Lipid-rich Membrane Research Articles

De novo lipid synthesis and polarized prenylation drive cell invasion through basement membrane.

To breach the basement membrane, cells in development and cancer use large, transient, specialized lipid-rich membrane protrusions. Using live imaging, endogenous protein tagging, and cell-specific RNAi during Caenorhabditis elegans anchor cell (AC) invasion, we demonstrate that the lipogenic SREBP transcription factor SBP-1 drives the expression of the fatty acid synthesis enzymes POD-2 and FASN-1 prior to invasion. We show that phospholipid-producing LPIN-1 and sphingomyelin synthase SMS-1, which use fatty acids as substrates, produce lysosome stores that build the AC's invasive protrusion, and that SMS-1 also promotes protrusion localization of the lipid raft partitioning ZMP-1 matrix metalloproteinase. Finally, we discover that HMG-CoA reductase HMGR-1, which generates isoprenoids for prenylation, localizes to the ER and enriches in peroxisomes at the AC invasive front, and that the final transmembrane prenylation enzyme, ICMT-1, localizes to endoplasmic reticulum exit sites that dynamically polarize to deliver prenylated GTPases for protrusion formation. Together, these results reveal a collaboration between lipogenesis and a polarized lipid prenylation system that drives invasive protrusion formation.

Penetration of oils into hair.

The objective of this work was to understand how triglyceride plant oils can deliver strength and softness benefits to hair by their penetration. These plant oils are complex mixtures of TAGs, so the initial studies performed were with pure TAGs and then these data compared to plant oils and their measured TAG compositions. LC-MS was used to identify the di and triglycerides in coconut oil, Camellia oleifera oil and safflower seed oil. Penetration of these plant oils and pure individual triglycerides was measured by a differential extraction method. Cross-sections of oils treated with 13C-labelled triolein were studied by NanoSIMS to visualize location of triglyceride inside hair. Fatigue strength was measured using constant stress to generate a survival distribution. Models of the lipid-rich cell membrane complex (CMC) were created with the equimolar ratio of 18-methyl-eicosanoic acid (MEAS), palmitic acid (C16:0) and oleic acid (C18:1). Penetration of the individual pure TAGs was confirmed for all chain lengths and degree of unsaturation tested with higher penetration for shorter chain lengths and unsaturated fatty acids. Detailed compositional analysis of selected plant oils showed a wide variety of TAGs and penetration was also demonstrated for these oils. NanoSIMS and modelling confirmed these TAGs are penetrating the lipid-rich CMC of hair and are interacting with the fatty acids that make up the CMC. All plant oils delivered a fatigue strength improvement by penetration into the CMC and it is proposed that these oils prevent formation and/or propagation of flaws in the CMC network that leads to breakage. Many plant oils with a wide range of triglyceride compositions can penetrate into hair and NanoSIMS data confirmed these oils partition into the lipid-rich cell membrane complex. Penetration studies of individual TAGs shown to be present in these oils confirmed TAGs of varying chain length can penetrate and there is a correlation between increased penetration efficacy and shorter chain lengths and presence of unsaturation in the fatty acid chains. All the oils studied delivered single fibre fatigue strength benefits.

Abstract WMP83: The Pentose Phosphate Pathway is Crucial for Combating Heme-Induced Ferroptosis in Red Blood Cells After ICH

