Cell Membrane Phospholipids Research Articles

Conceptualization of Well-Building with Reference to Air-Filtration with Biomaterials

Aims: Over the last decade, green building standards and standard-setting organizations have made significant strides towards the market transformation of the building industry, resulting in a rapid expansion of green buildings and environmentally conscious building practices throughout the world. The WELL Building Standard focuses on the people in the building [1]. One of the biggest problems in the world today, that has devastating effects on human health and on global warming, is air pollution. By developing knowledge of biomaterials production, ways can be found to reduce these pollutants. Methods: To write this article, a quasi-experimental research method has been used that examines the production of a biomaterial for air filtration in building skins. This shell, which is inspired by cell plasma membrane, meets WELL standards for the adsorption of air pollutant particles and their conversion into harmless particles, thereby optimizing indoor air quality, as well as helping to reduce air pollutants and improve global warming conditions. The use of peptoids -non-natural mimetics of peptides and proteins and like cell membrane phospholipids- to make this synthetic membrane is recommended in this article. Findings: According to studies, peptoids can have side chains to adsorb air pollutant particles. The structure of peptoids allows them to exhibit certain features of cell plasma membrane, such as self-healing and self-assembly. These synthetic membranes can be fabricated with a structure like a cellular plasma membrane. Conclusion: This research states that the time has come to elevate human health and comfort to the forefront of building practices and reinvent buildings that are not only better for the planet, but also for people [1]. Fabricating synthetic membranes, for buildings, with air filtration capabilities using peptoids, is one way to maintain human health and improve the planet.

In Silico Drug Design of Benzothiadiazine Derivatives Interacting with Phospholipid Cell Membranes.

The use of drugs derived from benzothiadiazine, a bicyclic heterocyclic benzene derivative, has become a widespread treatment for diseases such as hypertension, low blood sugar or the human immunodeficiency virus, among others. In this work we have investigated the interactions of benzothiadiazine and four of its derivatives designed in silico with model zwitterionic cell membranes formed by dioleoylphosphatidylcholine, 1,2-dioleoyl-sn-glycero-3-phosphoserine and cholesterol at the liquid–crystal phase inside aqueous potassium chloride solution. We have elucidated the local structure of benzothiadiazine by means of microsecond molecular dynamics simulations of systems including a benzothiadiazine molecule or one of its derivatives. Such derivatives were obtained by the substitution of a single hydrogen site of benzothiadiazine by two different classes of chemical groups, one of them electron-donating groups (methyl and ethyl) and another one by electron-accepting groups (fluorine and trifluoromethyl). Our data have revealed that benzothiadiazine derivatives have a strong affinity to stay at the cell membrane interface although their solvation characteristics can vary significantly—they can be fully solvated by water in short periods of time or continuously attached to specific lipid sites during intervals of 10–70 ns. Furthermore, benzothiadiazines are able to bind lipids and cholesterol chains by means of single and double hydrogen-bonds of characteristic lengths between 1.6 and 2.1 Å.

Relationship between HIV-1 Gag Multimerization and Membrane Binding.

HIV-1 viral particle assembly occurs specifically at the plasma membrane and is driven primarily by the viral polyprotein Gag. Selective association of Gag with the plasma membrane is a key step in the viral assembly pathway, which is traditionally attributed to the MA domain. MA regulates specific plasma membrane binding through two primary mechanisms including: (1) specific interaction of the MA highly basic region (HBR) with the plasma membrane phospholipid phosphatidylinositol (4,5) bisphosphate [PI(4,5)P2], and (2) tRNA binding to the MA HBR, which prevents Gag association with non-PI(4,5)P2 containing membranes. Gag multimerization, driven by both CA–CA inter-protein interactions and NC-RNA binding, also plays an essential role in viral particle assembly, mediating the establishment and growth of the immature Gag lattice on the plasma membrane. In addition to these functions, the multimerization of HIV-1 Gag has also been demonstrated to enhance its membrane binding activity through the MA domain. This review provides an overview of the mechanisms regulating Gag membrane binding through the MA domain and multimerization through the CA and NC domains, and examines how these two functions are intertwined, allowing for multimerization mediated enhancement of Gag membrane binding.

