key: cord-0024807-cxcuy6pe
authors: Torres, Manuel; Parets, Sebastià; Fernández-Díaz, Javier; Beteta-Göbel, Roberto; Rodríguez-Lorca, Raquel; Román, Ramón; Lladó, Victoria; Rosselló, Catalina A.; Fernández-García, Paula; Escribá, Pablo V.
title: Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids
date: 2021-11-24
journal: Membranes (Basel)
DOI: 10.3390/membranes11120919
sha: 17ec6471962a32b1b413fe5b90ac1e7b124aafc1
doc_id: 24807
cord_uid: cxcuy6pe

Membranes are mainly composed of a lipid bilayer and proteins, constituting a checkpoint for the entry and passage of signals and other molecules. Their composition can be modulated by diet, pathophysiological processes, and nutritional/pharmaceutical interventions. In addition to their use as an energy source, lipids have important structural and functional roles, e.g., fatty acyl moieties in phospholipids have distinct impacts on human health depending on their saturation, carbon length, and isometry. These and other membrane lipids have quite specific effects on the lipid bilayer structure, which regulates the interaction with signaling proteins. Alterations to lipids have been associated with important diseases, and, consequently, normalization of these alterations or regulatory interventions that control membrane lipid composition have therapeutic potential. This approach, termed membrane lipid therapy or membrane lipid replacement, has emerged as a novel technology platform for nutraceutical interventions and drug discovery. Several clinical trials and therapeutic products have validated this technology based on the understanding of membrane structure and function. The present review analyzes the molecular basis of this innovative approach, describing how membrane lipid composition and structure affects protein-lipid interactions, cell signaling, disease, and therapy (e.g., fatigue and cardiovascular, neurodegenerative, tumor, infectious diseases).

The human body is made up of trillions of cells that work in a coordinated manner. In this context, health problems originated due to cellular alterations that affect physiological processes [1] , and these alterations may induce malfunctions and/or abnormal levels of macromolecules, metabolites, hormones, etc. Membrane lipid alterations play a relevant role in many diseases [2, 3] , yet most studies of pathophysiological processes have been focused on protein function or gene expression. Accordingly, most treatments developed to combat diseases have targeted proteins and nucleic acids based on the knowledge of the structure and function of these macromolecules. Recently, new approaches that focus on regulating membrane structure and its lipid composition have emerged. Referred to as lipid replacement (LRT) [4] or membrane lipid therapy (MLT or melitherapy) [3] , a number of different therapeutic strategies fall under this umbrella, each sharing the common feature of regulating cell physiology by provoking relevant changes to the plasma membrane (PM) or the lipids in organelles. This review describes the critical roles of lipids in biological Furthermore, the lipid species in the different tissues of an organism are distributed heterogeneously [28, 29] . In this sense, studying the lipidomic fingerprint of several tissues in the rat confirmed that glycerophospholipids are the most abundant lipids, although the specific species identified depends on the tissue analyzed. In addition, the remaining lipid species often vary more quantitatively than qualitatively, such as the prevalence of sphingolipids in the renal cortex, acylcarnitines in skeletal muscle, and ubiquinone in cardiac tissue. Similarly, SM is mainly present in the brain and kidney, while PE is more concentrated in the spleen in mouse models [29] . In addition, the lipidome generally correlates with the expression of genes related to lipid metabolism, suggesting the potential to use lipidomics to identify metabolic disorders and associate them with specific anomalies in enzymatic activity [28] .

While forming lipidic structures in membranes, specific lipid species can also be packed and organized along with proteins in small domains that control different cell functions. These domains can be found at the PM and the different organelles, and they include lipid rafts, caveolae, and clathrin-coated pits. Lipid rafts (Figure 2A ) are membrane microdomains enriched in sphingolipids and Cho, environments that favor the activity of specific proteins [30, 31] . Some protein receptors critical for homeostasis and the regulation of lipid metabolism itself are localized to lipid rafts or Cho-enriched microdomains, such as the TNFR1 (tumor necrosis factor receptor 1) [32, 33] or the insulin receptor (IR) [34] . Furthermore, elaidic acid, one of the major trans fatty acids, induces inflammation through lipid rafts and their toll-like receptors (TLRs) [35] . Conversely, it has Furthermore, the lipid species in the different tissues of an organism are distributed heterogeneously [28, 29] . In this sense, studying the lipidomic fingerprint of several tissues in the rat confirmed that glycerophospholipids are the most abundant lipids, although the specific species identified depends on the tissue analyzed. In addition, the remaining lipid species often vary more quantitatively than qualitatively, such as the prevalence of sphingolipids in the renal cortex, acylcarnitines in skeletal muscle, and ubiquinone in cardiac tissue. Similarly, SM is mainly present in the brain and kidney, while PE is more concentrated in the spleen in mouse models [29] . In addition, the lipidome generally correlates with the expression of genes related to lipid metabolism, suggesting the potential to use lipidomics to identify metabolic disorders and associate them with specific anomalies in enzymatic activity [28] .

While forming lipidic structures in membranes, specific lipid species can also be packed and organized along with proteins in small domains that control different cell functions. These domains can be found at the PM and the different organelles, and they include lipid rafts, caveolae, and clathrin-coated pits. Lipid rafts (Figure 2A ) are membrane microdomains enriched in sphingolipids and Cho, environments that favor the activity of specific proteins [30, 31] . Some protein receptors critical for homeostasis and the regulation of lipid metabolism itself are localized to lipid rafts or Cho-enriched microdomains, such as the TNFR1 (tumor necrosis factor receptor 1) [32, 33] or the insulin receptor (IR) [34] . Furthermore, elaidic acid, one of the major trans fatty acids, induces inflammation through lipid rafts and their toll-like receptors (TLRs) [35] . Conversely, Other microdomains found in the cell membranes are the caveolae ( Figure 2B ), abundant in capillary endothelial cells [40] . These are 50-100 nm invaginated PM domains enriched in glycosphingolipids and Cho, and they are characterized by the presence of the integral membrane protein caveolin. The actin cytoskeleton anchors these microdomains in the PM, and thus, they do not participate in constitutive endocytosis, but they do play roles in Cho homeostasis [41] . Cho and caveolin are responsible for the characteristic curvature of caveolar membranes [39] . Caveolae can transport molecules across endothelial cells, and they may represent the route of entry for some pathogens [42] . They are also elementary structures in tissues that must be protected from the damage caused by mechanical stress, such as muscles, lungs, vessels, and adipose tissue. Recently, caveolae were seen to be plastic, and they flatten with increasing PM tension, which influences cell signaling [43] .

In general, nutritional or pharmacological lipid interventions are considered to be membrane lipid therapy when they (1) induce changes in membrane lipids that (2) regulate the cell signaling (3) involved in a pathological process and/or its treatment [3] . Various mechanisms have been described through which such effects may occur [24, 44] , and a critical feature of these approaches is that the therapeutic agent regulates the composition and structure of a cell or organelle membrane [24] . In general terms, changes in membrane lipid composition can be achieved directly by incorporating the agent (or metabolite) into cell membranes or indirectly through the regulation of a key enzyme of lipid metabolism ( Figure 3 ). For example, the lipid composition of cancer cell membranes varies from that of normal cells [45] , and the administration of lipid drugs that integrate into the cancer cell membrane and/or regulate lipid metabolism, such as 2-hidroxyoleic acid (2OHOA) [46, 47] , can induce selective changes [48] that specifically induce ER stress [49] , sphingolipidosis [48] and autophagy [50, 51] in cancer cells (Figure 3 , case 1 and 2). Another example focused on organelle membranes (Figure 3 , case 3) could be edelfosine, which acts on mitochondria, affecting membrane mitochondrial permeability and promoting redistribution of lipid rafts from membrane to mitochondria [52] . In this context, lipid peroxidation and fatty acid remodeling are known to cause mitochondrial dysfunction and pathologies by altering mitochondria membrane composition and integrity [53] . Such events are particularly relevant in patients receiving chemotherapy, those with chronic illnesses, or in aging people with fatigue, all of whom can be treated through nutraceutical approaches that provide glycerophospholipids plus fructooligosaccharides and antioxidants to replace damaged lipids (LRT) in the different cell membranes (Figure 3 , case 1 and 3), preventing lipid oxidation [54] . 

There are several key events in the history of melitherapy: (1) the recognition of the role of lipids and lipid structures in molecular and cellular events; (2) the identification of membrane lipid composition and structural alterations in human diseases; (3) a description of the molecular, cellular, physiological and pharmacological actions of lipids and their analogs to combat pathological processes; and finally, (4) the integration of this knowledge into the rational design of therapies that target cell membrane lipids.

From a historical point of view, early discoveries suggested the relevance of lipid Changes in membrane lipids modify the biophysical properties of membranes, such as surface lipid packing, bilayer thickness, lipid lateral mobility, microdomain distribution (e.g., lipid rafts), surface and core membrane fluidity, surface charge, lamellar and nonlamellar phase propensity, etc. [2, [55] [56] [57] . In this sense, the abundance and type of peripheral signaling proteins present at a given membrane are defined by the structural and physico-chemical properties of the membrane, such as its electric charge, membrane curvature, the presence of specific lipids, etc. Peripheral proteins, such as G proteins, PKC, Ras, Raf, etc., can be translocated to different PM microdomains or organelle membranes, as well as to soluble fractions. For example, the distribution of G proteins between membrane microdomains or aqueous compartments depends on the presence of certain lipids in membranes ( Figure 3, case 4) . Thus, nonlamellar prone domains favor interactions with dimeric (Gβγ) and trimeric (Gαβγ) forms of G proteins, whereas the monomeric form (Gα) prefers lamellar prone membrane microdomains [17, 58] . Similarly, the membrane surface charge provided by phosphatidylserine (PS), phosphatidic acid (PA), or phosphatidylinositols (PIs) influences the binding of these proteins to membranes [58] . In this regard, an example of reversible modification with a palmitoyl moiety reduces the affinity of Gαi 1 proteins to negatively charged and L d membrane microdomains (Figure 3 , case 5) [58] . Indeed, the restoration of the palmitoylation on cortical neuronal cells of patients with Huntington's disease through the acyl-protein thioesterase 1 (APT1) inhibition by ML348 has been proposed as a mechanism to restore the axonal transport, synapse homeostasis, and survival signaling [59] . In short, if lipid alterations are associated with relevant diseases, melitherapy can be used to treat these conditions.

There are several key events in the history of melitherapy: (1) the recognition of the role of lipids and lipid structures in molecular and cellular events; (2) the identification of membrane lipid composition and structural alterations in human diseases; (3) a description of the molecular, cellular, physiological and pharmacological actions of lipids and their analogs to combat pathological processes; and finally, (4) the integration of this knowledge into the rational design of therapies that target cell membrane lipids.

From a historical point of view, early discoveries suggested the relevance of lipid membranes in pathophysiological processes. Thus, in 1939, relevant lipid alterations were found in platelet membranes from patients with hematological disorders [60] . Similarly, the positive and negative effects of certain lipids in cardiovascular disease have been known for a long time [61] . Moreover, a relationship between inflammation-related conditions and lipids in both blood (plasma) and cell membranes was revealed long ago [62] . The involvement of lipids in these conditions has since been confirmed through mounting evidence, and numerous studies support the involvement of lipids in cardiovascular disease and in related metabolic syndrome-related disorders, such as diabetes and obesity [63, 64] . The abundant literature connecting lipid alterations to human diseases prompted the role of lipids and lipid structures in these pathological events to be studied in more detail.

A key point related to the development of melitherapy, the role of lipids and lipid structures in molecular and cellular events, was first investigated following the description of the fluid mosaic model of the structure of cell membranes [65] . Thus, the role of Cho in the generation of liquid-ordered (L o ) and -disordered (L d ) membrane microdomains [66, 67] was described many years before Cho-rich microdomains were called lipid rafts [68] and brought to the attention of scientists. Most of the early proofs of the membrane organization in specific microdomains came from observations made on model membranes [69] [70] [71] . Many proteins use different types of L o and L d microdomains as signaling platforms to exert productive lipid-protein-protein-lipid (LPPL) interactions ( Figure 4, [17] ). Thus, signaling across the PM is a matter of combined protein-lipid and protein-protein interactions. In fact, membrane regions induced by lipid-protein interactions were proposed as a physical basis for membrane-mediated processes [69] [70] [71] . Frequently, incoming messages imply the interaction of a first messenger (neurotransmitter, hormone, cytokine, growth factor, etc.) with a transmembrane receptor for a limited time.

As a result, signaling transducers (e.g., G protein, Ras, etc.) associated with these receptors can regulate the activity of their effector proteins (phospholipase C, ion channels, adenylyl cyclase, etc.), these in turn controlling the cytoplasmic levels of second messengers that modulate downstream elements of signaling cascades and eventually, gene expression (e.g., cyclic adenosine monophosphate [cAMP], DAG, Inositol trisphosphate [IP 3 ], Ca 2+ , etc.). In this context, while transmembrane receptors remain attached to the membrane, peripheral signaling proteins can translocate between the PM and the cytosol or internal membranes. Thus, if the membrane lipid composition is L 1 , productive receptor (P R ) and transducer (P T ) interactions in membrane lipid microdomains can occur through the formation of an L 1 -P R -P T -L 1 signalosome. By contrast, an L 2 lipid composition would not allow P R -P T interactions at the PM, and therefore, ligand binding would not trigger any signaling event. For example, reversible modification with a palmitoyl moiety reduces the affinity of Gαi 1 proteins to membrane microdomains enriched in PS and PE, which generate negatively charged and L d membrane microdomains, respectively. Palmitoylated Gαi 1 proteins have a higher binding affinity to uncharged membrane microdomains due to a twist of the N-terminal α-helix relative to the membrane surface that alters the localization of some cationic amino acids ( Figure 5 ) [58] . By contrast, the binding of Gγ 2 proteins and K-Ras increases to membrane microdomains enriched in PS and PE due to hydrophobic and electrostatic interactions [18, 72] . The preference of these proteins for membrane areas with negatively charged phospholipids (e.g., PS, PI, and PA) is due to the presence of several positively charged amino acids (e.g., Lys, Arg) at the protein-lipid interaction interface, which can be modified by the reversible addition/removal of lipid modifications (e.g., a palmitoyl moiety in Gα proteins), events that occur during the normal protein activation/deactivation cycle (see Figure 5) .

