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Biodiesel is a mixture of saturated and unsaturated Fatty Acid Methyl Esters (FAMEs) whose composition affects the corrosion behavior of metal containers during storage. This study examines the effect of the C=C bond present in selected FAMEs (Methyl Stearate, Methyl Oleate, and Methyl Linoleate) in aluminum corrosion in the absence of oxygen. First, mass loss assays were carried out at 100, 200, and 280 °C for 1000 h using pure Methyl Stearate (MS), 5% Methyl Oleate in Methyl Stearate (MS-5% MO), and 5% Methyl Linoleate in Methyl Stearate (MS-5% ML). Next, chemical changes in FAMEs were studied using FTIR, TGA, and GC/MS. SEM/EDS analysis allowed us to inspect the aluminum surfaces and their chemical characterization. We estimated higher corrosion rates for MS assays than those of unsaturated methyl ester mixtures. In a separate set of experiments, we used electrochemical techniques (potentiodynamic polarization, linear polarization resistance, and electrochemical impedance spectroscopy) to investigate aluminum corrosion induced by thermal-degraded products from FAMEs at 100, 200, and 280 °C for 300 h able to dissolve in aqueous extracts. These electrochemical experiments revealed that the products in the aqueous extracts from the unsaturated methyl ester mixture form a passive layer on the Al surface thicker than pure MS at the corresponding degradation temperatures.

In 2010, the Mediterranean diet was recognized by UNESCO as an Intangible Cultural Heritage of Humanity. Olive oil is the most characteristic food of this diet due to its high nutraceutical value. The positive effects of olive oil have often been attributed to its minor components; however, its oleic acid (OA) content (70-80%) is responsible for its many health properties. OA is an effective biomolecule, although the mechanism by which OA mediates beneficial physiological effects is not fully understood. OA influences cell membrane fluidity, receptors, intracellular signaling pathways, and gene expression. OA may directly regulate both the synthesis and activities of antioxidant enzymes. The anti-inflammatory effect may be related to the inhibition of proinflammatory cytokines and the activation of anti-inflammatory ones. The best-characterized mechanism highlights OA as a natural activator of sirtuin 1 (SIRT1). Oleoylethanolamide (OEA), derived from OA, is an endogenous ligand of the peroxisome proliferator-activated receptor alpha (PPARα) nuclear receptor. OEA regulates dietary fat intake and energy homeostasis and has therefore been suggested to be a potential therapeutic agent for the treatment of obesity. OEA has anti-inflammatory and antioxidant effects. The beneficial effects of olive oil may be related to the actions of OEA. New evidence suggests that oleic acid may influence epigenetic mechanisms, opening a new avenue in the exploration of therapies based on these mechanisms. OA can exert beneficial anti-inflammatory effects by regulating microRNA expression. In this review, we examine the cellular reactions and intracellular processes triggered by OA in T cells, macrophages, and neutrophils in order to better understand the immune modulation exerted by OA.

The innate immune system uses pattern recognition receptors to survey the intracellular and extracellular environment for signs of infection. Viral infection is detected through the presence of viral nucleic acids in infected cells. Pattern recognition receptor activation by viral nucleic acids induces the expression and secretion of type I IFNs (IFN-Is), important mediators of antiviral immunity. RIG-I-like receptors (RLRs) are RNA sensors that detect viral RNA in the cytosol and induce an IFN-I response. Viral RNAs contain features that set them apart from host RNAs, allowing RLRs to discriminate between cellular/self and viral/non-self RNA. The notion emerged that self RNAs can also engage RLRs and modulate the IFN-I response, indicating that the distinction between self and non-self RNA is not watertight. We review how self RNAs regulate RLR activation and the IFN-I response during viral infection and how recognition of self RNAs by RLRs is implicated in autoinflammatory disorders and cancer., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Objective: To evaluate the cost-effectiveness of insertable cardiac monitors (ICMs) compared with standard of care (SoC) for detecting atrial fibrillation (AF) in patients at high risk of stroke (CHADS 2 >2), using a UK National Health Service (NHS) perspective., Methods: Using patient characteristics and clinical data from the REVEAL AF trial, a Markov model assessed the cost-effectiveness of detecting AF with an ICM compared with SoC. Costs and benefits were extrapolated across modelled patient lifetime. Ischaemic and haemorrhagic strokes, intracranial and extracranial haemorrhages and minor bleeds were modelled. Diagnostic and device costs were included, plus costs of treating stroke and bleeding events and costs of oral anticoagulants (OACs). Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3.5% per annum. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken., Results: The total per-patient cost for ICM was £13 360 versus £11 936 for SoC (namely, annual 24 hours Holter monitoring). ICMs generated a total of 6.50 QALYs versus 6.30 for SoC. The incremental cost-effectiveness ratio (ICER) was £7140/QALY gained, below the £20 000/QALY acceptability threshold. ICMs were cost-effective in 77.4% of PSA simulations. The number of ICMs needed to prevent one stroke was 21 and to cause a major bleed was 37. ICERs were sensitive to assumed proportions of patients initiating or discontinuing OAC after AF diagnosis, type of OAC used and how intense the traditional monitoring was assumed to be under SoC., Conclusions: The use of ICMs to identify AF in a high-risk population is cost-effective for the UK NHS., Competing Interests: Competing interests: CR, LS and AD are employed by Symmetron Ltd, which received funding from Medtronic plc for this analysis. ME’s institution has received payments from Medtronic plc for ME’s participation in this analysis. KW and MR have received consultancy fees from Medtronic plc. ST, PZ and CW are employees and have equity interest in Medtronic plc. MQ was a Medtronic employee at the time of the analysis.