Risk of Thrombosis, Pregnancy Morbidity or Death in Antiphospholipid Syndrome.

The antiphospholipid syndrome is an autoimmune disease characterized by thrombosis and pregnancy morbidity. The manifestations are caused by antibodies targeting cell membrane phospholipids and/or associated proteins. The triggers leading to these antibodies' production are unknown but recent work suggests cross-reactivity between the autoantigens and peptides produced by the intestinal microbiome. Work on how the autoantibodies could cause clinical manifestations implicates different mechanisms. Binding to surface proteins of different cell types can induce intracellular signaling leading to cell activation and tissue factor expression. Complement activation and neutrophil extracellular-traps are also involved, and recent evidence implicates endothelial protein C receptor-lysobisphosphatidic acid complex. Pregnancy is a high-risk situation for antiphospholipid syndrome patients due to the increased risk of thrombosis and obstetric complications. Epidemiological and clinical research on APS is hampered by heterogeneity in populations, testing and treatment strategies. About one in 10 to one in fifty APS pregnancies is complicated by thrombosis, despite treatment. Pregnant patients with prior thrombosis are prescribed therapeutic dose heparins and low dose aspirin. Without prior thrombosis a prophylactic dose is used. The most frequent obstetrical manifestation is recurrent early pregnancy loss. The association of APS antibodies with late pregnancy loss is stronger, however. Prevention of recurrence is achieved with aspirin and prophylactic dose heparin, although the evidence is of low certainty. The third obstetrical classifying manifestation comprises preterm delivery due to placenta-mediated complications and is treated in subsequent pregnancies with aspirin with or without prophylactic dose heparin, again based on low quality evidence. New therapies are under investigation.

Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases.

Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, but when in excess, they exhibit cardio-lipotoxicity that causes cardiac dysfunction or heart failure with preserved ejection fraction. FAs also play a role as part of phospholipids that compose cell membranes, and the changes in mitochondrial phospholipid cardiolipin and the FA composition of plasma membrane phospholipids affect cardiomyocyte survival. In addition, FA metabolites exert a wide variety of bioactivities in the heart as lipid mediators. Recent advances in measurement using mass spectrometry have identified trace amounts of n-3 polyunsaturated fatty acids (PUFAs)-derived bioactive metabolites associated with heart disease. n-3 PUFAs have a variety of cardioprotective effects and have been shown in clinical trials to be effective in cardiovascular diseases, including heart failure. This review outlines the contributions of FAs to cardiac function and pathogenesis of heart diseases from the perspective of three major roles and proposes therapeutic applications and new medical perspectives of FAs represented by n-3 PUFAs.

A lipid viewpoint on the plant endoplasmic reticulum stress response.

Organisms, including humans, seem to be constantly exposed to various changes, which often have undesirable effects, referred to as stress. To keep up with these changes, eukaryotic cells may have evolved a number of relevant cellular processes, such as the endoplasmic reticulum (ER) stress response. Owing to presumably intimate links between human diseases and the ER function, the ER stress response has been extensively investigated in various organisms for a few decades. Based on these studies, we now have a picture of the molecular mechanisms of the ER stress response, one of which, the unfolded protein response (UPR), is highly conserved among yeasts, mammals, higher plants, and green algae. In this review, we attempt to highlight the plant UPR from the perspective of lipids, especially membrane phospholipids. Phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) are the most abundant membrane phospholipids in eukaryotic cells. The ratio of PtdCho to PtdEtn and the unsaturation of fatty acyl tails in both phospholipids may be critical factors for the UPR, but the pathways responsible for PtdCho and PtdEtn biosynthesis are distinct in animals and plants. We discuss the plant UPR in comparison with the system in yeasts and animals in the context of membrane phospholipids.

Ferroptosis: regulation by competition between NRF2 and BACH1 and propagation of the death signal.