Similarly, the preference of these proteins for L o or L d lipid bilayers is modulated by the preference of fatty acyl or isoprenyl moieties for lamellar and nonlamellar prone regions, respectively [18, 58, 73] . Other proteins such as protein kinase C (PKC) have specific amino acid domains (termed C1 and C2) that interact with membrane microdomains rich in negatively charged and nonlamellar prone lipids [74] [75] [76] . It is notable that in LPPL interactions, membrane lipid structure is regulated not only by membrane lipids but also by lipid modifications into proteins. For example, the fatty acyl and isoprenyl moieties that are present in numerous peripheral (amphitropic) membrane proteins regulate membrane lipid structure in a manner that favors the cooperative binding of the protein, thereby improving signal amplification [77] (see Figure 3 ).

To elicit conformational changes and activate proteins, it is necessary to recruit and bind proteins electrostatically to the head groups of charged lipids or to incorporate hydrophobic motifs into the membrane core. For example, PI3K belongs to the lipid kinase family that triggers cellular processes such as survival or migration [78] . Moreover, the integrins present in the PM serve as an attachment to the extracellular matrix (ECM), and they regulate the migration of the cells, which is linked to the stabilization in lipid rafts and caveolae. Once the lipid rafts and caveolae are internalized, there is an increase in cAMP and integrins are recycled, the cell detaching from the ECM. Interestingly, some signaling proteins that are linked to the integrin-lipid raft system remain in the PM, such as the flotillin2, connexin 43, and Gα s [79] .

signaling proteins that are linked to the integrin-lipid raft system remain in the PM, such as the flotillin2, connexin 43, and Gαs [79] . Other LPPL interaction modulated by the lipid composition and vice versa affects the pore-forming proteins (PFP), which alter plasma or intra-membranes permeability by creating pores and rearranging lipids. PFP is involved in various biological processes such as cell death, metabolism, inflammation, and immunity [80] . They are mostly synthetized as soluble proteins that bind their specific membrane lipid receptors through electrostatic and hydrophobic interactions, leading to a conformational change, followed by oligomerization and formation of the pore in the membrane. In turn, the pore structure generated modulates the biophysical properties of the membrane in terms of fluidity, curvature, lateral rearrangement, and deformation [81, 82] . Membrane receptors are specific for each PFP. One example is the case of gasdermin family proteins that bind phosphoinositides and cardiolipin and, in that way, trigger pyroptosis (inflammatory-like cell death potentially leading to immune diseases and septic shock) [83] . Other PFPs can bind preferentially to the liquid-ordered phase enriched in SM, such as the actinoporin family (including equinatoxin II) and lysenin, and thus their membranolytic activity is being developed as anticancer therapy [84] [85] [86] [87] . Finally, another approach within the melitherapy proposes that the changes induced in the membrane after their Other LPPL interaction modulated by the lipid composition and vice versa affects the pore-forming proteins (PFP), which alter plasma or intra-membranes permeability by creating pores and rearranging lipids. PFP is involved in various biological processes such as cell death, metabolism, inflammation, and immunity [80] . They are mostly synthetized as soluble proteins that bind their specific membrane lipid receptors through electrostatic and hydrophobic interactions, leading to a conformational change, followed by oligomerization and formation of the pore in the membrane. In turn, the pore structure generated modulates the biophysical properties of the membrane in terms of fluidity, curvature, lateral rearrangement, and deformation [81, 82] . Membrane receptors are specific for each PFP. One example is the case of gasdermin family proteins that bind phosphoinositides and cardiolipin and, in that way, trigger pyroptosis (inflammatory-like cell death potentially leading to immune diseases and septic shock) [83] . Other PFPs can bind preferentially to the liquid-ordered phase enriched in SM, such as the actinoporin family (including equinatoxin II) and lysenin, and thus their membranolytic activity is being developed as anticancer therapy [84] [85] [86] [87] . Finally, another approach within the melitherapy proposes that the changes induced in the membrane after their interaction with the PFP (as an oligomer or as a full pore structure) might activate the immune response against infectious processes [82] .

interaction with the PFP (as an oligomer or as a full pore structure) might activate the immune response against infectious processes [82] . Figure 5 . Effect of palmitoylation on Gαi1-membrane interactions. Gαi1 protein has N-terminal myristoyl (M) and palmitoyl (P) moieties. Whereas M is an irreversible lipidation, P can be enzymatically added or removed upon signaling control. Myristoylated-depalmitoylated G protein interacts with negatively charged membrane areas because the lipid anchor favors the exposure of positively charged amino acids to the membrane interface (M with arrow). Palmitoylation induces a twist in the N-terminal α-helix of Gαi1 protein that causes exposure of uncharged amino acids to the bilayer surface (P with arrow and M with arrow). This in part explains the ability of Gαi1 protein to have different lipid-protein-protein-lipid (LPPL) interactions, in which the configuration Lx-PG-Py-Ly (where G would be Gαi1) indicates that the transducer would interact with different lipids (Lx could be phosphatidylserine or another membrane lipid according to the palmitoylation status) and Py could be a G protein-coupled receptor (GPCR) or an effector protein (adenylyl cyclase). It has to be kept in mind that the Gβγ dimer also participates in these LPPL interactions [17] . Adapted from [58] .

The relevance of the composition, structure, and fluidity of the PM in the cell biology and the physiology of an organism has been touched on above, and this is the subject of considerable study. Indeed, its influence on the activity of hepatocytes was described as early as 1984 [88] , and liver regeneration was seen to be reliant on the presence of Cho-enriched microdomains in which the IR is embedded [34] . Lipids also participate in the morphological changes that occur during cell division [89] , when PIs are essential for mitotic cell rounding, cell elongation, spindle orientation, cytokinesis, and post-cytokinesis events [90] . During cell division, the membrane rearrangements that occur are driven by both proteins and lipids. Specifically, the membranes change their structure in the midbodies (the cytoplasmic bridge between daughter cells) to adapt to the process of division, characterized by enrichment in ceramides. This also constitutes an adaptive measure of the dividing cells to mechanical stress, increasing the membranes resistance to the high forces applied during cell division [91] .

Another example is the unique lipid composition of central nervous system (CNS) endothelial cells, which regulate vesicular transport and blood-brain barrier (BBB) permeability. In particular, elevated levels of docosahexaenoic acid (DHA)-containing phospholipids and Mfsd2a transporters suppress vesicular transport, helping to establish an appropriate environment in which the brain can function [92] . In this sense, membrane composition and structure are fundamental in the communication between cells and organelles, as highlighted by studying neurotransmitter release. In this process, the porosome is the structure that will fuse with the synaptic vesicles (SVs), and it is enriched in phosphoinositides, PA, ceramides, and DAG, whereas SVs have a distinct composition Figure 5 . Effect of palmitoylation on Gαi1-membrane interactions. Gαi1 protein has N-terminal myristoyl (M) and palmitoyl (P) moieties. Whereas M is an irreversible lipidation, P can be enzymatically added or removed upon signaling control. Myristoylated-depalmitoylated G protein interacts with negatively charged membrane areas because the lipid anchor favors the exposure of positively charged amino acids to the membrane interface (M with arrow). Palmitoylation induces a twist in the N-terminal α-helix of Gαi1 protein that causes exposure of uncharged amino acids to the bilayer surface (P with arrow and M with arrow). This in part explains the ability of Gαi1 protein to have different lipid-protein-protein-lipid (LPPL) interactions, in which the configuration Lx-PG-Py-Ly (where G would be Gαi1) indicates that the transducer would interact with different lipids (Lx could be phosphatidylserine or another membrane lipid according to the palmitoylation status) and Py could be a G protein-coupled receptor (GPCR) or an effector protein (adenylyl cyclase). It has to be kept in mind that the Gβγ dimer also participates in these LPPL interactions [17] . Adapted from [58] .

The relevance of the composition, structure, and fluidity of the PM in the cell biology and the physiology of an organism has been touched on above, and this is the subject of considerable study. Indeed, its influence on the activity of hepatocytes was described as early as 1984 [88] , and liver regeneration was seen to be reliant on the presence of Cho-enriched microdomains in which the IR is embedded [34] . Lipids also participate in the morphological changes that occur during cell division [89] , when PIs are essential for mitotic cell rounding, cell elongation, spindle orientation, cytokinesis, and post-cytokinesis events [90] . During cell division, the membrane rearrangements that occur are driven by both proteins and lipids. Specifically, the membranes change their structure in the midbodies (the cytoplasmic bridge between daughter cells) to adapt to the process of division, characterized by enrichment in ceramides. This also constitutes an adaptive measure of the dividing cells to mechanical stress, increasing the membranes resistance to the high forces applied during cell division [91] .

Another example is the unique lipid composition of central nervous system (CNS) endothelial cells, which regulate vesicular transport and blood-brain barrier (BBB) permeability. In particular, elevated levels of docosahexaenoic acid (DHA)-containing phospholipids and Mfsd2a transporters suppress vesicular transport, helping to establish an appropriate environment in which the brain can function [92] . In this sense, membrane composition and structure are fundamental in the communication between cells and organelles, as highlighted by studying neurotransmitter release. In this process, the porosome is the structure that will fuse with the synaptic vesicles (SVs), and it is enriched in phosphoinositides, PA, ceramides, and DAG, whereas SVs have a distinct composition with a high TAG and SM content [93, 94] . Moreover, in this process, the phase structure of the membrane is relevant to achieve SV fusion with the presynaptic membrane, whereby the two membranes must first be connected by forming a negatively curved monolayer with conical lipids (fatty acids, DAG, etc.). Subsequently, a positively curved monolayer with inverted conical lipids (lysophospholipids and PIs) is formed to generate the fusion pore [95] . Since the synthesis of phospholipids is compartmentalized in the cell, it is necessary to transfer different lipid species among organelle compartments, which is executed by a controlled system of vesicular transport [19] . For instance, ER lipid domains establish different contacts and fusions with other organelles depending on their lipid membrane order, with a preference for mitochondria, lipid droplets (LDs), endosomes, or the PM when lipids form an ordered phase, whereas this preference shifts to lysosomes and peroxisomes with disordered lipid phases [96] .

Membrane polarization is a characteristic of cells such as enterocytes, where the apical and basolateral membrane can be distinguished, each domain fulfilling specific functions. Elaborate mechanisms maintain this polarity, which also requires the participation of lipid rafts in the apical membrane region [97] . Membrane lipids involved in epithelial polarity are remodeled during tissue differentiation, and a change from SM to glycosphingolipids, along with an increase in plasmalogen, PE, and Cho content, has been observed during epithelial morphogenesis. Sphingolipids with longer acyl chains are produced in the apical domain, increasing their saturation and hydroxylation to constitute the protective barrier of the epithelial lamina [98] .

A second point relevant to the design of specific membrane lipid therapies was the identification of alterations to membrane lipid composition and structure in human diseases. There is clear epidemiological evidence of a correlation between dietary lipids and human health, suggesting that melitherapy interventions could have valuable therapeutic consequences. In this context, high saturated fatty acid (SFA) intake has been associated with a risk of cardiovascular disease [99] , whereas high mono- [100, 101] and polyunsaturated [102, 103] fatty acid intake is associated with a much lower risk of developing such problems. Moreover, unsaturated fatty acids (mainly eicosapentaenoic acid [EPA], DHA, and oleic acid [OA]) have been associated with a lower risk or incidence of cancer, metabolic syndrome, neurodegenerative pathologies, etc. [104] [105] [106] [107] [108] [109] . The normotensive effects of olive oil are mainly due to its high levels of a cis-monounsaturated fatty acid, OA, with high extra virgin olive oil intake reflected in an OA increase in membranes, which produces relevant changes in the signaling pathways that control blood pressure [64, 100] . Similarly, the protective effects of ω-3 fatty acids such as EPA and DHA are correlated with changes in the lipid composition of cell membranes [110, 111] .

The imbalance in lipid metabolism, when the activity of key enzymes is impaired or when there are deficits in lipid consumption, could lead to a series of disorders, including cancer, metabolic disorders, neurological diseases (such as Alzheimer's disease [AD]), susceptibility to infection and immunological diseases [5, 50, [112] [113] [114] . There are numerous pathologies in which lipid alterations play a relevant role, whereas, in other diseases, the regulation of signaling through changes in membrane lipid composition and structure may influence pathological signaling. In both cases, membrane lipid interventions may have therapeutic effects. As indicated above, connections between membrane lipids and cardiovascular diseases or cancer have been well established, although other pathologies are also caused or influenced by membrane lipids. Interestingly, an analysis of gene expression in glioma (brain cancer) samples from patients in the Rembrandt database indicated that the enzymes responsible for lipid metabolism were as important as the classic oncogene/tumor suppressor genes [115] . Indeed, some of these enzymes are responsible for the biosynthesis of specific lipids or the catalytic processes they are implicated in, which ultimately determines the membrane structures formed and affects the behavior of the organelle, cell, or tissue. The lipid composition of membranes can be controlled by mutations in different genes involved in lipid metabolism, regulating their activity or expression, or by epigenetic changes that may also modulate their expression.

Another example is spastic paraplegia (SPG35), which is caused by mutation of the enzyme fatty acid 2-hydroxylase (FA2H), the enzyme that produces C2-hydroxylated fatty acids. This mutation provokes abnormal hydroxylation of myelin galactocerebroside lipids and neurodegeneration [116] , in association with spinal cord atrophy and progressive spastic paraparesis [117] .

