

The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer's disease, improving behavioral motor function and survival.

We have compared the effect of the commonly used ω-3 fatty acid, docosahexaenoic acid ethyl ester (DHA-EE), and of its 2-hydroxylated DHA form (DHA-H), on brain lipid composition, behavior and lifespan in a new human transgenic Drosophila melanogaster model of Alzheimer's disease (AD). The transgenic flies expressed human Aβ42 and tau, and the overexpression of these human transgenes in the CNS of these flies produced progressive defects in motor function (antigeotaxic behavior) while reducing the animal's lifespan. Here, we demonstrate that both DHA-EE and DHA-H increase the longer chain fatty acids (≥18C) species in the heads of the flies, although only DHA-H produced an unknown chromatographic peak that corresponded to a non-hydroxylated lipid.

Role of the C-terminal basic amino acids and the lipid anchor of the Gγ protein in membrane interactions and cell localization.

Heterotrimeric G proteins are peripheral membrane proteins that frequently localize to the plasma membrane where their presence in molar excess over G protein coupled receptors permits signal amplification. Their distribution is regulated by protein-lipid interactions, which has a clear influence on their activity. Gβγ dimer drives the interaction between G protein heterotrimers with cell membranes.

Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation.

G protein-membrane interactions I: Gαi1 myristoyl and palmitoyl modifications in protein-lipid interactions and its implications in membrane microdomain localization.

G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with lipid compositions that resemble different membrane microdomains.

The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα- and Extracellular Signal-Regulated Kinase 1/2-Dependent Mechanism.

Membrane lipid therapy is a novel approach to rationally design or discover therapeutic molecules that target membrane lipids. This strategy has been used to design synthetic fatty acid analogs that are currently under study in clinical trials for the treatment of cancer. In this context, and with the aim of controlling tumor cell growth, we have designed and synthesized a hydroxylated analog of triolein, hydroxytriolein (HTO).

Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment.

Nowadays we understand cell membranes not as a simple double lipid layer but as a collection of complex and dynamic protein-lipid structures and microdomains that serve as functional platforms for interacting signaling lipids and proteins. Membrane lipids and lipid structures participate directly as messengers or regulators of signal transduction. In addition, protein-lipid interactions participate in the localization of signaling protein partners to specific membrane microdomains.

The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer's disease.

The unfolded protein response (UPR) and autophagy are two cellular processes involved in the clearing of intracellular misfolded proteins. Both pathways are targets for molecules that may serve as treatments for several diseases, including neurodegenerative disorders like Alzheimer's disease (AD). In the present work, we show that 2-hydroxy-DHA (HDHA), a docosahexaenoic acid (DHA) derivate that restores cognitive function in a transgenic mouse model of AD, modulates UPR and autophagy in differentiated neuron-like SH-SY5Y cells.

Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury.

Background: Recently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2-hydroxyoleic acid (2-OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses.

Methods: Initial antinociceptive behavioural screening of daily administration of 2-OHOA (400 mg/kg, p.