The present work investigates the modulation of grapefruit flavonoid naringenin over liver X receptor alpha (LXRα) and its target genes in THP-1 macrophages, focusing on AMP-activated protein kinase (AMPK) implication. Naringenin induced LXRα at mRNA and protein levels besides influencing the expression of LXRα target genes ABCA1, ABCG1 (ATP-binding cassette A1 and G1), and SREBP1c (sterol response element binding protein 1c) in THP-1 macrophages. The increased LXRα mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C or by transfection with AMPK α1 and α2 siRNA. Naringenin treatments were also able to promote reverse cholesterol transport in THP-1 cells, which is in line with the increase in the ABCA1 and ABCG1 expression found. Treatments with this flavonoid also inhibited cell migration in THP-1 cells. In conclusion, LXRα and its target genes are up-regulated by naringenin in an AMPK dependent manner in human macrophages. The enhancement in the expression of genes involved in cholesterol efflux may reveal a new mechanism by which this polyphenol can prevent atherosclerosis and foam cell progression.

Porphyromonas gingivalis is one of the major oral pathogens implicated in the widespread inflammatory disorder periodontitis. Moreover, in recent years, P. gingivalis has been associated with the autoimmune disease rheumatoid arthritis. The peptidylarginine deiminase enzyme of P. gingivalis (PPAD) is a major virulence factor that catalyzes the citrullination of both bacterial and host proteins, potentially contributing to production of anticitrullinated protein antibodies. Considering that these antibodies are very specific for rheumatoid arthritis, PPAD appears to be a link between P. gingivalis, periodontitis, and the autoimmune disorder rheumatoid arthritis. PPAD was thus far considered unique among prokaryotes, with P. gingivalis being the only bacterium known to produce and secrete it. To challenge this hypothesis, we investigated the possible secretion of PPAD by 11 previously collected Porphyromonas isolates from a dog, 2 sheep, 3 cats, 4 monkeys, and a jaguar with periodontitis. Our analyses uncovered the presence of secreted PPAD homologues in 8 isolates that were identified as Porphyromonas gulae (from a dog, monkeys, and cats) and Porphyromonas loveana (from sheep). In all 3 PPAD-producing Porphyromonas species, the dominant form of the secreted PPAD was associated with outer membrane vesicles, while a minor fraction was soluble. Our results prove for the first time that the citrullinating PPAD exoenzyme is not unique to only 1 prokaryotic species. Instead, we show that PPAD is produced by at least 2 other oral pathogens.