The importance of lipids in inflammation is highlighted by the role of arachidonic acid (AA) and its metabolites as pro-inflammatory bioactive lipids. Thus, this ω-6 polyunsaturated fatty acid (PUFA) is transformed into eicosanoids upon catalysis by phospholipases [118] . In this signaling, the fatty acid desaturases (FADS1 and FADS2) are key in the induction of the unsaturation of fatty acid chains and are regulated by the methylation state of the DNA, as important as any polymorphism, balancing the competition of PUFAs for the desaturases through ω-6 (pro-inflammatory) and ω-3 (anti-inflammatory) fatty acids [119] . In addition, cyclooxygenases catalyze the conversion of AA into prostaglandins and thromboxanes, which are involved in many pathophysiological processes. Furthermore, lipoxygenases produce leukotrienes in response to nerve injury and acute inflammatory disorders [120] . Finally, a profile in which the pro-inflammatory fatty acids are predominant in cell membranes rather than the anti-inflammatory ones is also found during aging due to weaker desaturase and elongase activities [121] . Importantly, aging signature, inflammation, and neuropathic pain can be treated with unsaturated fatty acid analogs administration [121] [122] [123] .

One of the fields with an obvious relationship between lipids and health is metabolic diseases, such as hyperlipidemias, obesity, diabetes, and metabolic syndrome. Beyond their use as an energy source, the predominant type of fatty acids in the diet may be beneficial or a risk factor in developing metabolic diseases. In many industrialized countries, obesity and related metabolic disorders are considered epidemic pathologies due to their increasing prevalence [124] , and these diseases alter the lipid composition of cell membranes [125, 126] . One of the lipids highly involved in the development of metabolic disorders is the Cho. Certain diseases and tissue damage can lead to a loss of Cho homeostasis, as in patients with liver damage due to alcohol intake or viral infection, with more Cho in the membrane of hepatocytes, a loss of its fluidity, and impaired liver function [127] . Furthermore, such liver damage can alter erythrocyte membranes, with enrichment in Cho, PC, and palmitic acid, while SM, AA, and stearic acid are reduced, with the consequent reduction in membrane fluidity [128] . Cho and some specific proteins can form lipoprotein complexes, such as LDLs (low-density lipoproteins). The main role of these particles is to transport Cho and other lipids through the bloodstream [129] , and they are also involved in cardiovascular diseases such as atherosclerosis and stroke [130] . In atherosclerosis, the wall of the artery develops lesions due to the build-up of atheroma. In the cellular mechanism proposed for early-stage atherosclerosis, these lesions start when the Cho in LDLs become oxidated [131] . This modification of LDL (oxLDL) promotes the formation of reactive oxygen species (ROS) and Cho crystals associated with the disease, which initiates local inflammation [132] . The oxidized phospholipids (oxPl) 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) are the cytotoxic components of oxidized LDL [133] . Recently, new evidence for the role of protein kinase C-delta (PKCδ) in oxPl cytotoxicity has arisen, indicating that the association of lipids with this enzyme is relevant in the cytotoxicity induced by oxidized LDLs [134] . Interestingly, EPA significantly reduces the levels of oxLDL in people with high triglyceride levels [135] .

Finally, LDs [136] are organelles that originate in the ER, and they consist of a hydrophobic core of neutral lipids surrounded by a monolayer of phospholipids coated with specific proteins. They have only been considered as lipid stores to be used as an energy source, yet their conserved structure across evolution and their participation in other cellular functions has led to them being considered organelles [137] . These LDs facilitate communication and coordination between different organelles, and they are essential for cell metabolism [138] . LDs can be mobilized by the cell through lipolysis, and they can protect against ER stress or mitochondrial damage during autophagy. Diseases such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neutral lipid storage disease, lipodystrophy, and hereditary spastic paraplegia are associated with a dysregulation of the physiological role of LDs, as well as in their number, composition, size, and distribution [138] . It would be expected that the disorders caused by or associated with aberrant lipid composition in different cell types and/or tissues, such as those indicated above, could be challenged by the normalization of their lipidic status following the membrane LRT and melitherapy approaches.

Following the discovery that lipids and lipid structures participate in cell signaling and given the evidence of the relationship between membrane lipid composition and structure in human diseases, identifying the molecular, cellular, physiological, and pharmacological mechanisms of action of lipids and their analogs in pathological processes has paved the way toward melitherapy drug discovery. Indeed, the discovery of lipid alterations in human disease has helped to define the role of numerous lipids. Thus, cis-monounsaturated fatty acids (MUFAs) regulate membrane lipid structure distinctly to saturated or trans-MUFAs. For example, while in dielaidoyl-PE model membranes 5 mol% OA (cis 18:1 ω-9) can induce lipid polymorphism and nonlamellar (H II ) phases at physiological temperatures (35-40 • C), its stearic (18:0) and elaidic (trans 18:1 ω-9) acid analogs do not [139] . This structural behavior may in part explain the positive effects of diets rich in cis-MUFAs (e.g., OA) in terms of cardiovascular health, as well as the negative effects of saturated and trans-unsaturated fatty acids. This regulation of the structure of lipid bilayers has an important effect on cell signaling due to the modulation of the proteins embedded in or associated with the membrane. Thus, OA but not stearic or elaidic acids regulate the activity of β 2A -adrenergic receptors, as well as their transduction pathway (G protein) and effector protein (adenylyl cyclase), without interacting directly with any of these proteins [140] . These data, in part, explain the differential effects of these fatty acids on physiological functions, and they support the pharmacological effects of synthetic cis-MUFA analogs.

On the other hand, hydroxylated fatty acids are also important in the context of myelin sheath formation since, as indicated above, mutations to the fatty acid hydroxylating FA2H cause relevant neurological abnormalities and provoke spastic paraplegia (SPG35) [116, 117] . In addition, DHA and EPA hydroxylated metabolites that form a family of D (derived from DHA) and E series (derived from EPA) neuroprotectins and resolvins are implicated in protection against inflammation and neurodegeneration, as well as in neurogenesis [141, 142] . Neuroprotectins and resolvins are hydroxylated at internal C atoms, such as 5S, 18Rhydroxy-EPE (RvE2), which is hydroxylated on C5 and C18 (considering the COOH group as C1) [141] . Their mechanism of action is associated with an interaction with specific membrane receptors and with the synthesis of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and semaphorin [142] .

These studies demonstrate that the knowledge gained regarding the structure and function of membrane lipids and proteins, as well as LPPL interactions, has been integrated into the design of therapies that target the lipid bilayer. In general terms, while there is no clear succession of events contributing to the development of melitherapy or LRTs, there has been a logical trend from the discovery of the cell membrane structure [65] to the formulation of the principles of melitherapy [3] . Between these two landmarks, research into lipid structure and function has helped to develop new therapies, some of them already approved by the FDA (Food and Drug Administration), EMA (European Medicines Agency), or other regulatory agencies.

Following the rational drug design, C2-hydroxylated fatty acids have been developed to treat several conditions. Examples of advanced clinical development in this regard are 2-hydroxyoleic acid (LAM561), which has shown safety and promising therapeutic activity against glioma and other types of tumor in humans [50, 113] , and 2-hydroxylinoleic acid (ABTL0812), which has demonstrated safety and efficacy against endometrial and lung cancers [143, 144] (reviewed below). On the other hand, another DHA hydroxylated analog with therapeutic properties is 2-hydroxydocosahexaenoic acid (DHA-H), which has been demonstrated to have neuroprotective and neuroregenerative activity, and to be safe and efficacious in mouse models of AD and Parkinson's disease (PD) in preclinical studies (PCS) [114, 145] (reviewed below). Moreover, treatment with natural and synthetic MUFAs (e.g., 2OHOA) can help reduce weight by specifically reducing white body fat deposits, both through a reduction in food intake and through the specific overexpression of uncoupling proteins in adipose tissue-like UCP1 (ca. 30-fold increase) and UCP3 (ca. 4-fold increase) [146] .

Mimetic triglycerides such as TGM5 (2-hydroxy-eicosapentaenoine) also raised as a melitherapy approach for adult polyglucosan body disease (APBD). This is a rare hereditary metabolic disease caused by mutations of the GBE1 glycogen-branching enzyme [147, 148] . In this context, the Y329S GBE1 mutation dampens its enzymatic activity to ca. 5% that of the wild-type enzyme, producing a poorly branched form of glycogen known as polyglucosan [149] . As this form of glycogen is less soluble than globular branched glycogen, deposits of densely packed filaments of polyglucosan form [150] . This mutation exposes internal hydrophobic regions of the enzyme that are stabilized by their interaction with membranes, which in turn reduces GBE1 activity [151] . Guaiacol and TGM5 have diseasemodifying activity [151, 152] . The latter affects GBE1-lipid interactions, increasing its activity above 25%, sufficient to maintain adequate levels of glycogen branching and prevent the symptoms of APBD [151] .

Likewise, the hydrophobic agent BGP15 modulates membrane structure and dynamics, regulating heat shock responses as a chaperone co-inducer [153] . This compound has been investigated for the treatment of cancer, diabetes, and metabolic syndrome [154, 155] . In another approach included in the melitherapy, pepducins are cell-penetrating peptides with amino acid sequences resembling intracellular loops of G protein-coupled receptors (GPCRs) that are involved in relevant pathophysiological processes [156] . They carry a membrane anchor (for example, a palmitoyl moiety) that interferes with the GPCR-G protein (LPPL) interactions involved in pathophysiological processes, showing efficacy in diverse pathologies such as cancer, cardiovascular diseases, asthma, etc. [157] [158] [159] .

Melitherapy can also be applied to infectious diseases, an example of which is the use of miltefosine against leishmaniasis. Leishmaniasis is caused by protozoa of the trypanosome genus Leishmania, and one of the most widely used drugs against this infectious disease is this alkyl phospholipid. Miltefosine, hexadecyl 2-(trimethylazaniumyl) ethyl phosphate (or hexadecylphosphocholine), is also used against other parasites, bacterial, and fungal infections [160] . This compound binds to membrane lipids and enzymes involved in membrane lipid metabolism, changing the composition and structure of the parasite's lipid bilayer [161, 162] . This and other alkyl phospholipids (e.g., edelfosine) have been used to treat distinct diseases, such as cancer and dermatitis, and their therapeutic benefits have been associated with effects on lipid rafts [163] . In addition to these applications of melitherapy, other approaches involving antimicrobial peptides to overcome bacterial antibiotic resistance or against membrane-bounded viruses such as HIV (human immunodeficiency virus), Ebola, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), etc., constitute particularly interesting areas of melitherapy research that will be reviewed below.

As indicated in this section, lipids analogs interacting with membranes and other hydrophobic small molecules or biological agents are currently being under development by different companies in clinical trials, e.g., Laminar Pharmaceuticals is a clinical phase II/III-biopharmaceutical company focused on melitherapy, membrane lipid regulatory drugs and the rational design of these compounds to treat cancer, pain, AD, etc. By contrast, LipidArt aims to discover membrane structure regulators to control the heat shock response, while Ability Pharma and Neurofix are clinical-stage biopharmaceutical companies that develop modified lipids to treat cancer and neuropathic pain, respectively. Moreover, N-Gene developed BGP15, and Anchor Therapeutics is studying the pepducins in different indications. Similarly, the biotechnology company JADO Technologies investigated the efficacy of the lipid raft regulator TF002 against cutaneous mastocytosis (ClinicalTrials.org identifier NCT00457288). In the nutraceutical area, several companies commercialize EPA, DHA, and other ω-3 fatty acids, and Nutritional Therapeutics has a formulation that includes soy glycophospholipids that reduce fatigue caused by aging or chemotherapy treatments.

In summary, an improved understanding of protein and DNA structures has led to intense basic research into medicines that regulate their activities. In the field of lipids, defining the lipid bilayer structure and the subsequent studies into its role in cell signaling and pathophysiological processes has become a prolific arena for drug development, specifically evolving into membrane lipid and replacement therapy technology platforms.

The lipid profile of the PM is a specific fingerprint of a particular cell type [29] . Alterations to lipid metabolism trigger changes in the composition and biophysical properties of membranes, modulating signal propagation and resulting in metabolic reprogramming [45, 164] . This characteristic has been associated with neoplastic cells that display quantitative changes in lipids relative to non-malignant cells [45] . These lipid imbalances produce several alterations in cancer cells, as described in the literature. In neoplastic cells, phospholipid biosynthesis is modified, such as an increase in PI3K by the inefficient phosphatase activity of the tumor suppressor phosphatase and tensin homolog (PTEN) [165] . Higher levels of PE or lower levels of SM are found in tumor cells, promoting proliferative signaling [50] . The upregulation of lipid metabolism genes such as oxidized low-density lipoprotein receptor 1 (ORL1), glutaredoxin (GLRX) are characteristics of breast and prostate cancer [166] . Other upregulated genes are related to poor prognoses in breast cancer, such as acetyl-CoA carboxylase (ACC), insulin-induced gene 1 (INSIG1), and sterol regulatory element-binding protein 1 (SREBP1) [167] . The lipid bilayer of cancer cells has less unsaturated fatty acids, preventing lipid peroxidation and increasing the fluidity of the PM [168] , a biophysical change associated with resistance to chemotherapy. Dynamic destabilization of lipid rafts, the main lipid microdomain, has been related to several pathologies [169] , particularly as these microdomains are enriched in Cho and sphingolipids that are essential for correct cell functioning [170, 171] .

Acidification of the outer leaflet of the PM from pH 7.3 in a non-malignant cell to pH 6.9 in a cancer cell occurs when acid phospholipids such as PS are exposed to the external medium [172, 173] . Cho is one of the principal components of the lipid bilayer, and its metabolism is altered in oncogenic conditions, affecting PM fluidity. Less Cho is associated with metastasis since an increase in membrane permeability augments the access of elements to the circulatory system. By contrast, high Cho content produces rigidity, preventing the entry of drugs (or other compounds) into the cell [174, 175] . Ceramide (Cer) is another sphingolipid related to multidrug resistance (MDR) mechanisms since it is implicated in tumor suppression by participating in cell cycle arrest and death processes [176, 177] . In contrast to Cho, MDR cells have less Cer, which favors uncontrolled proliferation [178] .