Intracerebral hemorrhage (ICH) occurs upon blood vessel rupture, allowing blood into brain tissue. Red blood cells (RBCs) make up 99%+ of blood cells. Brain-trapped RBCs undergo phagocytosis; however, many RBCs lyse prior to being phagocytosed due to their abundance. RBC lysis releases hemoglobin and toxic heme, driving oxidative stress especially in lipid-rich plasma membranes (PM), causing tissue damage and ferroptosis. Few studies have explored RBC fate in ICH, but unraveling the factors governing RBC lysis may yield ICH therapies.In in vitro human and murine RBC cultures, we observed RBCs are exquisitely sensitive to heme-induced death with increased oxidized fatty acids (FAs), a ferroptosis marker (Fig 1A-B). The ferroptosis inducer Erastin validated RBC susceptibility to ferroptosis (Fig 1C). Heme-induced cell death was countered by β-mercaptoethanol (β-ME), N-acetylcysteine (NAC), ferrostatin-1 (Fer-1) and Vitamin E (Vit. E), ferroptosis inhibitors, confirming RBC death was due to ferroptosis (Fig 1D-G). Heme and Erastin induced RBC ferroptosis differs from eryptosis, RBC specific programmed cell death, as it isn't Ca++ dependent (Fig1H&I). Unlike other cells, RBCs solely rely on the Pentose Phosphate Pathway (PPP) for NADPH production for oxidation defense. PPP inhibition with Dehydroisoandrosterone (DHEA) and treatment with ThioNa, an NADP+ synthesis inhibitor, both heightened heme-induced RBC ferroptosis (Fig 1J-L). These data support the PPP's role against heme-driven ferroptosis. Heme induced RBC ferroptosis may trigger a chain reaction of RBC lysis and ongoing heme release. Notably, 400 million people face G6PD deficiency, the rate-limiting PPP enzyme, leading to NADPH depletion in RBCs with enhanced susceptibility to oxidation. Hence, in addition to identifying the PPP in RBCs resistance to heme toxicity, our findings could aid in identifying a population that is particularly vulnerable to the devastating effects of ICH.

Abstract TMP83: Macrophage Metabolic Reprograming to Face Ferroptosis After ICH

Intracerebral Hemorrhage (ICH) is a destructive neurovascular disease with no efficient treatment. Trapped Red Blood Cells (RBCs) in the brain lyse releasing toxic heme from hemoglobin. Heme, a lipophilic molecule with iron, triggers severe oxidative stress, particularly to lipid-rich cell plasma membranes (PM), causing cell death via ferroptosis. Macrophages are specialized in hematoma phagocytosis; their survival determines hematoma detoxification in the brain. Using in vitro murine macrophage cultures treated with heme, we noted heme induced cell death (Fig 1A), along with heightened oxidized fatty acids (FAs), a marker of ferroptosis (Fig 1B). Heme-triggered cell death was countered by the ferroptosis inhibitors ferrostatin-1 (Fer-1), NAC, β-ME and Deferoxamine (DFO) (Fig 1C-F), which confirm that heme induces ferroptosis in macrophages. Macrophages may shift metabolism to the Pentose Phosphate Pathway (PPP) in the presence of heme to promotes NADPH synthesis, vital for heme degradation and oxidation defense. Dehydroisoandrosterone (DHEA), a potent PPP inhibitor, worsened heme-induced ferroptosis (Fig 1 G&H). This underscores the PPP's vital role against heme-driven ferroptosis. Ferroptosis involves PM oxidation and loss of integrity, causing cell death. Heme induced rapid extracellular ATP release (Fig I). Lysosomes contain abundant ATP, thus we hypothesized that ATP release triggers by heme is the result of PM repair by lysosomal exocytosis/endocytosis. Using metabolomics, we found that heme induced accumulation of membrane components like phospholipids, sphingolipids, and cholesterol (Fig J-L), all which require NADPH for synthesis. This suggests PPP aids NADPH production, aiding lysosomal synthesis for PM repair. Overall, the findings support a critical role for the PPP in macrophage resistance to ferroptosis in the presence of heme and suggest a possible new therapeutic target for macrophage survival after ICH.

Carriers for hydrophobic drug molecules: lipid-coated hollow mesoporous silica particles, and the influence of shape and size on encapsulation efficiency.