Ferroptosis is triggered by a chain of intracellular labile iron-dependent peroxidation of cell membrane phospholipids. Ferroptosis is important not only as a cause of ischaemic and neurodegenerative diseases but also as a mechanism of cancer suppression, and a better understanding of its regulatory mechanism is required. It has become clear that ferroptosis is finely controlled by two oxidative stress-responsive transcription factors, NRF2 (NF-E2-related factor 2) and BACH1 (BTB and CNC homology 1). NRF2 and BACH1 inhibit and promote ferroptosis, respectively, by activating or suppressing the expression of genes in the major regulatory pathways of ferroptosis: intracellular labile iron metabolism, the GSH (glutathione) -GPX4 (glutathione peroxidase 4) pathway and the FSP1 (ferroptosis suppressor protein 1)-CoQ (coenzyme Q) pathway. In addition to this, NRF2 and BACH1 control ferroptosis through the regulation of lipid metabolism and cell differentiation. This multifaceted regulation of ferroptosis by NRF2 and BACH1 is considered to have been acquired during the evolution of multicellular organisms, allowing the utilization of ferroptosis for maintaining homeostasis, including cancer suppression. In terms of cell-cell interaction, it has been revealed that ferroptosis has the property of propagating to surrounding cells along with lipid peroxidation. The regulation of ferroptosis by NRF2 and BACH1 and the propagation phenomenon could be used to realize anticancer cell therapy in the future. In this review, these points will be summarized and discussed.

Modulation of plasma membrane phospholipids in red blood cells for extension of cell shelf-life and studies of membrane-particle interactions

The cell plasma membrane is an asymmetric lipid bilayer with respect to composition of phospholipids in each leaflet. The complex nature of the plasma membrane raises specific problems when investigating the effects of different phospholipids on membrane behavior. In this work, we use cyclodextrin-mediated phospholipid exchange for altering the phospholipid composition of the membrane outer leaflet of Red Blood Cells (RBCs). Cyclodextrins are a group of cyclic molecules, with a highly hydrophobic inner cavity, that have been shown to facilitate phospholipid exchange with bilayer membranes.

Acute PI(4,5)P2 regulation of Cav1.2 l-type Ca2+channels in the heart

CaV1.2 channels are essential in cardiac excitation-contraction coupling. They can be tuned by physiological signaling pathways and dysregulated in diseases such as heart failure (HF). One such regulatory pathway is stimulated by angiotensin II (AngII) signaling through Gq-coupled AT1 receptors (AT1R). AngII is a peptide hormone with physiological roles in blood pressure regulation and pathological roles in hypertension and HF. AT1R activation results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a plasma membrane (PM) phospholipid which regulates several ion channels and exchangers including CaV1.2.

Deranged Myocardial Fatty Acid Metabolism in Heart Failure.

The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges.

New Target for Prevention and Treatment of Neuroinflammation: Microglia Iron Accumulation and Ferroptosis.

Microglia play an important role in maintaining central nervous system homeostasis and are the major immune cells in the brain. In response to internal or external inflammatory stimuli, microglia are activated and release numerous inflammatory factors, thus leading to neuroinflammation. Inflammation and microglia iron accumulation promote each other and jointly promote the progression of neuroinflammation. Inhibiting microglia iron accumulation prevents neuroinflammation. Ferroptosis is an iron-dependent phospholipid peroxidation-driven type of cell death regulation. Cell iron accumulation causes the peroxidation of cell membrane phospholipids and damages the cell membrane. Ultimately, this process leads to cell ferroptosis. Iron accumulation or phospholipid peroxidation in microglia releases a large number of inflammatory factors. Thus, inhibiting microglia ferroptosis may be a new target for the prevention and treatment of neuroinflammation.

Adipose tissue macrophages and atherogenesis – a synergy with cholesterolaemia

Excessive LDL cholesterol concentration together with subclinical inflammation, in which macrophages play a central role, are linked pathologies. The process starts with the accumulation of macrophages in white adipose tissue and the switch of their polarization toward a pro-inflammatory phenotype. The proportion of pro-inflammatory macrophages in adipose tissue is related to the main risk predictors of cardiovascular disease. The cholesterol content of phospholipids of cell membranes seems to possess a crucial role in the regulation of membrane signal transduction and macrophage polarization. Also, different fatty acids of membrane phospholipids influence phenotypes of adipose tissue macrophages with saturated fatty acids stimulating pro-inflammatory whereas ω3 fatty acids anti-inflammatory changes. The inflammatory status of white adipose tissue, therefore, reflects not only adipose tissue volume but also adipose tissue macrophages feature. The beneficial dietary change leading to an atherogenic lipoprotein decrease may therefore synergically reduce adipose tissue driven inflammation.