Not only is the synthesis of bioactive lipids relevant in the neoplastic process, but β-oxidation of fatty acids plays an important role in pathogenic diseases. This catabolic process participates in one of the main pathways to obtain ATP, which is involved in metastasis. Moreover, enzymes involved in the oxidative degradation of fatty acids are upregulated in a variety of cancers [179] .

The Ras superfamily is made up of small GTPases that act as molecular switches in signaling pathways, and they control fundamental processes such as cell growth and differentiation [180] . Mutations in Ras genes are implicated in 20-30% of human cancers [181, 182] . One important feature of some Ras proteins is their regulation through post-translational modification [183] , including prenylation and palmitoylation [184] . In order to signal, RAS proteins must be located at the inner surface of the PM [185] . Prenylation and palmitoylation occur at the membrane anchoring domain of RAS proteins, and it is crucial in mediating protein-membrane interactions [186] . Indeed, each RAS isoform can be directed to different microdomains of the PM based on the differences in this membrane anchor. For example, H-Ras but not K-Ras activity is critically dependent on lipid rafts in the PM, and its association with these domains is mediated by S-palmitoylation [187] . This model is consistent with the observation that human N-Ras is preferentially localized to Ld domains and accumulates at the Lo/Ld interphase of the domain, forming model raft membranes [188] . These important post-translational lipidations of RAS have become an interesting therapeutic target for drug development programs [189] .

The EGFR is a transmembrane protein receptor for protein ligands of the EGF family. EGFR plays an important role in cell growth, mobility, proliferation, and differentiation, and it is a key factor in the development and progression of many types of cancer due to mutations affecting its expression or activity [190] . This receptor interacts with several lipids, including PC, PS, phosphatidylinositol phosphate (PIP), Cho, gangliosides, and palmitate [191] . The reconstitution of EGFR into proteoliposomes with different lipidic compositions demonstrated that interactions between this receptor and membrane lipids promote changes in protein tyrosine kinase activity. Indeed, EGFR autophosphorylation, but not its dimerization and activation, is prevented using a mixture of unsaturated PC, SM, and Cho in molar ratios that phase separate into co-existing Ld and Lo domains.

Wnts form a large family of protein ligands that interact with several receptors (Frizzle and LRP6) in the PM. Mutation of proteins in the Wnt signaling pathways has been associated with several types of cancer, such as breast, prostate, and glioblastoma [192] . Two types of lipid-protein interactions can influence Wnt signaling: those in the PM environment [193] and the palmitoylation of Wnt proteins [194] . PM composition affects the lipid-protein interactions that influence the initiation of Wnt signaling. GPI-anchored Lypd6 protein is primarily associated with ordered membrane domains, and Lrp6 coreceptors are recruited at these locations, promoting Lypd6 phosphorylation through the canonical Wnt/β-catenin pathway. Moreover, disruption of these lipid rafts severely dampens Wnt signaling in vitro and in vivo [195] . Wnts are also subjected to lipidation through post-translational modifications, mainly palmitoylation, although the relevance of this modification remains largely unclear [196, 197] .

Hedgehog signaling plays a key role in cell differentiation, and abnormal activation of this pathway has been implicated in several cancers, probably through the differentiation of adult stem cells to cancer stem cells [198] . Hedgehog signaling is regulated by several lipidic interactions, as the N-and C-terminus of Hedgehog proteins are covalently modified with palmitate and Cho, respectively [199] . Exocytotic vesicles convey lipid-modified hedgehog proteins from the ER to the PM, where they are released into the extracellular environment. Subsequently, they can bind to their receptor (patched, PTCH1) on the target cell, which in turn activates smoothened (SMO) [200] . SMO is also a lipid-regulated protein, and Cho, oxysterols, and phosphatidylinositol-4-phosphate (PI(4)P) are SMO activators, whereas cyclopamine and DHCEO (7DHC, 3,5-dihydroxycholest-7-en-6-one) inhibit it [200] . Significantly, several drugs that target SMO are being studied in clinical trials [201] .

Due to the lipidomic remodeling observed in cancer cells relative to non-neoplastic cells, certain lipids could be considered as potential biomarkers, diagnostic tools, or thera-peutic targets. Research into the application of lipidomics in oncology has advanced of late, and several potential treatments are at different stages of development. The importance of pharmacologically modulating the lipid content of tumor cells may in part reside in the need to synthesize lipids to provide energy for an increased rate of proliferation [202] . Melitherapy involves regulating the lipid composition of the PM, its microdomains, and that of intracellular membranes, targeting these structures with two different groups of drugs [19, 45] . The first group is comprised of proteins or small molecules [175, 203] that target a specific lipid or its metabolism [204] . For example, treatment with drugs that inhibit enzymes that act early in the de novo Cer-SM biosynthetic pathway (fumonisin B1, myriocin, GT11 or K1), acid sphingomyelinase (ASM) inhibitors (fendiline, desipramine, imipramine, and amitriptyline), or sphingomyelin synthase 1 (SMS1) activators (2OHOA) have been shown to promote K-Ras mislocalization by altering the SM and PS content and organization in the cell, affecting pancreatic cancer [205] . Such approaches also show clinical benefits against sarcomas, and ovarian and pancreatic tumors, which are characterized by a dysregulation of lipid metabolism [206] [207] [208] . Another promising lipid is PS, which has been targeted, among others, using liposomes. For example, phosphatidylcholinestearylamine (PC-SA) and peptide-peptoid hybrid (PPS1) by direct interaction with PS using liposome-based assays showed an antitumor effect in several cancer cell lines such as glioma, melanoma, and leukemia in PC-SA studies [209] and lung cancer in PPS1 assays [210] . The second group of drugs diminishes the content of certain lipids, such as statins that are used to reduce Cho biosynthesis in order to dampen cell proliferation [211] , although some side effects have been associated with their use [203] . Another compound used to deplete membrane Cho is 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), resulting in leukemic cells apoptosis (6) . However, another study revealed that the variations on Cho content are in an HP-β-CD concentration-dependent manner [212] . Lipid-lowering drugs were effective against carcinomas that are characterized by a high Cho content, such as breast cancer [213] . In other cases, lipid molecules are administered directly as drugs to assess their potential anti-neoplastic effect, as is the case of alkylphospholipids. Miltefosine is used as a topical anti-neoplastic agent in breast cancer [214] , while edelfosine (a synthetic analog of lysophosphatidylcholine) is being studied for its use in lung cancer [215] . In addition, peptides derivate from bacterial protein azurin, such as CT-p19LC, have been shown to alter the properties of biomembranes by binding to the PMs, making them less rigid. These alterations induced cell proliferation inhibition in a variety of cancer cell lines [216] .

Variations in lipids caused by using drugs to target the PM have different regulatory effects, such as the modulation of protein-protein interactions, the regulation of enzyme activities, the modification of gene expression, and altered membrane binding affinity. All these regulatory effects trigger changes to the structural and biophysical properties of the membrane, altering signaling cascades [19] . Many molecules have been designed to regulate membrane composition and structure. One of these molecules is 2OHOA (LAM561), which has suitable efficacy and safety against glioma and other types of tumors in animal models and humans [50, 113] . In this context, several clinical trials have demonstrated the high safety by itself or in combination with radiotherapy (RT) and remozolomide (TMZ), as well as the potential clinical activity of LAM561 in the treatment of cancer in adult patients (ClinicalTrials.gov Identifiers NCT01792310, NCT03867123). Its efficacy is currently being evaluated in both adult and pediatric cancer patients (ClinicalTrials.gov Identifiers NCT04250922, NCT04299191). While the molecular mechanism of action is not yet fully understood, it is based on SM synthesis through the activation of SMS, normalizing the PE:SM ratio in tumor cells that have less SM and more PE [46] , while not affecting this ratio in healthy cells [113] . As SM contributes to lipid rafts, this regulation modifies signaling cascades, inducing the translocation of Ras from the PM to the cytoplasm [50, 113] and autophagic cell death [56] . This membrane lipid reorganization induces endoplasmic reticulum (ER) stress, sphingolipidosis, and autophagic cancer cell death without affecting normal cells [48] [49] [50] . Similarly, 2-hydroxylinoleic acid (ABTL0812) has been demonstrated to be safe and efficacious against endometrial and lung cancers, both in model systems and in clinical trials (NCT02201823, NCT03366480, NCT03417921, NCT04431258), producing specific cancer cell death. Thus, ABTL0812 binding to the membrane inhibits Akt/mTORC1, enhances sphingolipid dihydroceramide activity, provoking ER stress and autophagic cell death without inducing undesired side effects [143, 144] .

Another type of molecule under study is the hydroxylated analog of triolein, hydroxytriolein (HTO), which has an antiproliferative effect in lung cancer cells through ERK activation by PKC, producing ROS and autophagy [217] and also has an antiproliferative effect through a mechanism dependent on dihydroceramide and Akt in triple-negative mammary breast cancer cells [218] . More recently, the molecule named 2-hydroxycervonic acid (HCA, 2-hydroxy-docosahexaenoic acid) has been shown to promote glioma cell death by inducing endoplasmic reticulum stress and autophagy [219] . Antibodies are also used as modulators of membrane properties. Bavituximab is a monoclonal antibody that has completed a phase Ib trial in advanced non-small cell lung cancer (NSCLC). It showed inhibition of tumor progression by targeting PS, promoting activation of the immune system. This immunomodulator is also undergoing a phase II clinical trial in patients with newly diagnosed glioblastoma [220] . On the other hand, inhibitors of enzymes related to lipid metabolism are also used as MLT drugs. For instance, orlistat (Roche Xenical®) disrupts fatty acid synthase, and it promotes apoptosis in breast cancer [221] and prostate tumors [222] . ABC294640, currently undergoing a phase Ib/II safety and efficacy trial, inhibits sphingosine kinase 2 and dihydroceramide desaturase, and it appears to be useful to treat multiple myeloma (ClinicalTrials.gov identifier #NCT02757326). A combination of lipoic and hydroxycitric acids has been seen to have efficacy in PCS, inhibiting ATP citrate lyase and pyruvate dehydrogenase kinase [223, 224] . In addition, ND-630 acts as an inhibitor of ACC, and it is currently undergoing a clinical phase 2 for treatment of NAFLD, displaying suitable results in treating non-small-cell lung cancer [223, 225] .

In addition to therapeutic applications, lipid content has also been shown to be a useful diagnostic tool in cancer. In pediatric brain tumors, the metabolic lipid profile obtained by nuclear magnetic resonance (NMR) may be useful to assess the tumor grade in a non-invasive manner [226] . Similarly, mass spectrometry imaging (MSI) of the lipid profile may make it possible to discriminate between two types of brain tumors, medulloblastoma and pineoblastoma [227] . Not only diagnosis but prognosis could also be determined by lipid content or lipidic gene expression, as SMS1 expression has been related to higher 5-year survival, and the content of specific lipids determined by H magnetic resonance spectroscopy (MRS) can predict poor survival in pediatric patients with brain tumors [228] . The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it as a useful biomarker for cancer molecular imaging. Evaluation of PS as a cancer biomarker is used by several imaging modalities, such as optical imaging, magnetic resonance imaging (MRI) or positron emission tomography (PET), and single-photon emission computed tomography (SPECT) [229] . These technics have interesting applications allowing identification of tumor margins or sentinel lymph node metastases [230] or providing detailed information about the intratumor distribution of tumor vascular endothelial cells [231] .

In conclusion, due to the implication of lipid metabolism in cancer progression, and the differences in lipid profiles between cancer and healthy cells, MLT is a promising therapeutic strategy with a good prognosis when using either natural or mimetic lipids as drugs for the potential treatment of different pathologies.

The CNS is the second richest region in terms of lipid content, following adipose tissue [232] , with lipids making up 50% of the brain's dry weight [233] . Lipids are crucial for the correct functioning of the CNS, and they are involved in cell signaling, energy balance, BBB homeostasis, inflammation, structural maintenance, and many other activities [234] . As a consequence, disrupting the lipid membrane composition can alter brain cell homeostasis and trigger neurological disorders, even those involving neurodegeneration such as AD, PD, or Huntington's disease (HD) [235] . AD is the leading worldwide cause of dementia among the population over 65 years of age. People affected by this pathology suffer a progressive loss of memory and a decrease in their cognitive capabilities in the earliest stages of the disease, which develops into dementia in its most advanced stages [236] . This section focuses on the brain lipid alterations related to neurodegenerative diseases and to AD in particular.

Of all the brain lipids, most of them can be classified as glycerophospholipids, sphingolipids, or Cho. Notably, PUFAs are usually associated with glycerophospholipids, and they represent around 30% of the total fatty acids in brain membranes [233, 237] . The ω-3 PUFAs are of particular interest for membrane LRT since they have been shown to provide great benefits in brain membranes by modifying their signaling, biophysical properties, and gene expression, thereby providing a degree of neuroprotection [24,44,238].

Cho is a key molecule involved in CNS activity, and 25% of the total Cho in the body is concentrated in the CNS. Alterations to Cho homeostasis are related to the etiology of AD [239] and other neurodegenerative pathologies such as HD and Niemann-Pick type C disease [235] . Cho metabolism is disrupted during AD, either its synthesis or its transport to the brain [237] . Most of the Cho in the human brain is carried by lipoproteins, the vast majority of which contain apolipoprotein E (ApoE). ApoE is expressed as three different isoforms, ApoE2, ApoE3, and ApoE4, the latter the most important risk factor for sporadic AD (SAD) as this isoform is expressed in nearly 50% of SAD cases [239, 240] . Curiously, ApoE4 is the isoform with the lowest capacity to bind membrane lipoprotein receptors [241, 242] , triggering alterations in Cho homeostasis in neurons [243, 244] . Finally, lipidomic analysis also revealed a reduction in high-density lipoproteins (HDL) accompanied by an increase in LDL levels in AD brains [245] . Interestingly, lower levels of HDL Cho have been correlated with a stronger cognitive decline in AD [246] .