Hydrophobic drugs, while designed to interact with specific receptors or enzymes located in lipid-rich cell membranes, often face challenges of limited bioavailability and insufficient circulation time due to their insolubility in aqueous environments. One plausible pathway to increase their blood circulation time is to load these drugs into biocompatible and hydrophilic carriers to enhance their uptake. In this study, mesoporous silica (mSiO2) nanocarriers of various morphologies (including cubes, capsules, and spheres) were synthesized. These nanocarriers were then surface-functionalized with alkyl chain hydrocarbons, specifically octadecyl-trimethoxysilane, (OCH3)3Si(CH2)17CH3, to render them hydrophobic. The resulting nanocarriers (((OCH3)3Si(CH2)17CH3)@mSiO2) showed up to 80% uptake for hydrophobic drugs. However, a significant drawback was observed as most of the drugs were prone to uncontrollable release within 6 h. This challenge of premature drug release was successfully mitigated by effectively sealing the drug-loaded nanocarriers with a pH-sensitive lipid overlayer. The lipid-coated nanocarriers prolonged drug containment and sustained release up to 72 h, compared to 6 h for uncoated nanocarriers, thereby facilitating longer blood circulation times. Moreover, the shape and size of nanocarriers were found to influence both drug entrapment capacity and release behavior with cubic forms exhibiting superior loading capacity due to higher surface area and porosity. Additionally, it was observed that the molecular weight and chemical structure of the drug molecules played a crucial role in determining their uptake and release profiles. Furthermore, the influence of different morphologies of nanocarriers on cell uptake and cytotoxicity in immune cells was elucidated. These findings underscore the importance of nanocarrier morphology and drug properties to enhance loading capacities and controlled release profiles, for designing drug delivery systems tailored for hydrophobic drugs.

Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures.

Combined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribute to neurocognitive dysfunction as the lipid-rich myelin membrane of oligodendrocytes is essential for efficient nerve conduction. Because of the importance of lipids to proper myelination, we examined the regulation of lipid synthesis in oligodendrocyte cultures exposed to the integrase strand transfer inhibitor elvitegravir (EVG), which is administered to persons with HIV as part of their initial regimen. We show that protein levels of genes involved in the fatty acid pathway were reduced, which correlated with greatly diminished de novo levels of fatty acid synthesis. In addition, major regulators of cellular lipid metabolism, the sterol regulatory element-binding proteins (SREBP) 1 and 2, were strikingly altered following exposure to EVG. Impaired oligodendrocyte differentiation manifested as a marked reduction in mature oligodendrocytes. Interestingly, most of these deleterious effects could be prevented by adding serum albumin, a clinically approved neuroprotectant. These new findings, together with our previous study, strengthen the possibility that antiretroviral therapy, at least partially through lipid dysregulation, may contribute to the persistence of white matter changes observed in persons with HIV and that some antiretrovirals may be preferable as life-long therapy.

The Roles of Caloric Restriction Mimetics in Central Nervous System Demyelination and Remyelination.

The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes. Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this Review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.

RIT1 deficiency alters cerebral lipid metabolism and reduces white matter tract oligodendrocytes and conduction velocities

Oligodendrocytes (OLs) generate lipid-rich myelin membranes that wrap axons to enable efficient transmission of electrical impulses. Using a RIT1 knockout mouse model and in situ high-resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) coupled with MS-based lipidomic analysis to determine the contribution of RIT1 to lipid homeostasis. Here, we report that RIT1 loss is associated with altered lipid levels in the central nervous system (CNS), including myelin-associated lipids within the corpus callosum (CC). Perturbed lipid metabolism was correlated with reduced numbers of OLs, but increased numbers of GFAP+ glia, in the CC, but not in grey matter. This was accompanied by reduced myelin protein expression and axonal conduction deficits. Behavioral analyses revealed significant changes in voluntary locomotor activity and anxiety-like behavior in RIT1KO mice. Together, these data reveal an unexpected role for RIT1 in the regulation of cerebral lipid metabolism, which coincide with altered white matter tract oligodendrocyte levels, reduced axonal conduction velocity, and behavioral abnormalities in the CNS.