Graphene Oxide as a Collagen Modifier of Amniotic Membrane and Burnt Skin.

IntroductionThe aim of this interdisciplinary study was to answer the question of whether active antioxidants as graphene oxide (GO), sodium ascorbate, and L-ascorbic acid modify at a molecular and supramolecular level the tissue of pathological amnion and the necrotic eschar degraded in thermal burn. We propose new solutions of modifiers based on GO that will become innovative ingredients to be used in transplants (amnion) and enhance regeneration of epidermis degraded in thermal burn.MethodsA Nicolet 6700 spectrophotometer with Omnic software and the EasiDiff diffusion accessory were used in FTIR spectroscopic analysis. A Nicolet Magna-IR 860 spectrometer with an FT Raman accessory was used to record the Raman spectra of the samples. The surface of the samples was examined using a Phenom ProX scanning electron microscope with an energy-dispersive X-ray spectroscopy detector to diagnose and illustrate morphological effects on skin and amnion samples. SAXS measurements were carried out with a compact Kratky camera equipped with the SWAXS optical system.ResultsCharacterisation of amide I–III regions, important for molecular structure, on both FTIR and FTR spectra revealed distinct shifts, testifying to organization of protein structure after GO modification. A wide lipid band associated with ester-group vibrations in phospholipids of cell membranes and vibrations of the carbonyl group of GO in the 1,790–1,720 cm−1 band were observed in the spectra of thermally degraded and GO-modified epidermis and pathological amnion. SAXS studies revealed that GO caused a significant change in the structure of the burnt skin, but its influence on the structure of the amnion was weak.ConclusionModification of burn-damaged epidermis and pathological amnion by means of GO results in stabilization and regeneration of tissue at the level of molecular (FTIR, FTR) and supramolecular (SAXS) interactions.

Effects of Arachidonic Acid Metabolites on Cardiovascular Health and Disease.

Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP) enzymes, and lipid oxygenase (LOX) pathways to regulate complex cardiovascular function under physiological and pathological conditions. Various AA metabolites include prostaglandins, prostacyclin, thromboxanes, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. The AA metabolites play important and differential roles in the modulation of vascular tone, and cardiovascular complications including atherosclerosis, hypertension, and myocardial infarction upon actions to different receptors and vascular beds. This article reviews the roles of AA metabolism in cardiovascular health and disease as well as their potential therapeutic implication.

Neuronal HSF-1 coordinates the propagation of fat desaturation across tissues to enable adaptation to high temperatures in C. elegans.

To survive elevated temperatures, ectotherms adjust the fluidity of membranes by fine-tuning lipid desaturation levels in a process previously described to be cell autonomous. We have discovered that, in Caenorhabditis elegans, neuronal heat shock factor 1 (HSF-1), the conserved master regulator of the heat shock response (HSR), causes extensive fat remodeling in peripheral tissues. These changes include a decrease in fat desaturase and acid lipase expression in the intestine and a global shift in the saturation levels of plasma membrane's phospholipids. The observed remodeling of plasma membrane is in line with ectothermic adaptive responses and gives worms a cumulative advantage to warm temperatures. We have determined that at least 6 TAX-2/TAX-4 cyclic guanosine monophosphate (cGMP) gated channel expressing sensory neurons, and transforming growth factor ß (TGF-β)/bone morphogenetic protein (BMP) are required for signaling across tissues to modulate fat desaturation. We also find neuronal hsf-1 is not only sufficient but also partially necessary to control the fat remodeling response and for survival at warm temperatures. This is the first study to show that a thermostat-based mechanism can cell nonautonomously coordinate membrane saturation and composition across tissues in a multicellular animal.

Arabidopsis ADR1 helper NLR immune receptors localize and function at the plasma membrane in a phospholipid dependent manner.