Sphingolipids represent around 30% of the lipid content in brain membranes [247] , playing a key role as the skeleton for the production of different second messengers such as sphingosine-1-phosphate. They are also constituents of different cell components such as the PM and the myelin that sheathes axons or in the oligodendrocytes that produce the myelin in the CNS [248] . Sphingolipids are represented by SM, ceramides, and sulfatides. SM is the major sphingolipid in the brain [249] , and increased SM has been reported in the brain of some AD cases [250] . Nevertheless, there are other studies revealing a reduction in the SM content due to its enhanced metabolism as a result of sphingomyelinase activity [251, 252] . In this sense, ceramides levels are higher in AD than in healthy brains [253, 254] , cerebrospinal fluid (CSF) [255] , and blood, which is in turn correlated with cognitive impairment and memory decline [247] . On the other hand, sulfatides (an essential component of myelin) are also dramatically reduced in AD [256, 257] .

Other neurological disorders are related to a mutation in the lysosomal glucocerebrosidase gene (GBA) that reduces the activity of the enzyme responsible for the conversion of glycosylated sphingolipids into ceramides. Deficient GBA induces a pathological accumulation of glucosylceramide and glucosylsphingosine in the membranes of different cell types, resulting in disorders such as Gaucher (lysosomal storage disorder) disease (GD), or PD [258] . Indeed, these mutations can provoke the deposition of α-synuclein in the brain due to changes in the composition of sphingolipids [259] . Different glucosylceramide synthase inhibitors, a key enzyme in the first step of the glycosphingolipid synthesis, are being tested to palliate the visceral and blood symptoms of GD [260, 261] . Moreover, new drugs with the ability to cross the BBB are currently being tested to reduce the levels of the glycosphingolipids in the brain of patients with PD [262] . In the case of multiple sclerosis (MS), a neurological disease characterized by the immune-dependent loss of myelin, an imbalance in the sphingolipid profile has been portrayed as an increase in hexylceramides (glucosylceramide and galactosylceramide) and ceramide-1-phosphate, whereas the Cer, dihydroceramide, and SM decrease relative to the normal-appearing white matter [263] . In demyelinating disorders similar phenomenon may be controlled by the mutation of multiple genes in combination or as a single-gene disease, for example, through the mutation of GALC, a galactocerebrosidase enzyme, which induces the accumulation of galactosylceramide and its derivatives [264] .

Phospholipids are the most abundant lipids in brain membranes, and they control membrane fluidity and thickness, as well as membrane protein activity [265, 266] . There are lower levels of several phospholipids in AD brains, and several studies report a decrease in PS [267] , PI [268] , PC, and PE [269, 270] , although increases in certain species have also been reported [271] . Interestingly, all these changes are more pronounced in areas involved in AD, such as the frontal cortex and hippocampus but not in undamaged regions such as the auditory cortex [269] . Accordingly, this general reduction indicates increased phospholipid metabolism in affected AD brain areas, with PE and PC those most affected, suggesting that membrane LRT may be a suitable approach to treat AD [272] .

Fatty acids form part of cell membranes, and they are incorporated into more complex lipids such as phospholipids [273] . The main groups of fatty acids are PUFAs, MUFAs, and SFAs. The balance between SFAs and PUFAs in cell membranes has a key influence on biophysical cell membrane properties [274] , and alterations to this ratio aggravate the pathophysiological alterations that lead to neurological diseases [275] . SFAs are considered the unhealthiest fatty acids, and in fact, SFA intake has been related to a higher risk of AD and cognitive decline [276, 277] . Moreover, elevated levels of SFAs such as palmitic acid (16:0) and stearic acid (18:0) are found in the brain and blood of AD patients [278] .

PUFAs are commonly classified according to the site of the last double bond in their acyl chain, mainly categorized as ω-3 or ω-6 PUFAs [279] . DHA, the most abundant PUFA in the brain, is a ω-3 PUFA, the levels of which have been widely related to cognitive functions [280] . The involvement of DHA in AD pathogenesis has been studied intensely since its levels were reported to be reduced in AD-affected brain regions such as the hippocampus [268, [281] [282] [283] [284] [285] . Such reductions in DHA are usually concomitant with PE reductions, which suggests membrane LRT may be an interesting approach to restore healthy levels of PE and DHA [114, 232] . A decrease in DHA has been reported in circulation and in the CSF [286] [287] [288] and is related to cognitive decline. In AD, other ω-3 PUFAs such as EPA are also reduced in the brain and circulation [286] . By contrast, the ω-6 PUFA AA is elevated in individuals with mild cognitive impairment (MCI) and AD, either in the brain or CSF [287, 289, 290] . OA is the most abundant ω-9 MUFA, and it is believed to ameliorate cognitive decline and produce beneficial effects against AD. OA content also decreases in AD brains [268, 276] . In this sense, several studies concluded that higher levels of ω-3 and ω-9 species favor the ω-3/ω-6 FAs ratio, leading to a reduced risk of AD and preventing cognitive decline [291, 292] .

Finally, PUFAs play an important role in the brain as precursors of inflammatory mediators [273] . In this context, AD is characterized by a continued excessive inflammatory response mediated by activated glial cells, whereby ω-6 PUFAs such as AA serves as a precursor of pro-inflammatory eicosanoids [293] . Alternatively, ω-3 PUFAs promote an antiinflammatory status through lipid mediators named specialized pro-resolving mediators (SPMs) that are synthesized from DHA and EPA [294, 295] . As indicated above, these D series (derived from DHA) and E series (derived from EPA) families are neuroprotectins, and resolvins with anti-inflammatory properties protect against neurodegeneration and potentiate neurogenesis [141, 142] . Thus, pro-inflammatory eicosanoids are upregulated in AD, whereas anti-inflammatory SPMs are down-regulated in AD patients [296] .

Amyloid precursor protein (APP) is a single-pass transmembrane protein with a wide extracellular domain, best recognized as the precursor molecule as its proteolysis produces amyloid-β (Aβ), the predominant component of the amyloid plaques identified in AD [297] . The cholesterol-binding site (CBS) in APP is required for its interaction with several Cho metabolizing proteins (e.g., SREBP1) and for its localization to the lipid raft domains in synaptic vesicle and mitochondria-associated ER membranes (MAMs) [298] . MAMs are lipid rafts with a high Cho and SM content that favors physical contact. They have been proposed as regulators of APP processing by secretases through direct lipidprotein interactions in the CNS, while they are also important in the metabolism of glucose, phospholipids, Cho, and calcium [299, 300] . In this sense, APP processing is also modulated by the levels of unsaturated fatty acids, particularly DHA. Non-amyloidogenic APP processing is preferred when membranes are enriched in DHA, thereby avoiding Aβ aggregation as plaques or soluble oligomers [232] . In this situation, a well-structured membrane favors APP cleavage by the α-secretase, which releases the secreted sAPPα ectodomain into the extracellular space, as well as p3 and the APP intracellular C-terminal domain (AICD) [237] . This secreted sAPPα plays a role as a neurotrophic factor and prevents Aβ-induced neuron death [301] . By contrast, the presence of saturated and oxidized fatty acids causes cell membrane rupture, which favors β-secretase activation. β-secretase cleaves APP at its N-terminus, releasing the soluble sAPPβ ectodomain and the Aβ peptide into the extracellular milieu, promoting the formation of Aβ plaques [114, 302] .

Fatty acid-binding proteins (FABPs) are a family of fatty acid transport proteins for lipophilic compounds, including eicosanoids and retinoids. The transport of fatty acids between extracellular and intracellular membranes is thought to be facilitated by these proteins [303, 304] , and FABP3, FABP5, and FABP7 are the three members of the family expressed in the brain. FABP3 is a protein involved in neurogenesis and synaptogenesis, and it is linked to FABPs 5 and 7, which are in turn involved in neural stem/progenitor cells (NSPC) differentiation and migration [5] . Interestingly, FABP 7 has also been proposed as a candidate risk gene for mental health diseases such as schizophrenia and other related disorders [305] . All FABPs bind fatty acids with high affinity, although there are differences between the length of the chain preferred by each FABP. For example, FABP7 binds long PUFAs (EPA, DHA, and AA) with higher affinity [306] , whereas FABP3 binds shorter FAs more strongly (OA and linoleic acids) [307] .

Peripheral myelin protein P2 is another FABP, and, as one of the most abundant proteins in the human peripheral nervous system (PNS), P2 dysfunction may well lead to myelin degeneration [308] . The structure of this protein has been elucidated, revealing multiple features shared among FABPs, that can drive lipid interactions, including a ligand-binding pocket inside a barrel-like structure [309] .

α-synuclein is a small protein found at presynaptic terminals. A variety of neurodegenerative illnesses are characterized by the conversion of α-synuclein into aggregates such as soluble oligomers and fibrils, including PD and Lewy body dementia. The importance of α-synuclein interactions with lipids in the pathogenesis of PD has been reviewed extensively [310] . The interaction of α-synuclein with membrane lipids affects the properties of the protein but also some membrane traits such as expansion, its melting temperature, and remodeling. Several phospholipids have been proposed to promote or inhibit α-synuclein aggregation, including PE, PA, phosphoglycerol (PG), PS, sphingolipids, or fatty acids [311] .

Currently, there are just two types of drugs available to treat AD: acetylcholinesterase inhibitors and NMDA receptor antagonists. The first of these inhibit acetylcholine hydrolysis in an attempt to keep acetylcholine levels stable at synapses in a degenerating cholinergic system [312] . By antagonizing NMDA receptors, the latter prevent the sustained flow of Ca 2+ ions into neurons that provokes neuron death due to excitotoxicity, a characteristic of AD [313, 314] . However, neither cholinesterase inhibitors nor NMDA receptors antagonists have shown conclusive responses to combat pathophysiological AD alterations. In fact, only a small number of AD patients treated with these drugs have shown some improvement, and such effects are restricted in duration [315, 316] . In this context, the accelerated approval of Aducanumab (June 2021) by the FDA must be noted, even amidst the limited evidence of clinical effects in most AD patients [317, 318] .

Another clinical approach for AD is based on regulating Cho levels with statins since disruption of Cho homeostasis is crucial for AD development. Statins inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), the main enzyme involved in Cho biosynthesis. Nevertheless, favorable effects of statins are not only related to Cho regulation. It has been shown that statins administration exerts several pleiotropic effects such as decreased neuroinflammation and oxidative stress accompanied by an increase in glutamatergic receptors and superoxide dismutase activity [319] . In animal models, statin administration reduces Aβ levels in the brain, the accumulation of which as oligomers or fibrils is considered one of the main neuropathological hallmarks of AD. Indeed, statins have also been seen to prevent cognitive impairment [320, 321] . Similarly, results from another study indicated that AD progression was attenuated with early administration of statins to individuals, which was associated with improved cognitive capacities [322] [323] [324] . However, controversial results have been obtained in clinical trials using statins, making it difficult to reach conclusions about the use of statins to prevent AD progression [325] [326] [327] [328] [329] .

Fat-soluble vitamins such as vitamin A and E are considered antioxidant compounds located at cell membranes, protecting some PUFAs such as DHA from oxidative damage [330, 331] . These vitamins are shown to be more restricted in AD patients [332, 333] , and several trials have been proposed administering vitamins to ameliorate AD progression. Although promising results were obtained in animal models [334, 335] , no conclusive results have been obtained in humans [336, 337] .

The benefits of ω-3 PUFAs in AD have been widely reported, and hence, several clinical trials have been developed based on the administration of ω-3 PUFAs to AD patients, with particular attention paid to DHA and EPA [338] . Nevertheless, direct administration of these fatty acids [339] or via fish oil [340] failed to show clear benefits in AD patients. PUFA administration may be a promising therapy, although no clear conclusions have been obtained due to a lack of clinical improvement in most patients and discrepancies among the different clinical trials. ω-3 PUFAs have antioxidant properties and can attenuate age-related cognitive decline in animal models and humans [341, 342] . In addition, administration of ω-3 PUFAs improves synaptic plasticity and hippocampal neurogenesis in animal models [343] , whereas some trials in humans have shown cognitive improvement in mild-to-moderate patients [338] . Although the molecular mechanism involved in these neuroprotective effects is not fully understood, modulation of lipid raft composition, favoring liquid-disordered structures, has been proposed as the main mechanism promoting neuroprotective signaling [114, 344] .

Other approaches have also been investigated to combat AD pathogenesis, such as the use of hydroxylated derivatives of DHA (2-hydroxy-docosahexanoic acid, DHA-H, or HDHA). Treatment with DHA-H restored PE and PUFAs levels in the brain of AD mice [114] . Furthermore, promising results were obtained in a mouse model of AD, reducing the main neuropathological hallmarks of AD (Aβ accumulation and tau hyperphosphorylation) and preventing cognitive decline [114, 345] . DHA-H administration also protects neurons from AD-related neurotoxicity, and it induces neuronal proliferation in mouse models [345, 346] . Interestingly, recent studies demonstrated that DHA-H is not primarily metabolized by β-oxidation such as other PUFAs but rather, it is converted into other an ω-3 PUFA via α-oxidation, named heneicosapentaenoic acid (HPA, C21:5 ω-3), which seems to be involved in the neuroprotective effects of DHA-H in AD [302] .

In summary, the data available suggest that MLT and LRT could be a promising approach as AD therapy, which in turn points to membrane-related upstream events as suitable targets for the prevention/treatment of AD that are not currently addressed by available therapies.

The relationship between the plasma lipid membrane and infectious diseases caused by invading pathogens seems obvious: the lipid bilayer separates the intra-and extracellular environments, acting as the first barrier against exogenous pathogens [347] . However, beyond that, this relationship is even more complex.

Steps in the Infectious Process as a Candidate for Lipid Therapy 5.1.