P82: Platelet Exogenous Lipid Uptake: A Step Toward Lipid Membrane Mechanoceuticals

Background: Mechanical circulatory support (MCS) remains limited by bleeding and clotting adverse events driven by altered platelet function related to supraphysiologic shear exposure. As the primary target of platelet shear exposure is the lipid-rich plasma membrane, in prior work we demonstrated that organic solvents altering membrane properties limit SMPA while preserving platelet function to avoid bleeding. These chemical agents limiting mechanical (shear) activation have been termed “mechanoceuticals.” Natural lipids exhibit membrane altering properties similar to solvents, yet avoid the risk of toxicity, are safe for human use and offer potential therapeutic translation. As a first step here we investigated whether lipids could be taken up and incorporated into the platelet membrane. Methods: Two distinct methods were utilized - fluorescence microscopy and flow cytometry. Gel-filtered platelets (GFP) were prepared from aspirin/NSAID-free human volunteers. Platelet uptake of three differing lipids were tested: 1. cholesterol, 2. Palmitic acid (16:0 – a saturated medium chain fatty acid) and 3. Oleic acid (18:1 – partially unsaturated fatty acid). GFP were stained with Nile Red (to allow platelet visualization, fluoresces red) and aliquots incubated with one of the three lipids (30 minutes at 37.) pre-tagged with nitrobenzoxadiazole (NBD – fluoresces green). GFP was imaged via fluorescence microscopy (1000X) using red and green filters successively to visualized platelets (red), platelets with lipid uptake (green), and to confirm co-registration (green and red overlap). GFP were also incubated with NBD-tagged lipids, followed by CD-41a antibody for platelet detection and analyzed via flow cytometry. Results: Platelets were readily stained and detected via Nile Red fluorescent imaging. All lipids tested appeared to be taken up by platelets with clear incorporation in their membrane. Overlap of imaging revealed clear registration of “platelet-lipid” images (green) with platelets alone (red), with evident co-registration confirming uptake and ruling out micelle artifact. Lipids alone did not reveal detectable particle imaging (see Figure). Flow Cytometry similarly demonstrated overlap of fluorescent lipid signals with those of anti-platelet antibody (CD41-a) confirming lipid uptake by platelets. Conclusion: Platelets appear to readily uptake lipids. Both saturated and unsaturated fatty acids, as well as cholesterol are incorporated into the platelet membrane with reasonable time exposure. As these differing lipids have a range of membrane-modulating properties, such as altering fluidity and stiffness, they offer promise as potential mechanoceutical agents. As next steps, studies are now ongoing to examine the cell mechanobiological effects of these lipids and their ability to modulate shear-mediated alteration of platelet function.Figure 1. Fluorescence microscopy imaging of 100000u/uL platelets stained with Nile Red upon incubation with NBD- Cholesterol, NBD-16:0 (Palmitic acid), and NBD-18:1 (Oleic acid) lipids each at 4uM concentrations for 30 minutes at 37ο C. Magnification ×1000. Scale bar =4 μm.

In vivo imaging of MmpL transporters reveals distinct subcellular locations for export of mycolic acids and non-essential trehalose polyphleates in the mycobacterial outer membrane

The mycobacterial cell envelope consists of a typical plasma membrane, surrounded by a complex cell wall and a lipid-rich outer membrane. The biogenesis of this multilayer structure is a tightly regulated process requiring the coordinated synthesis and assembly of all its constituents. Mycobacteria grow by polar extension and recent studies showed that cell envelope incorporation of mycolic acids, the major constituent of the cell wall and outer membrane, is coordinated with peptidoglycan biosynthesis at the cell poles. However, there is no information regarding the dynamics of incorporation of other families of outer membrane lipids during cell elongation and division. Here, we establish that the translocation of non-essential trehalose polyphleates (TPP) occurs at different subcellular locations than that of the essential mycolic acids. Using fluorescence microscopy approaches, we investigated the subcellular localization of MmpL3 and MmpL10, respectively involved in the export of mycolic acids and TPP, in growing cells and their colocalization with Wag31, a protein playing a critical role in regulating peptidoglycan biosynthesis in mycobacteria. We found that MmpL3, like Wag31, displays polar localization and preferential accumulation at the old pole whereas MmpL10 is more homogenously distributed in the plasma membrane and slightly accumulates at the new pole. These results led us to propose a model in which insertion of TPP and mycolic acids into the mycomembrane is spatially uncoupled.