Activation of nucleotide-binding leucine-rich repeat receptors (NLRs) results in immunity and a localized cell death. NLR cell death activity requires oligomerization and in some cases plasma membrane (PM) localization. The exact mechanisms underlying PM localization of NLRs lacking predicted transmembrane domains or recognizable lipidation motifs remain elusive. We used confocal microscopy, genetically encoded molecular tools and protein-lipid overlay assays to determine whether PM localization of members of the Arabidopsis HeLo-/RPW8-like domain 'helper' NLR (RNL) family is mediated by the interaction with negatively charged phospholipids of the PM. Our results show that PM localization and stability of some RNLs and one CC-type NLR(CNL) depend on the direct interaction with PM phospholipids. Depletion of phosphatidylinositol-4-phosphate from the PM led to a mis-localization of the analysed NLRs and consequently inhibited their cell death activity. We further demonstrate homo- and hetero-association of members of the RNL family. Our results provide new insights into the molecular mechanism of NLR localization and defines an important role of phospholipids for CNL and RNL PM localization and consequently, for their function. We propose that RNLs interact with anionic PM phospholipids and that RNL-mediated cell death and immune responses happen at the PM.

Inositol supplementation and body mass index: A systematic review and meta-analysis of randomized clinical trials.

BackgroundInositol is a sugar‐alcohol and recognized as a key component of cell membrane phospholipids. It has crucial role in the cell signaling pathways and contribute to improving glycemic responses. Although some earlier studies have revealed the effect of inositol mediating glucose uptake by improving insulin sensitivity, the benefit of inositol supplementation in patients with overweight and obesity is not completely understood. This study aimed to assess the impact of inositol supplementation on body mass index (BMI) through a systematic review and meta‐analysis of controlled clinical trials.MethodsA systematic search was performed to August 2021 in the following databases: PubMed‐Medline, Embase, Web of Science and Scopus. Fifteen controlled clinical trials investigating the effect of inositol on adult's BMI were finally included in the study. A random‐effects model was employed to estimate the effect size. Subgroup analysis was performed by dose, duration, age, type of inositol. Meta‐regression was used to investigate presence of any linear relationship. Begg's and Egger's tests were carried out to detect small study effect.ResultsThe results of pooled analysis showed that inositol supplementation significantly decreased BMI scores (WMD = −0.41 kg/m2; 95% CI: −0.78, −0.04; p = 0.028). Subgroup analysis was performed to identify the source of heterogeneity among studies (I 2 = 73.9%, p < 0.001), demonstrating supplementation duration, baseline BMI, mean age of participants, type of inositol and dosage were potential sources of heterogeneity. The effect of intervention was more clinically significant in participants with polycystic ovary syndrome (PCOS) and overweight/obesity. Inositol in the form of myo‐inositol (MI) had stronger effect on BMI reduction.ConclusionThe meta‐analysis suggests that oral inositol supplementation has positive effect on BMI reduction. Inositol supplementation could be considered as an adjunct treatment to improve body mass index.

Enzymatic-metabolic support of oxidative homeostasis in patients with hypoxic-ischemic brain lesions in the stages of cardiosurgical interventions

To study the features of enzymatic and metabolic support of oxidative homeostasis in patients with hypoxic-ischemic brain lesions before and after cardiac surgery using artificial circulation we examined 38 patients, in particular: ischemic stroke — 14 people, encephalopathy — 15 people, severe cognitive dysfunction — 9 people ; diagnosis of neurological status was performed according to clinical protocols. Clinical and biochemical study was performed at the preoperative (3—5 days) and postoperative (5—7 days) stages: determined the content of superoxide dismutase, glutathione peroxidase, catalase in erythrocytes and α-tocopherol acetate in the serum of the blood, as well as the product cells: diene conjugates, metabolites of nitritanion in plasma. Variation statistics, probabilistic distribution of data with the subsequent estimation of reliability of results are applied; relative biochemical parameters were used: metabolic index, metabolic coefficient and metabolic effect for each. Standard methods using the program adapted to the “Excel” environment were used for calculations. The obtained data support the formation of patients with specific postoperative enzymatic-metabolic support of oxidative homeostasis, which should be considered as one of the triggers of hypoxic-ischemic brain lesions. In particular, at the level of the enzymatic chain of pro-, antioxidant protection and at the level of metabolic processes associated with peroxidation of phospholipids of cell membranes, a number of significant metabolic effects were revealed, which are generalized due to secondary oxidation products and NO‑dependent metabolites.