Viruses are known to be capable of subjugating and reprogramming host-cell lipids in order to bind to and enter the host cell and to be able to propagate and release their progeny [348] . Ebola, HIV, Zika, influenza, Marburg, or SARS-CoV-2 are only a few of the clinically relevant viruses whose replication is interrupted by approaches and drugs that modulate or disrupt the lipid bilayer, specific lipids, lipid domains, and lipid structures in the cell [349] [350] [351] . Moreover, free Cho is involved in multiple steps in the pathogen cycle of these viruses [352] .

The entry of viral particles into human cells is critical to the pathological effects of infectious viruses. Different pathogens must interact with different receptors and coreceptors almost simultaneously to enter the cell. This is easily achieved when all the complex receptors co-localize in the same microdomain [353] . Indeed, the distribution of the different partners can be altered or randomized along the surface of the cell, reducing the probability of these successive interactions and lowering the fusion efficiency and infection. As such, a key role of lipid rafts in the infection process has been demonstrated for a variety of pathogens (HIV, influenza, Ebola, SARS-CoV-2, most clinically relevant bacteria, and protozoa). Lipid rafts are platforms that contain the endocytotic machinery used by viruses and bacteria to enter cells, and, in turn, they are the points of exit for their progeny [354] [355] [356] . Escherichia coli was one of the first bacterial pathogens recognized to invade host cells via clustered lipid rafts [357] . However, fungi and parasites also use host lipid rafts as their preferred point of entry [358] . Consequently, disruption or modulation of lipid rafts by LRT offers a novel therapeutic approach for pathogen infection. However, the relevance of the cell membrane in the infection process goes further than the interaction of the pathogens with the lipid membrane itself. For certain viruses (e.g., HIV-1, Ebola virus, hepatitis B virus, varicella-zoster virus, etc.), activation by the cellular protease furin upon binding to the cell receptor is essential to exert their infectious activity (reviewed in [359] ).

Not only do host lipids play a critical role in the infection of the host, but pathogens also make use of the full complexity of the host cell lipidome [360] . When the virus' genome is expressed, the nucleocapsids generated use the human cell membrane to form their lipid envelope. Therefore, both the composition of the infectious agent envelope and that of the human PM are crucial for infective expansion and, indeed, lipid replacement, reduction, and/or redistribution might be used to interfere with pathogen spread. As an example, the envelope from the infectious agent is amenable to a less fusogenic configuration using lipopeptides, and this might potentially compromise SARS-CoV-2 virus infection [361] . Alternatively, those essential lipids required for pathogen replication can be targeted by chemical compounds or even by antibodies to inhibit pathogen multiplication (reviewed in [362] [363] [364] ). The common objective of all these therapies is to modulate, replace or disrupt lipid composition.

As indicated above, LDs are evolutionary conserved cytoplasmic organelles in which cell lipids are stored to produce metabolic energy. These lipids, essential fatty acids, and Cho are preserved by converting them into neutral lipids such as TAGs and cholesteryl esters. LD biogenesis has been detected soon after infection with several different pathogens, bacteria, parasites, and viruses [365] . Different clinically relevant pathogens such as Salmonella, Klebsiella, Pseudomonas, Staphylococcus, Trypanosoma, or viruses such as hepatitis C, dengue, Zika, or SARS-CoV-2 were found to trigger LD biogenesis to fuel their replication [366] . Disruption of the pathway driving LD formation should and has been proven to interrupt or compromise pathogen replication [367] .

However, viruses are not the only pathogens that exploit the host cell's lipids for infection and that might be susceptible to LRT. The regulation of lipids is crucial for arthropod-borne pathogens, for example, regardless of whether they are viruses, bacteria, or protozoa, or if they act extra-or intracellularly [368] . Specifically, bacteria of the genus Anaplasma, Ehrlichia, and Borrelia are known to use host cell Cho and different fatty acids for their growth [369] [370] [371] [372] . For Anaplasma and Ehrlichia, the use of host phospholipids is also essential to their viability [373] . Different arthropod-borne protists such as Plasmidium, Leishmania, and Trypanosoma require at least one of the lipid groups mentioned above for their survival and proliferation [374] [375] [376] [377] [378] . In the case of the flaviviruses transmitted by arthropods, Cho, fatty acids, phospholipids, and sphingolipids from the host cell are essential for replication [379] [380] [381] [382] . These data have prompted the development of novel therapies for vector-borne diseases that focus on the modulation of lipid composition, and LRT fits within this kind of therapy. In fact, drugs targeting lipid metabolism have been shown to inhibit arboviral and parasite infection in mouse models [383, 384] .

Lipid metabolism offers different targets and opportunities to treat or prevent pathogen infections: free Cho; fatty acid biosynthesis; LDs; specific lipids in the membrane; membrane fluidity; the distribution of receptors and co-receptors; lipid rafts; lipid-based defense strategies in human hosts. The control of inflammatory processes is also used as a symptomatic treatment beyond the fight against the pathogen itself. All in all, molecules involved in LRT or that alter the membrane composition, in turn weakening pathogen infection, are already available (Table 1) . When considering lipid-based defense strategies in human hosts, crosstalk between lipid metabolism and inflammatory signaling pathways offers exciting opportunities for therapeutic interventions. For example, the activation of type I interferon (IFN) signaling dampens Cho biosynthesis and vice versa. Thus, decreasing Cho biosynthesis in vitro appears to have a protective effect against MHV-68 and HIV-1 [385] . Reduction in lipid biosynthesis also has an impact on reducing lipid raft stability, and the use of Miglustat-Zavesca (currently used to treat inherited diseases that affect body processing of fats) has promising effects of impeding damaging pro-inflammatory activities in vitro [386, 387] . In summary, LRT and other approaches aimed at targeting lipids either on the infectious agent or on the host offer a promising landscape, especially when many of them are already marketed for other uses. 

Lipid composition is crucial to maintaining cellular homeostasis. Lipid alterations are associated with several diseases, and normalization of their levels has therapeutic potential. This therapeutic approach, termed membrane lipid therapy or membrane lipid replacement, is currently in use for drug discovery and nutraceutical interventions. Several clinical trials and therapeutic products have validated this technology, which is based on the understanding of cell membrane composition, structure, and functions. This review addresses the molecular and cellular basis of this therapeutic approach, describing how membrane lipid composition and structure affect protein-lipid interactions, cell signaling, cell physiology, pathophysiology, and therapy, making a particular emphasis on oncology, neurodegeneration, and infectious diseases. Acknowledgments: Figure 1, Figure 3 , and Figure 5 were reproduced from references [3] , [24] , and [58] , respectively, with permission from Elsevier. All these three references were authored by the corresponding author Pablo V. Escribá. Please, see the reference list for further details. 

Physiological and Pathological Tissues

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The lipid distribution of human platelets in health and disease 1

Experimental Atherosclerosis; the Effect of Feeding Olive Oil on the Absorption and Deposition of Cholesterol

Studies on Patients with Cirrhosis of the Liver

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DIGs, and the Dynamics of Sphingolipid-Cholesterol Microdomains

Lateral Phase Separation in Phospholipid Membranes

Molecular Interactions in Mixed Lecithin Systems

Mattress Model of Lipid-Protein Interactions in Membranes

Electrical Properties of Plasma Membrane Modulate Subcellular Distribution of K-Ras

Interaction of the C-Terminal Region of the Gγ Protein with Model Membranes

Role of the Lysine-Rich Cluster of the C2 Domain in the Phosphatidylserine-Dependent Activation of PKCα

The Membrane Binding Kinetics of Full-Length PKCα Is Determined by Membrane Lipid Composition

Classical Protein Kinases C Are Regulated by Concerted Interaction with Lipids: The Importance of Phosphatidylinositol-4,5-Bisphosphate

Protein-Membrane Interactions II: Effect of G Protein-Linked Lipids on Membrane Structure and G Protein-Membrane Interactions

Phosphoinositide 3-Kinases in Cell Migration

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More Than a Pore: The Interplay of Pore-Forming Proteins and Lipid Membranes

Beyond Pore Formation: Reorganization of the Plasma Membrane Induced by Pore-Forming Proteins

Pore-Forming Activity and Structural Autoinhibition of the Gasdermin Family

Equinatoxin II Permeabilizing Activity Depends on the Presence of Sphingomyelin and Lipid Phase Coexistence

Structures of Lysenin Reveal a Shared Evolutionary Origin for Pore-Forming Proteins and Its Mode of Sphingomyelin Recognition

Sea Anemone Heteractis Crispa Actinoporin Demonstrates In Vitro Anticancer Activities and Prevents HT-29 Colorectal Cancer Cell Migration

Cytotoxic and Apoptosis-Inducing Effects of Wildtype and Mutated Hydra Actinoporin-like Toxin 1 (HALT-1) on Various Cancer Cell Lines

Fluidity and Function of Hepatocyte Plasma Membranes

Cell Biology: A Focus on Lipids in Cell Division

Phosphoinositides: Lipids with Informative Heads and Mastermind Functions in Cell Division

Dividing Cells Regulate Their Lipid Composition and Localization

Blood-Brain Barrier Permeability Is Regulated by Lipid Transport-Dependent Suppression of Caveolae-Mediated Transcytosis

Unique Lipid Chemistry of Synaptic Vesicle and Synaptosome Membrane Revealed Using Mass Spectrometry

A Neuroscientist's Guide to Lipidomics

Membranes Exhibit Phase Behavior at Sites of Organelle Contact

Polarized Sorting and Trafficking in Epithelial Cells

Membrane Lipidome of an Epithelial Cell Line

Reduction in Saturated Fat Intake for Cardiovascular Disease

Oleic Acid Content Is Responsible for the Reduction in Blood Pressure Induced by Olive Oil

Mediterranean Diet and Cardiovascular Health: An Historical Perspective

Omega-3 Fatty Acids for the Primary and Secondary Prevention of Cardiovascular Disease. Cochrane Database Syst

Marine Omega-3 (N-3) Fatty Acids for Cardiovascular Health: An Update for 2020

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Structured Form of DHA Prevents Neurodegenerative Disorders: A Better Insight into the Pathophysiology and the Mechanism of DHA Transport to the Brain

Effects of Dietary Eicosapentaenoic Acid and Docosahexaenoic Acid Supplementation on Metabolic Syndrome: A Systematic Review and Meta-Analysis of Data from 33 Randomized Controlled Trials

Omega-3 Fatty Acids Reduce Cardiometabolic Risk in First-Episode Schizophrenia Patients Treated with Antipsychotics: Findings from the OFFER Randomized Controlled Study

A Three-Month Consumption of Eggs Enriched with ω-3, ω-5 and ω-7 Polyunsaturated Fatty Acids Significantly Decreases the Waist Circumference of Subjects at Risk of Developing Metabolic Syndrome: A Double-Blind Randomized Controlled Trial

Mechanisms of Action of (n-3) Fatty Acids

The Metabolic Syndrome and the Membrane Content of Polyunsaturated Fatty Acids in Hypertensive Patients

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

Membrane Lipid Modifications and Therapeutic Effects Mediated by Hydroxydocosahexaenoic Acid on Alzheimer's Disease

Regulation of the Cancer Cell Membrane Lipid Composition by NaCHOleate: Effects on Cell Signaling and Therapeutical Relevance in Glioma

Mutation of FA2H Underlies a Complicated Form of Hereditary Spastic Paraplegia (SPG35)

FA2H-Related Disorders: A Novel c.270+3A>T Splice-Site Mutation Leads to a Complex Neurodegenerative Phenotype

Arachidonic Acid Derivatives and Their Role in Peripheral Nerve Degeneration and Regeneration

FADS1-FADS2 Genetic Polymorphisms Are Associated with Fatty Acid Metabolism through Changes in DNA Methylation and Gene Expression

Cyclooxygenases, Lipoxygenases, and Epoxygenases in CNS: Their Role and Involvement in Neurological Disorders

Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications

Hydroxy Arachidonic Acid: A New Non-Steroidal Anti-Inflammatory Drug

Treatment with Albumin-Hydroxyoleic Acid Complex Restores Sensorimotor Function in Rats with Spinal Cord Injury: Efficacy and Gene Expression Regulation

Obesity and Type 2 Diabetes: Which Patients Are at Risk? Diabetes Obes

ER Phospholipid Composition Modulates Lipogenesis during Feeding and in Obesity

Membrane Lipid Alterations in the Metabolic Syndrome and the Role of Dietary Oils

The Fluidity of Liver Plasma Membranes from Patients with Different Types of Liver Injury

Decreased Erythrocyte Membrane Fluidity and Altered Lipid Composition in Human Liver Disease

LDL-Cholesterol Transport to the Endoplasmic Reticulum: Current Concepts

LDL Cholesterol and the Development of Stroke Subtypes and Coronary Heart Disease in a General Japanese Population the Hisayama Study

The Dynamics of Oxidized LDL during Atherogenesis

OxLDL-Induced IL-1β Secretion Promoting Foam Cells Formation Was Mainly via CD36 Mediated ROS Production Leading to NLRP3 Inflammasome Activation

The Role of Oxidized Phospholipids in the Development of Disease

Role of Protein Kinase C δ in Apoptotic Signaling of Oxidized Phospholipids in RAW 264.7 Macrophages

Eicosapentaenoic Acid (EPA) Has Optimal Chain Length and Degree of Unsaturation to Inhibit Oxidation of Small Dense LDL and Membrane Cholesterol Domains as Compared to Related Fatty Acids in Vitro

Mechanisms of Lipid-Body Formation

The Lipid Droplet: A Conserved Cellular Organelle

Dynamics and Functions of Lipid Droplets

Effects of Oleic Acid and Its Congeners, Elaidic and Stearic Acids, on the Structural Properties of Phosphatidylethanolamine Membranes

Influence of the Membrane Lipid Structure on Signal Processing via G Protein-Coupled Receptors

Novel Omega-3-Derived Mediators, and Their Aspirin-Triggered Endogenous Epimers: An Overview of Their Protective Roles in Catabasis

Docosanoid Signaling Modulates Corneal Nerve Regeneration: Effect on Tear Secretion, Wound Healing, and Neuropathic Pain