The Impact of Antimicrobial Peptides on the Acinetobacter baumannii Inner Membrane Is Modulated by Lipid Polyunsaturation.

The Gram-negative pathogen Acinetobacter baumannii is a primary contributor to nosocomial multi-drug-resistant (MDR) infections. To combat the rise of MDR infections, novel features of A. baumannii need to be considered for the development of new treatment options. One such feature is the preferential scavenging of exogenous lipids, including host-derived polyunsaturated fatty acids (PUFAs), for membrane phospholipid synthesis. These alterations in membrane composition impact both the lipid chemistry and the membrane biophysical properties. In this work we examine how antimicrobial peptides (AMPs) interact with the inner membranes of A. baumannii in the presence and absence of polyunsaturated phospholipids. Using coarse-grained molecular dynamics simulations of complex A. baumannii inner membrane models derived from lipidomes of bacteria grown in the presence and absence of PUFAs, we examine the impact of the adsorption of four prototypical AMPs (CAMEL, LL-37, pexiganan, and magainin-2) on the membrane biophysical properties. Our simulations reveal that the impact of AMP adsorption on the membrane biophysical properties was dependent on both the membrane composition and the specific AMP involved. Both lipid headgroup charge and tail unsaturation played important roles in driving the interactions that occurred both within the membrane and between the membrane and AMPs. The changes to the membrane biophysical properties also showed a complex relationship with the AMP's physical properties, such as AMP charge, chain length, and charge-to-mass ratio. Cumulatively, this work highlights the importance of studying AMPs using a complex membrane environment and provides insights into the mechanistic action of AMPs in polyunsaturated lipid-rich bacterial membranes.

Recent Trends in Phytosome Nanocarriers for Improved Bioavailability and Uptake of Herbal Drugs

Phytopharmaceuticals or herbal drugs have a significant therapeutic impact on healthcare systems. Though herbal extracts and their active constituents show excellent pharmacological in vitro effects, they still have indigent in vivo biological effects because of their considerable molecular weight and low lipid solubility, leading to low systemic availability. Phytosome is a novel approach for overcoming the drawbacks of conventional delivery methods of herbal actives. The phospholipids, mainly phosphatidylcholine, form a bond with herbal extracts or actives, forming a herb-lipid complex. The encapsulation of herbal actives with phospholipid allows an effective tool for the delivery to the affected area with enhanced pharmacological effect. Moreover, the amphiphilic nature of the phospholipid provides a good hydrophilic-lipophilic balance, thereby improving a better dissolution profile in the lipid-rich membranes of the gastrointestinal tract. This review focuses on the various phytosome nanocarriers to improve herbal medication bioavailability and uptake—recent trends in their industrial applicability, and applications in clinical management for various diseases, including other challenges.

Cell reprogramming for oligodendrocytes: A review of protocols and their applications to disease modeling and cell-based remyelination therapies.

Oligodendrocytes are a type of glial cells that produce a lipid-rich membrane called myelin. Myelin assembles into a sheath and lines neuronal axons in the brain and spinal cord to insulate them. This not only increases the speed and efficiency of nerve signal transduction but also protects the axons from damage and degradation, which could trigger neuronal cell death. Demyelination, which is caused by a loss of myelin and oligodendrocytes, is a prominent feature of many neurological conditions, including Multiple sclerosis (MS), spinal cord injuries (SCI), and leukodystrophies. Demyelination is followed by a time of remyelination mediated by the recruitment of endogenous oligodendrocyte precursor cells, their migration to the injury site, and differentiation into myelin-producing oligodendrocytes. Unfortunately, endogenous remyelination is not sufficient to overcome demyelination, which explains why there are to date no regenerative-based treatments for MS, SCI, or leukodystrophies. To better understand the role of oligodendrocytes and develop cell-based remyelination therapies, human oligodendrocytes have been derived from somatic cells using cell reprogramming. This review will detail the different cell reprogramming methods that have been developed to generate human oligodendrocytes and their applications to disease modeling and cell-based remyelination therapies. Recent developments in the field have seen the derivation of brain organoids from pluripotent stem cells, and protocols have been devised to incorporate oligodendrocytes within the organoids, which will also be reviewed.