Liver X receptor alpha (LXRα) is a nuclear receptor involved in cholesterol homeostasis. Curcumin, a traditional Chinese derivative from the rhizomes of Curcuma longa and a well-known AMP-activated protein kinase (AMPK) activator, possess hypocholesterolemic activity, however, the possible link between AMPK and cholesterol is unknown. In this study, we have investigated whether curcumin regulates metabolic changes in cholesterol metabolism via LXRα in THP-1 human macrophages, the cells implicated in atheroma plaques formation. Results showed that curcumin induced AMPK phosphorylation, increased LXRα mRNA and protein expression. Curcumin up-regulated mRNA expression of genes involved in cholesterol transport and metabolism as ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the sterol response element binding protein 1c (SREBP1c). On the other hand, this increased LXRα mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C. Transfection with AMPK α1 and α2 siRNA decreased the LXRα mRNA expression and its target genes. Curcumin treatment inhibited cell migration and was also able to promote reverse cholesterol transport in THP-1 cells. This enhanced reverse cholesterol transport might be related to the up-regulating of ABCA1 and ABCG1 mRNA expression by activating AMPK-LXRα signaling in THP-1 cells. This study describes a possible mechanism for understanding the hypocholesterolemic effects of curcumin and expand knowledge about the LXRα regulation by AMPK., (Copyright © 2017. Published by Elsevier Inc.)

Background: The risk of recurrence after an initial ischemic stroke or transient ischemic attack (TIA) may be impacted by undiagnosed atrial fibrillation (AF). We therefore assessed the impact of AF diagnosis and timing on stroke/TIA recurrence rates in a large real-world sample of patients., Methods and Results: Using commercial claims data (Truven Health Analytics MarketScan), we performed a retrospective cohort study of patients with an index stroke or TIA event recorded in years 2008 through 2011. Patients were characterized by baseline oral anticoagulation, CHADS 2 and CHA 2 DS 2 -VASc scores, AF diagnosis and timing with respect to the index stroke, and presence or absence of post-index ambulatory cardiac monitoring. The primary outcome was the recurrence of an ischemic stroke or TIA. Of 179 160 patients (age 67±16.2 years; 53.7% female), the Kaplan-Meier estimate for stroke/TIA recurrence within 1 year was 10.6%. Not having oral anticoagulation prescribed at baseline and having AF first diagnosed >7 days post-stroke (late AF) was highly associated with recurrent stroke/TIA (hazard ratio, 2.0; 95% confidence interval, 1.9-2.1). Among patients with at least 1 year of follow-up, only 2.6% and 9.7% had ambulatory ECG monitoring in the 7 days and 12 months post-stroke, respectively., Conclusions: AF diagnosed after stroke is an important hallmark of recurrent stroke risk. Increasing the low utilization of cardiac monitoring after stroke could identify undiagnosed AF earlier, leading to appropriate oral anticoagulation treatment and a reduction in stroke/TIA recurrence., (© 2017 American Heart Association, Inc.)

Liver X receptors (LXRs) are ligand-activated nuclear receptors involved mainly in the regulation of cholesterol metabolism in many organs, including liver and intestine, as well as in macrophages and neutrophils. Besides, both anti-inflammatory and pro-inflammatory properties have been ascribed to LXRs. The effect of the inflammatory condition on the expression of LXRα and its target genes has not been previously addressed in human neutrophils. We have described that platelet-activating factor (PAF) and hydrogen peroxide (H2O2) are potent pro-inflammatory mediators that link the haemostatic and innate immune systems. In this work we report that H2O2 at low doses (1 pM-1μM) exerts an inhibitory effect on TO901317-induced mRNA expression of LXRα and of its target genes encoding the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the sterol regulatory element-binding protein 1c (SREBP1c). However, an opposite behaviour, i.e., a transcription-enhancing effect, was found at higher H2O2 doses (100-500μM) on most of these genes. A similar dual effect was observed when the pro-inflammatory molecule PAF was used. Interestingly, H2O2 production separately elicited by 10nM PAF or 1μM H2O2 was similarly low, and analogously, H2O2 production levels elicited by 5μM PAF or 100μM H2O2 were similarly high when they were compared. On the other hand, low doses of PAF or H2O2 induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2) and NF-κB activation, However, PAF or H2O2 at high doses did not produce changes in NF-κB activation levels. In summary, our results show that H2O2, either exogenous or PAF-induced, exerts a dual regulation on mRNA expression of LXRα and its target genes., (Copyright © 2016. Published by Elsevier B.V.)