Pathogenetic rationale for using an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and an antioxidant coenzyme Q&lt;sub&gt;10&lt;/sub&gt; in the treatment and prevention of cardiovascular disease

The review discusses atherosclerosis-related mechanisms of car-diovascular disease development, as well as the optimization of their prevention and treatment methods. Recent experimental and clinical studies have shown the important role of vascular endothelium in the development and progression of atherosclerosis. Myocardial ischemia, activation of free-radical processes and impaired bioenergetics initiate a decrease in production of nitric oxide, which plays major vasodilator role. In this regard, the scientists is interested in the search for new drugs that can affect the main pathogenetic links of coronary artery disease. Statins are currently the drugs of choice. However, they are not always effective and have an ambiguous effect on oxidative potential of myocardial cells and endothelial function. Moreover, inhibition of mevalonic pathway for cholesterol synthesis is accompanied by a deficiency of coenzyme Q10, which is the central cellular antioxidant that protects phospholipids of cell membranes from free radicals. Rationale of using coenzyme Q10 in the complex treatment and secondary prev ention of cardiovascular diseases, including coronary artery di sease, is discussed.

Controversy about the critical role of long-chain polyunsaturated fatty acids, arachidonic acid (ARA) and docosahexaenoic acid (DHA), during infancy

Long-chain polyunsaturated fatty acids (LC-PUFAs) are critical for infant growth and development, particularly arachidonic acid (ARA, C20:4n-6) and docosahexaenoic acid (DHA, C22:6n-3). ARA and DHA are components of cell membrane phospholipids and play an important role in cell division, differentiation, and signaling; and DHA is the n-3 fatty acid predominant in the developing brain and retina. During the third trimester of pregnancy, LC-PUFAs increase substantially in fetal circulation, and a "biomagnification" process in the fetal brain is observed. Moreover, LC-PUFAs are precursors of eicosanoids and metabolites, which modulate the intensity and duration of the immune response. LC-PUFA synthesis implies complex desaturation and elongation processes on their principal precursors, linoleic acid (LA) (18:3 n-6) (series n-6) and α-linolenic acid (LNA) (20:3 n-3) (series n-3), where fatty acid desaturases (FADS) and elongases (ELOVL) are competing. It is important to notice that during the first months of life, as a consequence of low enzymatic activity, LC-PUFA synthesis from LA and LNA is reduced, especially in those infants carrying variations in the FADS and ELOVL genes, which are involved in LC-PUFA synthesis, and so they are unable to supply their own DHA and ARA needs. Homozygote infants for FADS haplotype A (97 % of the Latinoamerican population) show low levels of ARA (only 43 %) and DHA (only 24 %) when compared to those carrying haplotype D (more prevalent in Europe, Africa and Asia). Human milk is the only source of LA, LNA, ARA, and DHA for the neonate and infant till complementary feeding (CF) is introduced. Infants fed with infant formulas must receive enough amounts of LA, LNA, ARA, and DHA to cover their nutritional requirements. The new guidelines by the European Food Safety Authority (EFSA) (2016) recommend that infant formulas and follow-on formulas must contain 20-50 mg of DHA/100 kcal (0.5-1 % of total fatty acids, which is higher than in human milk and the majority of infant formulas in the market), and it is not necessary to add ARA. This new regulation, which is already applicable since February 2020, has resulted in profound controversy because there is no scientific evidence about its appropriateness and safety for healthy children. Then, different international expert groups have revised the research already published about the effects of ARA and DHA addition to infant formulas, and discussed different emerging questions from this European directive. The expert group led from the University of Granada (Spain) recommends the addition of ARA in similar or higher concentrations than those of DHA, at least equal to those present in human milk (0.3 % of total fatty acids), although preferably 0.5 % and up to around 0.64 % of total fatty acids, since new studies confirm the optimal intake of ARA and DHA during the different developmental stages. This recommendation could be of particular importance for infants carrying the haplotype A of FADS.