Myelin protein zero - the structural foundation behind peripheral compact myelin.

Schwann cells are the myelinating glia of the peripheral nervous system (PNS). During PNS development, Schwann cell precursors differentiate into mature Schwann cells after the radial sorting of axons and form myelin around selected axonal segments. This multilayered, highly lipid-rich and insulative membrane structure significantly accelerates nerve impulse propagation, which is a pre-requisite for the efficient function of the PNS. During this differentiation process, protein zero (P0), a single-pass transmembrane protein, is expressed in high amounts. P0 is the most abundant PNS myelin protein, at up to 50% of total protein, and its accumulation in membranes eventually forms stable compact myelin. Failure to do so, like in the case of mutated or truncated protein, results in non-compacted myelin and demyelination. This subsequently causes incurable peripheral neuropathies, such as Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS), where CMT alone afflicts nearly 3 million people globally. To understand the compaction and maturation of PNS myelin, and the molecular etiology of disease, uncovering the structure-function relationships of P0 are of great importance. We demonstrate the molecular foundation of P0-mediated membrane stacking using a hybrid structural biology approach: on the extracellular side, immunoglobulin (Ig)-like domains form a zipper-like assembly of apposing protein monomers, whereas on the cytoplasmic side, the short, positively charged P0 tail (P0ct) glues membranes together. P0ct undergoes a substantial folding event during membrane binding, and we provide rationale to why membrane stacking is affected in diseases through functional in vitro mutagenesis studies. Additionally, we speculate on how post-translational modifications in P0ct help P0 locate to its target compartments, without inducing premature membrane stacking. Our results shed light on the essential role of P0 in during myelin maturation, and why other proteins fail to replace P0 when its function is compromised.

A Comprehensive Review of Therapeutic Approaches Available for the Treatment of Dermatitis.

Dermatitis or eczema is a prevalent skin disorder worldwide and is also very common as a pediatric inflammatory skin disorder. Its succession gets worse with the multiple comorbidities which exhibit mechanisms that are poorly understood. Its management further becomes a challenge due to the limited effective treatment options available. However, the Novel Drug Delivery Systems (NDDS) along with new targeting strategies can easily bypass the issues associated with dermatitis management. If we compare the active constituents against phytoconstituents effective against dermatitis then phytoconstituents can be perceived to be more safe and gentle. Administration of NDDS of plant extract or actives displays improved absorption behavior, which helps them to permeate through lipid-rich biological membrane leading to increased bioavailability. The newer efficient discoveries related to eczema can face various exploitations. This can be intervened by the subjection of patent rights, which not only safeguard the novel works of individual(s) but also give them the opportunity to share details of their inventions with people globally. The present review focuses on the available research about the use of nanoformulations in the topical delivery. It further elaborates the use of different animal models as the basis to characterize the different features of dermatitis. The review also highlights the recent nanoformulations which have the ability to amplify the delivery of active agents through their incorporation in transfersomes, ethosomes, niosomes or phytosomes, etc.