The Anti-Cancer Drug ABTL0812 Induces ER Stress-Mediated Cytotoxic Autophagy by Increasing Dihydroceramide Levels in Cancer Cells

The Antitumour Drug ABTL0812 Impairs Neuroblastoma Growth through Endoplasmic Reticulum Stress-Mediated Autophagy and Apoptosis

Beneficial Effects of N-3 Polyunsaturated Fatty Acids Administration in a Partial Lesion Model of Parkinson's Disease: The Role of Glia and NRf2 Regulation

Structure-Effect Relation of C18 Long-Chain Fatty Acids in the Reduction of Body Weight in Rats

Hereditary Branching Enzyme Dysfunction in Adult Polyglucosan Body Disease: A Possible Metabolic Cause in Two Patients

Adult Polyglucosan Body Disease in Ashkenazi Jewish Patients Carrying the Tyr329 Ser Mutation in the Glycogen-Branching Enzyme Gene

A Novel Mouse Model That Recapitulates Adult-Onset Glycogenosis Type 4

Immunohistochemical and Ultrastructural Changes in the Brain in Probable Adult Glycogenosis Type IV: Adult Polyglucosan Body Disease

Triacylglycerol Mimetics Regulate Membrane Interactions of Glycogen Branching Enzyme: Implications for Therapy

Guaiacol as a Drug Candidate for Treating Adult Polyglucosan Body Disease

Membrane-Lipid Therapy in Operation: The HSP Co-Inducer BGP-15 Activates Stress Signal Transduction Pathways by Remodeling Plasma Membrane Rafts

Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment

Inhibition of Cancer Growth and Induction of Apoptosis by BGP-13 and BGP-15

Pepducin-Based Intervention of Thrombin-Receptor Signaling and Systemic Platelet Activation

Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis

Cell-Penetrating Pepducin Therapy Targeting PAR1 in Subjects with Coronary Artery Disease

Pepducins as a Potential Treatment Strategy for Asthma and COPD

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Interaction of Miltefosine with the Lipid and Protein Components of the Erythrocyte Membrane

Miltefosine Inhibits the Membrane Remodeling Caused by Phospholipase Action by Changing Membrane Physical Properties

Edelfosine and Miltefosine Effects on Lipid Raft Properties: Membrane Biophysics in Cell Death by Antitumor Lipids

Reprogramming of Fatty Acid Metabolism in Cancer

New Insights into Tumor Suppression: PTEN Suppresses Tumor Formation by Restraining the Phosphoinositide 3-Kinase/AKT Pathway

A Transcriptional Signature and Common Gene Networks Link Cancer with Lipid Metabolism and Diverse Human Diseases

Novel Theranostic Opportunities Offered by Characterization of Altered Membrane Lipid Metabolism in Breast Cancer Progression

Lipid Metabolic Reprogramming in Cancer Cells

Lipids: Implication for Diseases and Membrane Trafficking

Identification of Novel Sphingolipid-Binding Motifs in Mammalian Membrane Proteins

Computational Investigation of Cholesterol Binding Sites on Mitochondrial VDAC

Increased Exposure of Phosphatidylethanolamine on the Surface of Tumor Vascular Endothelium

Surface Exposure of Phosphatidylserine in Pathological Cells

Cell Membrane Modulation as Adjuvant in Cancer Therapy

Perturbing the Dynamics and Organization of Cell Membrane Components: A New Paradigm for Cancer-Targeted Therapies

Advances in Lipidomics for Cancer Biomarkers Discovery

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Interaction of Membrane/Lipid Rafts with the Cytoskeleton: Impact on Signaling and Function

Fatty Acid Metabolism in Breast Cancer Subtypes

The Ras Superfamily of Small GTPases in Non-Neoplastic Cerebral Diseases

A Comprehensive Survey of Ras Mutations in Cancer

Post-Translational Modification of RAS Proteins

Activation of Ras by Post-Translational Modifications

Palmitoylation as a Key Regulator of Ras Localization and Function. Front. Mol. Biosci. 2021, 8, 151

Activated K-Ras and H-Ras Display Different Interactions with Saturable Nonraft Sites at the Surface of Live Cells

Interaction of the Human N-Ras Protein with Lipid Raft Model Membranes of Varying Degrees of Complexity

Targeting the Ras Palmitoylation/Depalmitoylation Cycle in Cancer

Epidermal Growth Factor Receptor (EGFR) Signaling in Cancer

Regulation of EGFR Activation and Signaling by Lipids on the Plasma Membrane

The Physiological Role of Wnt Pathway in Normal Development and Cancer

Binding of Canonical Wnt Ligands to Their Receptor Complexes Occurs in Ordered Plasma Membrane Environments

LRP6 Mediated Signal Transduction Pathway Triggered by Tissue Plasminogen Activator Acts through Lipid Rafts in Neuroblastoma Cells

Post-Translational Palmitoylation and Glycosylation of Wnt-5a Are Necessary for Its Signalling

Glycosylation and Palmitoylation of Wnt-3a Are Coupled to Produce an Active Form of Wnt-3a

Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

Palmitoylation of Hedgehog Proteins by Hedgehog Acyltransferase: Roles in Signalling and Disease

Lipid Metabolism Fattens up Hedgehog Signaling

Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as

Lipid Metabolism and Carcinogenesis, Cancer Development

Small-Molecule Modulation of Lipid-Dependent Cellular Processes against Cancer: Fats on the Gunpoint

Targeting Membrane Lipid a Potential Cancer Cure?

Sphingomyelin Metabolism Is a Regulator of K-Ras Function

Dual Blocking of PI3K and MTOR Signaling by NVP-BEZ235 Inhibits Proliferation in Cervical Carcinoma Cells and Enhances Therapeutic Response

Therapeutic Benefit of Selective Inhibition of P110α PI3-Kinase in Pancreatic Neuroendocrine Tumors

NVP-BEZ235 as a New Therapeutic Option for Sarcomas

A Novel Therapeutic Strategy for Cancer Using Phosphatidylserine Targeting Stearylamine-Bearing Cationic Liposomes

A Comprehensive Lipid Binding and Activity Validation of a Cancer-Specific Peptide-Peptoid Hybrid PPS1

Lovastatin Inhibits Cancer Stem Cells and Sensitizes to Chemo-and Photodynamic Therapy in Nasopharyngeal Carcinoma

2-Hydroxypropyl-β-Cyclodextrin Regulates the Epithelial to Mesenchymal Transition in Breast Cancer Cells by Modulating Cholesterol Homeostasis and Endoplasmic Reticulum Stress

Statins: A Role in Breast Cancer Therapy?

Phase II Study of Miltefosine 6% Solution as Topical Treatment of Skin Metastases in Breast Cancer Patients

Edelfosine: An Antitumor Drug Prototype

The Azurin-Derived Peptide CT-P19LC Exhibits Membrane-Active Properties and Induces Cancer Cell Death

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

The Triacylglycerol, Hydroxytriolein, Inhibits Triple Negative Mammary Breast Cancer Cell Proliferation through a Mechanism Dependent on Dihydroceramide and Akt

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

Phase Ib Study of Bavituximab with Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer

Antitumoral Actions of the Anti-Obesity Drug Orlistat (Xenical TM ) in Breast Cancer Cells: Blockade of Cell Cycle Progression, Promotion of Apoptotic Cell Death and PEA3-Mediated Transcriptional Repression of Her2/Neu (ErbB-2) Oncogene

Caveolin-1 Interacts with a Lipid Raft-Associated Population of Fatty Acid Synthase

Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat

Adding a Combination of Hydroxycitrate and Lipoic Acid (METABLOC TM ) to Chemotherapy Improves Effectiveness against Tumor Development: Experimental Results and Case Report

Synthesis and Anti-Cancer Activity of ND-646 and Its Derivatives as Acetyl-CoA Carboxylase 1 Inhibitors

Monleon Comparative Metabolic Profiling of Paediatric Ependymoma, Medulloblastoma and Pilocytic Astrocytoma

Rapid Discrimination of Pediatric Brain Tumors by Mass Spectrometry Imaging

Magnetic Resonance Spectroscopy Metabolite Profiles Predict Survival in Paediatric Brain Tumours

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential

Fluorescence-Guided Surgery with 5-Aminolevulinic Acid for Resection of Malignant Glioma: A Randomised Controlled Multicentre Phase III Trial

Phosphatidylserine-Targeted Molecular Imaging of Tumor Vasculature by Magnetic Resonance Imaging

Brain Lipids in the Pathophysiology and Treatment of Alzheimer's Disease

Lipids of Nervous Tissue: Composition and Metabolism

Dietary Polyunsaturated Fatty Acids Improve Cholinergic Transmission in the Aged Brain

Membrane Rafts in Alzheimer's Disease β-Amyloid Production

Membrane Aging as the Real Culprit of Alzheimer's Disease: Modification of a Hypothesis

Involvement of Lipids in Alzheimer's Disease Pathology and Potential Therapies

Membranes: A Meeting Point for Lipids, Proteins and Therapies

Cholesterol Metabolism, Diabetes, and the Convergence of Risk Factors for Alzheimer's Disease and Cardiovascular Disease

APOE Genotype Effects on Alzheimer's Disease Onset and Epidemiology

Cholesterol Transport and Synthesis in Sporadic Alzheimer's Disease

Implication of ApoE Isoforms in Cholesterol Metabolism by Primary Rat Hippocampal Neurons and Astrocytes

A Novel Strategy for the Comprehensive Analysis of the Biomolecular Composition of Isolated Plasma Membranes

Loss of Gamma-Secretase Function Impairs Endocytosis of Lipoprotein Particles and Membrane Cholesterol Homeostasis

Elevated Low-Density Lipoprotein in Alzheimer's Disease Correlates with Brain Aβ 1-42 Levels

HDL and Cognition in Neurodegenerative Disorders

Could Plasma Sphingolipids Be Diagnostic or Prognostic Biomarkers for Alzheimer's Disease?

Intra-and Intercellular Trafficking in Sphingolipid Metabolism in Myelination

An Overview of Sphingolipid Metabolism: From Synthesis to Breakdown

Brain and Blood Metabolite Signatures of Pathology and Progression in Alzheimer Disease: A Targeted Metabolomics Study

Deregulation of Sphingolipid Metabolism in Alzheimer's Disease

Amyloid-β Peptide Induces Oligodendrocyte Death by Activating the Neutral Sphingomyelinase-Ceramide Pathway

Increased Ceramide in Brains with Alzheimer's and Other Neurodegenerative Diseases

Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and A β Accumulation

Astroglial Expression of Ceramide in Alzheimer's Disease Brains: A Role during Neuronal Apoptosis

Substantial Sulfatide Deficiency and Ceramide Elevation in Very Early Alzheimer's Disease: Potential Role in Disease Pathogenesis

Cerebrospinal Fluid Sulfatide Is Decreased in Subjects with Incipient Dementia

Gaucher Disease, and Parkinson's Disease: From Genetic to Clinic to New Therapeutic Approaches

Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies

Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3

Glucosylceramide Synthase Inhibitors Differentially Affect Expression of Glycosphingolipids

Glucosylceramide Synthase Inhibition Alleviates Aberrations in Synucleinopathy Models

Distinctive Sphingolipid Patterns in Chronic Multiple Sclerosis Lesions

The Role of Sphingolipids in Myelination and Myelin Stability and Their Involvement in Childhood and Adult Demyelinating Disorders

The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

Interactions between Amyloid β Peptide and Lipid Membranes

Plasmalogen-Selective Phospholipase A2 and Its Involvement in Alzheimer's Disease

Regional Membrane Phospholipid Alterations in Alzheimer's Disease

Evidence for a Membrane Defect in Alzheimer Disease Brain

Lipidomics of Alzheimer's Disease: Current Status

Disturbed Choline Plasmalogen and Phospholipid Fatty Acid Concentrations in Alzheimer's Disease Prefrontal Cortex

Roles for Dysfunctional Sphingolipid Metabolism in Alzheimer's Disease Neuropathogenesis

Lipids and Alzheimer's Disease

The Role of Alterations in Membrane Lipid Composition in Enabling Physiological Adaptation of Organisms to Their Physical Environment

The Role of Polyunsaturated Fatty Acids in Restoring the Aging Neuronal Membrane

Dietary Fat Composition and Dementia Risk

Dietary Fats and the Risk of Incident Alzheimer Disease

Human Cerebrospinal Fluid Fatty Acid Levels Differ between Supernatant Fluid and Brain-Derived Nanoparticle Fractions, and Are Altered in Alzheimer's Disease

Region-Specific Vulnerability to Lipid Peroxidation and Evidence of Neuronal Mechanisms for Polyunsaturated Fatty Acid Biosynthesis in the Healthy Adult Human Central Nervous System

Fatty Acid Composition of Brain Phospholipids in Aging and in Alzheimer's Disease

Plasmalogen Deficiency in Early Alzheimer's Disease Subjects and in Animal Models: Molecular Characterization Using Electrospray Ionization Mass Spectrometry

A Role for Docosahexaenoic Acid-Derived Neuroprotectin D1 in Neural Cell Survival and Alzheimer Disease

Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease

The Pleiotropic Effects of Omega-3 Docosahexaenoic Acid on the Hallmarks of Alzheimer's Disease

Blood Fatty Acids in Alzheimer's Disease and Mild Cognitive Impairment: A Meta-Analysis and Systematic Review

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-Symptomatic Alzheimer's Disease Cohort

Association between Fatty Acid Metabolism in the Brain and Alzheimer Disease Neuropathology and Cognitive Performance: A Nontargeted Metabolomic Study

Plasma Fatty Acid Lipidomics in Amnestic Mild Cognitive Impairment and Alzheimer's Disease. J. Alzheimer's Dis

Dietary Arachidonic Acid as a Risk Factor for Age-Associated Neurodegenerative Diseases: Potential Mechanisms

Additive Effects of Fatty Acid Mixtures on the Levels and Ratio of Amyloid B40/42 Peptides Differ from the Effects of Individual Fatty Acids

Dietary Long-Chain Fatty Acids and Cognitive Performance in Older Australian Adults

Pro-Resolving Lipid Mediators: Agents of Anti-Ageing?