Purpose: Regulation of liver X receptors (LXRs) is essential for cholesterol homeostasis and inflammation. The present study was conducted to determine whether oleic acid (OA) could regulate mRNA expression of LXRα and LXRα-regulated genes and to assess the potential promotion of oxidative stress by OA in neutrophils., Methods: Human neutrophils were treated with OA at different doses and LXR target gene expression, oxidative stress production, lipid efflux and inflammation state were analyzed., Results: We describe that mRNA synthesis of both LXRα and ABCA1 (a reverse cholesterol transporter) was induced by OA in human neutrophils. This fatty acid enhanced the effects of LXR ligands on ABCA1 and LXR expression, but it decreased the mRNA levels of sterol regulatory element-binding protein 1c (a transcription factor that regulates the synthesis of triglycerides). Although OA elicited a slight oxidative stress in the short term (15-30 min) in neutrophils, it is unlikely that this is relevant for the modulation of transcription in our experimental conditions, which involve longer incubation time (i.e., 6 h). Of physiological importance is our finding that OA depresses intracellular lipid levels and that markers of inflammation, such as ERK1/2 and p38 mitogen-activated protein kinase phosphorylation, were decreased by OA treatment. In addition, 200 μM OA reduced the migration of human neutrophils, another marker of the inflammatory state. However, OA did not affect lipid peroxidation induced by pro-oxidant agents., Conclusions: This work presents for the first time evidence that human neutrophils are highly sensitive to OA and provides novel data in support of a protective role of this monounsaturated acid against the activation of neutrophils during inflammation.

Liver X receptors (LXRs) are ligand-activated members of the nuclear receptor superfamily that regulate the expression of genes involved in lipid metabolism and inflammation, although their role in inflammation and immunity is less well known. It has been reported that oxysterols/LXRs may act as anti-inflammatory molecules, although opposite actions have also been reported. In this study, we investigated the effect of platelet-activating factor (PAF), a proinflammatory molecule, on LXRα signalling in human neutrophils. We found that PAF exerted an inhibitory effect on mRNA expression of TO901317-induced LXRα, ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and sterol response element binding protein 1c. This negative action was mediated by the PAF receptor, and was dependent on the release of reactive oxygen species elicited by PAF, as it was enhanced by pro-oxidant treatment and reversed by antioxidants. Current data also support the idea that PAF induces phosphorylation of the LXRα molecule in an extracellular signal-regulated kinase 1/2-mediated fashion. These results suggest that a possible mechanism by which PAF exerts its proinflammatory effect is through the downregulation of LXRα and its related genes, which supports the notion that LXRα ligands exert a modulatory role in the neutrophil-mediated inflammatory response., (© 2013 FEBS.)

Calcineurin (protein phosphatase 2B) (CN) comprises a family of serine/threonine phosphatases that play a pivotal role in signal transduction cascades in a variety of cells, including neutrophils. Angiotensin II (Ang II) increases both activity and de novo synthesis of CN in human neutrophils. This study focuses on the role that intracellular redox status plays in the induction of CN activity by Ang II. Both de novo synthesis of CN and activity increase promoted by Ang II were downregulated when cells were treated with L-buthionine-(S,R)-sulfoximine, an inhibitor of synthesis of the antioxidant glutathione. We have also investigated the effect of pyrrolidine dithiocarbamate and phenazine methosulfate, which are antioxidant and oxidant compounds, respectively, and concluded that the intracellular redox status of neutrophils is highly critical for Ang II-induced increase of CN expression and activity. Results obtained in neutrophils from hypertensive patients were very similar to those obtained in these cells on treatment with Ang II. We have also addressed the possible functional implication of CN activation in the development of hypertension. Present findings indicate that downregulation of hemoxygenase-1 expression in neutrophils from hypertensive subjects is likely mediated by CN, which acts by hindering translocation to the nucleus of the transcription factor NRF2. These data support and extend our previous results and those from other authors on modulation of CN expression and activity levels by the intracellular redox status.

Objective: To estimate the annual cost of treating patients with cirrhosis at the Mexican Institute of Social Security (IMSS per its abbreviation in Spanish)., Material and Methods: The annual cost of treating three stages of cirrhosis (Child-Pugh A, Child-Pugh B and Child-Pugh C) was estimated using micro-costing techniques and medical experts. These results were compared and contrasted with prices reported by IMSS., Results: The annual cost of treatment, in USA dollars, by Child-Pugh stage was: a) micro-costing results: $1110.17 stage A, $549.55 stage B and $348.16 stage C; b) opinion of medical experts: $1 633.64, $6564.04 and $19660.35, respectively; and c) IMSS costs: $4269.00, $16949.63 and $30249.25, respectively., Conclusions: The cost of treating patients with cirrhosis is considerable, and costs increase as the disease worsens. Cost estimates vary depending on the source of information, and the methodology used. There are discrepancies between the procedures reported in medical records and treatment recommendations by IMSS liver experts.