Poly(lactic acid) nanofibers containing phosphorylcholine grafts for transdermal drug delivery systems

The continuous and prolonged releases of chemotherapeutic drugs are required for successful treatment in cancer treatment. The project focused on a new material design to meet this requirement. We developed a constant and sustained release system and investigated the release profiles of Paclitaxel (PTX). Polylactic acid (PLA) nanofiber surface was grafted with poly (methacryloyloxyethyl phosphorylcholine) (PMPC) by the UV-induced grafting method. The morphological structure of the PLA nanofibers did not change with an increase in the MPC content. PMPC blocks contribute to the solubility of PTX, which shows low resolution. When the amount of MPC is 5%, the PTX loading efficiency increased two times compared with PLA nanofiber. The nanofiber mats exhibited an initial fast release during the first 3 h. Endothelial cells were cultured on nanofiber mats to investigate whether this material was toxic or not. The mats showed good biocompatibility with HUVEC. Thus, it was confirmed that nanofiber mats would not be toxic when releasing drugs during in vivo use. We think that PMPC facilitates the pass of drugs through the lipid-rich biological membrane and so anticancer drugs can be delivered to direct tumor sites.

Phytosomes - An emerging approach for effective management of Dermatological Disorder

The word ”Phyto” means plant, and also sometimes, it can be signified as cell- like. The development of phytosomes produces a little cell by itself, by which the active ingredient of the herbal extracts is protected from the intestinal secretions and instinctive bacteria destruction. The introduction of phyto- somes into herbal formulation is very recent and useful because they have advanced bioavailability, and they are better absorbed. Also, they consume this enhanced ability to cross lipid-rich bio membranes to finally reach the blood. Phytosomes can also be defined as complex chemical mixtures which are formulated by countering more than one mole synthetic or natural phos- pholipids phosphatidyl ethanolamine or phosphatidylserines with the one mole of another component. There are various plants materials which can be merged in the process of phytosomes, such as several herbal extracts includ- ing quercetin, grape seed, Rhein, neem, green tea, aloe vera, marigold and ginseng. The bioavailability of phytosomes further as linked to conventional herbal extracts because it has enhanced capability to penetrate the lipid bio membrane to finally reach the systemic blood circulation. Phytosomes has been categorized as a novel line for herbal drug delivery. Various conven- tional dosage forms such as gels and creams remained expressed using these constituents, but they appeared to be a better dermatological effect. Hence, phytosomes were formulated by binding phosphatidylcholine (acts as a trans- porter and protect the skin) and herbal extracts. They consist of a phospho- lipid molecular structure which includes two fat-soluble tails and a water- soluble head, and because of its dual solubility, it was absorbed better and was also used for the treatment of skin carcinomas, antiaging and skin disorders.

Unravelling structural organization of individual α-Synuclein oligomers grown in the presence of phospholipids

Parkinson’s disease (PD) is a severe neurological disorder that affects more than 1 million people in the U.S. alone. A hallmark of PD is the formation of intracellular α-synuclein (α-Syn) protein aggregates called Lewy bodies (LBs). Although this protein does not have a particular localization in the central neural system, α-Syn aggregates are primarily found in certain areas of the midbrain, hypothalamus, and thalamus. Microscopic analysis of LBs reveals fragments of lipidrich membranes, organelles, and vesicles.

Metabolically-incorporated deuterium in myelin localized by neutron diffraction and identified by mass spectrometry.