Specialized Pro-Resolving Mediators: Endogenous Regulators of Infection and Inflammation

Impaired Resolution of Inflammation in Alzheimer's Disease: A

The Role of Eicosanoids in Alzheimer's Disease

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

Alzheimer's Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α

On the Pathogenesis of Alzheimer's Disease: The MAM Hypothesis

Increased Localization of APP-C99 in Mitochondria-Associated ER Membranes Causes Mitochondrial Dysfunction in Alzheimer Disease

Age-Dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (SAPP(α)) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

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

Role of Fatty Acid Binding Proteins (FABPs) in Cancer Development and Progression

Diverse Roles of Fatty Acid Binding Proteins (FABPs) in Development and Pathogenesis of Cancers

Characterization of Fatty Acid Binding Protein 7 (FABP7) in the Murine Retina

Brain Fatty Acid-Binding Protein and ω-3/ω-6 Fatty Acids: Mechanistic Insight into Malignant Glioma Cell Migration

Possible Involvement of Fatty Acid Binding Proteins in Psychiatric Disorders

Human Myelin Protein P2: From Crystallography to Time-Lapse Membrane Imaging and Neuropathy-Associated Variants

Structure and Dynamics of a Human Myelin Protein P2 Portal Region Mutant Indicate Opening of the β Barrel in Fatty Acid Binding Proteins

The Role of Lipids Interacting with α-Synuclein in the Pathogenesis of Parkinson's Disease

α-Synuclein Adopts an α-Helical Conformation in the Presence of Polyunsaturated Fatty Acids to Hinder Micelle Formation

The Cholinergic System in Alzheimer's Disease

Amyloid β Peptide Oligomers Directly Activate NMDA Receptors

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline

Cholinesterase Inhibitors for Patients with Alzheimer's Disease: Systematic Review of Randomised Clinical Trials

Aducanumab and the Business of Alzheimer Disease-Some Choice

Failure to Demonstrate Efficacy of Aducanumab: An Analysis of the EMERGE and ENGAGE Trials as Reported by Biogen

Pleiotropic Effects of Statins: A Focus on Cancer

Simvastatin Enhances Learning and Memory Independent of Amyloid Load in Mice

Simvastatin Strongly Reduces Levels of Alzheimer's Disease β-Amyloid Peptides Aβ 42 and Aβ 40 in Vitro and in Vivo

Evidence for Benefit of Statins to Modify Cognitive Decline and Risk in Alzheimer's Disease

Treatment with Simvastatin in Patients with Alzheimer's Disease Lowers Both α-and β-Cleaved Amyloid Precursor Protein

Early Statin Use and the Progression of Alzheimer Disease

The Effect of Simvastatin Treatment on the Amyloid Precursor Protein and Brain Cholesterol Metabolism in Patients with Alzheimer's Disease

Double-Blind, Placebo-Controlled Trial of Simvastatin to Treat Alzheimer Disease

Randomized Controlled Trial of Atorvastatin in Mild to Moderate Alzheimer Disease: LEADe

The Atorvastatin/Donepezil in Alzheimer's Disease Study (LEADe): Design and Baseline Characteristics

Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER): A Randomised Controlled Trial

Vitamin E Function and Requirements in Relation to PUFA

The Antioxidant Requirement for Plasma Membrane Repair in Skeletal Muscle. Free Radic

Plasma Antioxidants Are Similarly Depleted in Mild Cognitive Impairment and in Alzheimer's Disease

Plasma Antioxidant Status in Patients with Alzheimer's Disease and Cognitively Intact Elderly: A Meta-Analysis of Case-Control Studies

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Quinine Ameliorates Spatial Memory Deficits by Reducing β-Amyloid Oligomers, Neuroinflammation and Oxidative Stress in Transgenic Mice with Alzheimer's Disease. Behav

Vitamin E for Alzheimer's Dementia and Mild Cognitive Impairment

Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial (PREADViSE)

A Randomized Placebo-Controlled Pilot Trial of Omega-3 Fatty Acids and α Lipoic Acid in Alzheimer's Disease

Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease: A Randomized Trial

ω-3 Fatty Acid Treatment in 174 Patients with Mild to Moderate Alzheimer Disease: OmegAD Study-A Randomized Double-Blind Trial

Long-Chain Polyunsaturated Fatty Acids (LCPUFA) from Genesis to Senescence: The Influence of LCPUFA on Neural Development, Aging, and Neurodegeneration

Beneficial Effects of Docosahexaenoic Acid on Cognition in Age-Related Cognitive Decline

Mechanisms of N-3 Fatty Acid-Mediated Development and Maintenance of Learning Memory Performance

Lipid Alterations in Lipid Rafts from Alzheimer's Disease Human Brain Cortex

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

The Unfolded Protein Response in the Therapeutic Effect of Hydroxy-DHA against Alzheimer's Disease

Membrane Lipids: Where They Are and How They Behave

Lipid Interactions during Virus Entry and Infection

Lipid Rafts and Pathogens: The Art of Deception and Exploitation

Unraveling the Role of Membrane Microdomains during Microbial Infections

Lipids in Infectious Diseases-The Case of AIDS and Tuberculosis

Interaction of Pathogens with Host Cholesterol Metabolism

Mechanisms of Receptor/Coreceptor-Mediated Entry of Enveloped Viruses

The Role of Lipid Rafts in the Pathogenesis of Bacterial Infections

Lipid-Mediated Endocytosis

Targeting Lipid Rafts-A Potential Therapy for COVID-19

Survival of FimH-Expressing Enterobacteria in Macrophages Relies on Glycolipid Traffic

Host-Cell Lipid Rafts: A Safe Door for Micro-Organisms?

Furin-Mediated Protein Processing in Infectious Diseases and Cancer

Lipids in Host-Pathogen Interactions: Pathogens Exploit the Complexity of the Host Cell Lipidome

SARS-CoV-2-Derived Fusion Inhibitor Lipopeptides Exhibit Highly Potent and Broad-Spectrum Activity against Divergent Human Coronaviruses

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

Targeting Inside-out Phosphatidylserine as a Therapeutic Strategy for Viral Diseases

Phase I Safety and Pharmacokinetic Study of Bavituximab, a Chimeric Phosphatidylserine-Targeting Monoclonal Antibody, in Patients with Advanced Solid Tumors

The Roles of Lipid Droplets in Human Infectious Disease

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response

Modulation of Lipid Droplet Metabolism-A Potential Target for Therapeutic Intervention in Flaviviridae Infections

Hijacking: A Unifying Theme in Vector-Borne Diseases

Functional Inhibition of Acid Sphingomyelinase Disrupts Infection by Intracellular Bacterial Pathogens

Hijacking and Use of Host Lipids by Intracellular Pathogens

Structural Analysis of Glycolipids from Borrelia Burgdorferi

Host Membrane Lipids Are Trafficked to Membranes of Intravacuolar Bacterium Ehrlichia Chaffeensis

Changes to Cholesterol Trafficking in Macrophages by Leishmania Parasites Infection

Phospholipid and Sphingolipid Metabolism in Leishmania

Type II Fatty Acid Synthesis Is Essential Only for Malaria Parasite Late Liver Stage Development

Host Cell Phosphatidylcholine Is a Key Mediator of Malaria Parasite Survival during Liver Stage Infection

Host Triacylglycerols Shape the Lipidome of Intracellular Trypanosomes and Modulate Their Growth

The Increase in Cholesterol Levels at Early Stages after Dengue Virus Infection Correlates with an Augment in LDL Particle Uptake and HMG-CoA Reductase Activity

Dengue Virus Nonstructural Protein 3 Redistributes Fatty Acid Synthase to Sites of Viral Replication and Increases Cellular Fatty Acid Synthesis

Dengue Virus Reduces AGPAT1 Expression to Alter Phospholipids and Enhance Infection in Aedes Aegypti

A Global Lipid Map Defines a Network Essential for Zika Virus Replication

Modification of the Host Cell Lipid Metabolism Induced by Hypolipidemic Drugs Targeting the Acetyl Coenzyme A Carboxylase Impairs West Nile Virus Replication

Targeting Host Metabolism by Inhibition of Acetyl-Coenzyme A Carboxylase Reduces Flavivirus Infection in Mouse Models

Miglustat-Induced Intestinal Carbohydrate Malabsorption Is Due to the Inhibition of α-Glucosidases, but Not β-Galactosidases

Metabolic Control of Astrocyte Pathogenic Activity via CPLA2-MAVS

Statins for Infection and Sepsis: A Systematic Review of the Clinical Evidence

Efficacy and Safety of Statin Treatment for Cardiovascular Disease: A Network Meta-Analysis of 170 255 Patients from 76 Randomized Trials

Statins: A Viable Candidate for Host-Directed Therapy against Infectious Diseases

Statins as Anticancer Agents in the Era of Precision Medicine

Inhibition of Fatty Acid Synthesis in Isolated Adipocytes by 5-(Tetradecyloxy)-2-Furoic Acid

Systems-Level Metabolic Flux Profiling Identifies Fatty Acid Synthesis as a Target for Antiviral Therapy

How Bacterial Pathogens Eat Host Lipids: Implications for the Development of Fatty Acid Synthesis Therapeutics

Targeting Host Lipid Flows: Exploring New Antiviral and Antibiotic Strategies

Characterization of the Inactivation of Rat Fatty Acid Synthase by C75: Inhibition of Partial Reactions and Protection by Substrates

Stearoly-CoA Desaturase 1 Differentiates Early and Advanced Dengue Virus Infections and Determines Virus Particle Infectivity

Stearoyl Coenzyme A Desaturase 1 Is Associated with Hepatitis C Virus Replication Complex and Regulates Viral Replication

Recent Progress in the Discovery and Development of Stearoyl CoA Desaturase Inhibitors

New Cholesterol-Specific Antibodies Remodel HIV-1 Target Cells' Surface and Inhibit Their in Vitro Virus Production

A Phosphatidylserine Receptor Family and Its Implications in Viral Infections

Glycyrrhizic Acid Inhibits Virus Growth and Inactivates Virus Particles

The Broad Anti-Viral Agent Glycyrrhizin Directly Modulates the Fluidity of Plasma Membrane and HIV-1 Envelope

Influence of Glycyrrhizin on Permeability and Elasticity of Cell Membrane: Perspectives for Drugs Delivery

A Broad Antiviral Neutral Glycolipid, Fattiviracin FV-8, Is a Membrane Fluidity Modulator

Cepharanthine Inhibited HIV-1 Cell-Cell Transmission and Cell-Free Infection via Modification of Cell Membrane Fluidity

Inhibition of HIV-1 Entry by the Tricyclic Coumarin GUT-70 through the Modification of Membrane Fluidity

Cholesterol Is Required for Stability and Infectivity of Influenza A and Respiratory Syncytial Viruses

The Anti-Dengue Virus Properties of Statins May Be Associated with Alterations in the Cellular Antiviral Profile Expression

Sphingomyelinase Restricts the Lateral Diffusion of CD4 and Inhibits Human Immunodeficiency Virus Fusion

Involvement of Ceramide in the Propagation of Japanese Encephalitis Virus

Ceramide Enrichment of the Plasma Membrane Induces CD81 Internalization and Inhibits Hepatitis C Virus Entry

Modulation of Host Cell Membrane Fluidity: A Novel Mechanism for Preventing Bacterial Adhesion

Unexpected Antimicrobial Effect of Statins

Antimicrobial Action of Atorvastatin and Rosuvastatin

Statin Decreases Helicobacter Pylori Burden in Macrophages by Promoting

In Vitro and in Vivo Efficacy of Ether Lipid Edelfosine against Leishmania Spp. and SbV-Resistant Parasites

Glycyrrhizic Acid Attenuates Growth of Leishmania Donovani by Depleting Ergosterol Levels

Understanding Bacterial Resistance to Antimicrobial Peptides: From the Surface to Deep Inside

Design and Application of Antimicrobial Peptide Conjugates

Beyond Conventional Antibiotics-New Directions for Combination Products to Combat Biofilm

Small Synthetic Peptides Bioconjugated to Hybrid Gold Nanoparticles Destroy Potentially Deadly Bacteria at Submicromolar Concentrations

Bacterial Membrane Lipids in the Action of Antimicrobial Agents

HIV Entry in Macrophages Is Dependent on Intact Lipid Rafts

Antibacterial and Cytotoxic Effects of Cyclodextrin-Triazole-Titanium Based Nanocomposite

CD-SACE2 Inclusion Compounds: An Effective Treatment for Coronavirus Disease 2019 (COVID-19)

Cyclodextrin Derivatives as Anti-Infectives

Regulation of Lipid Rafts, Angiogenesis and Inflammation by AIBP

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States

Shapira, S.D. A Structure-Informed Atlas of Human-Virus Interactions

Up-Regulation of the ATP-Binding Cassette Transporter A1 Inhibits Hepatitis C Virus Infection

The Dynamin Chemical Inhibitor Dynasore Impairs Cholesterol Trafficking and Sterol-Sensitive Genes Transcription in Human HeLa Cells and Macrophages

Protective Role of the Dynamin Inhibitor Dynasore against the Cholesterol-Dependent Cytolysin of Trueperella Pyogenes

Meneses, P.I. HPV16 and BPV1 Infection Can Be Blocked by the Dynamin Inhibitor Dynasore

HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes

Dynasore Disrupts Trafficking of Herpes Simplex Virus Proteins

Cyclodextrin Promotes Atherosclerosis Regression via Macrophage Reprogramming

Anti-Inflammatory Therapy for COVID-19 Infection: The Case for Colchicine

Vectorized Delivery of α-Galactosylceramide and Tumor Antigen on Filamentous Bacteriophage Fd Induces Protective Immunity by Enhancing Tumor-Specific T Cell Response

Inhibition of HIV Replication by Apolipoprotein A-I Binding Protein Targeting the Lipid Rafts