Bending the rules: Molecular dynamics of hydroxylated sphingolipid membranes with 2-hydroxyoleic acid.

In this study, we introduce a novel method for quantifying the mechanical properties of lipid membranes-bending rigidity (κ), Gaussian rigidity (κ), and surface tension (γ) using molecular dynamics (MD) simulations. Our approach is applied to membranes incorporating 2-hydroxyoleic acid (2OHOA), a synthetic oleic acid derivative currently under clinical investigation for its anticancer properties. 2OHOA modifies the plasma membrane composition in cancer cells and activates sphingomyelin synthase 1 (SMS1), an enzyme critical for maintaining sphingolipid levels in the plasma membrane.

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).

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.

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).

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.

Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma.

This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis.

The effect of hydroxylated fatty acid-containing phospholipids in the remodeling of lipid membranes.

The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) is an antitumor drug that regulates membrane lipid composition and structure. An important effect of this drug is the restoration of sphingomyelin (SM) levels in cancer cell membranes, where the SM concentration is lower than in non-tumor cells. It is well known that free fatty acid concentration in cell membranes is lower than 5%, and that fatty acid excess is rapidly incorporated into phospholipids.

Differential effect of 2-hydroxyoleic acid enantiomers on protein (sphingomyelin synthase) and lipid (membrane) targets.

The complex dual mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent anti-tumor compound used in membrane lipid therapy (MLT), has yet to be fully elucidated. It has been demonstrated that 2OHOA increases the sphingomyelin (SM) cell content via SM synthase (SGMS) activation. Its presence in membranes provokes changes in the membrane lipid structure that induce the translocation of PKC to the membrane and the subsequent overexpression of CDK inhibitor proteins (e.

Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative pathology with relevant unmet therapeutic needs. Both natural aging and AD have been associated with a significant decline in the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), and accordingly, administration of DHA has been proposed as a possible treatment for this pathology. However, recent clinical trials in mild-to-moderately affected patients have been inconclusive regarding the real efficacy of DHA in halting this disease.

Cognitive recovery and restoration of cell proliferation in the dentate gyrus in the 5XFAD transgenic mice model of Alzheimer's disease following 2-hydroxy-DHA treatment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly. In the last years, abnormalities of lipid metabolism and in particular of docosahexaenoic acid (DHA) have been recently linked with the development of the disease. According to the recent studies showing how hydroxylation of fatty acids enhances their biological activity, here we show that chronic treatment with a hydroxylated derivative of DHA, the 2-hydroxy-DHA (2OHDHA) in the 5XFAD transgenic mice model of AD improves performance in the radial arm maze test and restores cell proliferation in the dentate gyrus, with no changes in the presence of beta amyloid (Aβ) plaques.

Description of extreme longevity in the Balearic Islands: Exploring a potential Blue Zone in Menorca, Spain.

Aim: We aimed to determine whether there was a Blue Zone, an area characterized by extreme longevity, in Menorca, Spain.

Methods: We explored official statistics of the Balearic Islands, Spain, and calculated life expectancy from 1991 to 2009, by sex and island, among other demographic estimators.

Results: The life expectancy at birth in Menorca reached a peak in 2007 with 82.