The Abl-interactor (Abi) family of adaptor proteins has been linked to signaling pathways involving the Abl tyrosine kinases and the Rac GTPase. Abi proteins localize to sites of actin polymerization in protrusive membrane structures and regulate actin dynamics in vitro. Here we demonstrate that Abi2 modulates cell morphogenesis and migration in vivo. Homozygous deletion of murine abi2 produced abnormal phenotypes in the eye and brain, the tissues with the highest Abi2 expression. In the absence of Abi2, secondary lens fiber orientation and migration were defective in the eye, without detectable defects in proliferation, differentiation, or apoptosis. These phenotypes were consistent with the localization of Abi2 at adherens junctions in the developing lens and at nascent epithelial cell adherens junctions in vitro. Downregulation of Abi expression by RNA interference impaired adherens junction formation and correlated with downregulation of the Wave actin-nucleation promoting factor. Loss of Abi2 also resulted in cell migration defects in the neocortex and hippocampus, abnormal dendritic spine morphology and density, and severe deficits in short- and long-term memory. These findings support a role for Abi2 in the regulation of cytoskeletal dynamics at adherens junctions and dendritic spines, which is critical for intercellular connectivity, cell morphogenesis, and cognitive functions.

Murine osteoclast precursors and osteoblasts express the integrin alpha(v)beta(5), the appearance of which on the cell surface is controlled by the beta(5), and not the alpha(v), subunit. Here, we show that a 173-base pair proximal region of the beta(5) promoter mediates beta(5) basal transcription in macrophage (osteoclast precursor)-like and osteoblast-like cells. DNase I footprinting reveal four regions (FP1-FP4) within the 173-base pair region, protected by macrophage nuclear extracts. In contrast, osteoblast nuclear extracts protect only FP1, FP2, and FP3. FP1, FP2, and FP3 bind Sp1 and Sp3 from both macrophage and osteoblast nuclear extracts. FP4 does not bind osteoblast proteins but binds PU.1 from macrophages. Transfection studies show that FP1 and FP2 Sp1/Sp3 sites act as enhancers in both MC3T3-E1 (osteoblast-like) and J774 (macrophage-like) cell lines, whereas the FP3 Sp1/Sp3 site serves as a silencer. Mutation of the FP2 Sp1/Sp3 site totally abolishes promoter activity in J774 cells, with only partial reduction in MC3T3-E1 cells. Finally, we demonstrate that PU.1 acts as a beta(5) silencer in J774 cells but plays no role in MC3T3-E1 cells. Thus, three Sp1/Sp3 sites regulate beta(5) gene expression in macrophages and osteoblast-like cells, with each element exhibiting cell-type and/or activation-suppression specificity.

We previously noted that the initial receptor by which murine osteoclast precursors bind matrix is the integrin alphav beta5 and that granulocyte-macrophage colony-stimulating factor (GM-CSF) decreases expression of this heterodimer by suppressing transcription of the beta5 gene. We herein report cloning of the beta5 integrin gene promoter and identification of a GM-CSF-responsive sequence. A 13-kilobase (kb) genomic fragment containing part of the beta5 gene was isolated by screening a mouse genomic library with a probe derived from the most 5'-end of a murine beta5 cDNA. A combination of primer extension and S1 nuclease studies identifies two transcriptional start sites, with the major one designated +1. A 1-kb subclone containing sequence -875 to + 110 is transcriptionally active in a murine myeloid cell line. This 1-kb fragment contains consensus binding sequences for basal (Sp1), lineage-specific (PU.1), and regulatable (signal transducer and activator of transcription) transcription factors. Reflecting our earlier findings, promoter activity is repressed in transfected myeloid cells treated with GM-CSF. Using deletion mutants, we localized a 109-base pair (bp) promoter region responsible for GM-CSF-inhibited beta5 transcription. We further identified a 19-bp sequence within the 109-bp region that binds GM-CSF-induced nuclear proteins by gel shift/competition assays. Mutation of the 19-bp sequence not only ablates its capacity to bind nuclear proteins from GM-CSF-treated cells, in vitro, but the same mutation, when introduced in the 1-kb promoter, abolishes its ability to respond to GM-CSF treatment. Northern analysis demonstrates that cycloheximide treatment abrogates the capacity of GM-CSF to decrease beta5 mRNA levels. In summary, we have identified a 19-bp cis-element mediating GM-CSF-induced down-regulation of beta5 by a mechanism requiring protein synthesis.