Myelin is a natural and dynamic multilamellar membrane structure that continues to be of significant biological and neurological interest, especially with respect to its biosynthesis and assembly during its normal formation, maintenance, and pathological breakdown. To explore the usefulness of neutron diffraction in the structural analysis of myelin, we investigated the use of in vivo labeling by metabolically incorporating non-toxic levels of deuterium (2H; D) via drinking water into a pregnant dam (D-dam) and her developing embryos. All of the mice were sacrificed when the pups (D-pups) were 55 days old. Myelinated sciatic nerves were dissected, fixed in glutaraldehyde and examined by neutron diffraction. Parallel samples that were unfixed (trigeminal nerves) were frozen for mass spectrometry (MS). The diffraction patterns of the nerves from deuterium-fed mice (D-mice) vs. the controls (H-mice) had major differences in the intensities of the Bragg peaks but no appreciable differences in myelin periodicity. Neutron scattering density profiles showed an appreciable increase in density at the center of the lipid-rich membrane bilayer. This increase was greater in D-pups than in D-dam, and its localization was consistent with deuteration of lipid hydrocarbon, which predominates over transmembrane protein in myelin. MS analysis of the lipids isolated from the trigeminal nerves demonstrated that in the pups the percentage of lipids that had one or more deuterium atoms was uniformly high across lipid species (97.6% ​± ​2.0%), whereas in the mother the lipids were substantially less deuterated (60.6% ​± ​26.4%) with levels varying among lipid species and subspecies. The mass distribution pattern of deuterium-containing isotopologues indicated the fraction (in %) of each lipid (sub-)species having one or more deuteriums incorporated: in the D-pups, the pattern was always bell-shaped, and the average number of D atoms ranged from a low of ∼4 in fatty acid to a high of ∼9 in cerebroside. By contrast, in D-dam most lipids had more complex, overlapping distributions that were weighted toward a lower average number of deuteriums, which ranged from a low of ∼3–4 in fatty acid and in one species of sulfatide to a high of 6–7 in cerebroside and sphingomyelin. The consistently high level of deuteration in D-pups can be attributed to their de novo lipogenesis during gestation and rapid, postnatal myelination. The widely varying levels of deuteration in D-dam, by contrast, likely depends on the relative metabolic stability of the particular lipid species during myelin maintenance. Our current findings demonstrate that stably-incorporated D label can be detected and localized using neutron diffraction in a complex tissue such as myelin; and moreover, that MS can be used to screen a broad range of deuterated lipid species to monitor differential rates of lipid turnover. In addition to helping to develop a comprehensive understanding of the de novo synthesis and turnover of specific lipids in normal and abnormal myelin, our results also suggest application to studies on myelin proteins (which constitute only 20–30% by dry mass of the myelin, vs. 70–80% for lipid), as well as more broadly to the molecular constituents of other biological tissues.

The Akt-mTOR Pathway Drives Myelin Sheath Growth by Regulating Cap-Dependent Translation.

In the vertebrate CNS, oligodendrocytes produce myelin, a specialized membrane, to insulate and support axons. Individual oligodendrocytes wrap multiple axons with myelin sheaths of variable lengths and thicknesses. Myelin grows at the distal ends of oligodendrocyte processes, and multiple lines of work have provided evidence that mRNAs and RNA binding proteins localize to myelin, together supporting a model where local translation controls myelin sheath growth. What signal transduction mechanisms could control this? One strong candidate is the Akt-mTOR pathway, a major cellular signaling hub that coordinates transcription, translation, metabolism, and cytoskeletal organization. Here, using zebrafish as a model system, we found that Akt-mTOR signaling promotes myelin sheath growth and stability during development. Through cell-specific manipulations to oligodendrocytes, we show that the Akt-mTOR pathway drives cap-dependent translation to promote myelination and that restoration of cap-dependent translation is sufficient to rescue myelin deficits in mTOR loss-of-function animals. Moreover, an mTOR-dependent translational regulator was phosphorylated and colocalized with mRNA encoding a canonically myelin-translated protein in vivo, and bioinformatic investigation revealed numerous putative translational targets in the myelin transcriptome. Together, these data raise the possibility that Akt-mTOR signaling in nascent myelin sheaths promotes sheath growth via translation of myelin-resident mRNAs during development.SIGNIFICANCE STATEMENT In the brain and spinal cord, oligodendrocytes extend processes that tightly wrap axons with myelin, a protein- and lipid-rich membrane that increases electrical impulses and provides trophic support. Myelin membrane grows dramatically following initial axon wrapping in a process that demands protein and lipid synthesis. How protein and lipid synthesis is coordinated with the need for myelin to be generated in certain locations remains unknown. Our study reveals that the Akt-mTOR signaling pathway promotes myelin sheath growth by regulating protein translation. Because we found translational regulators of the Akt-mTOR pathway in myelin, our data raise the possibility that Akt-mTOR activity regulates translation in myelin sheaths to deliver myelin on demand to the places it is needed.