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Colloids and Surfaces. B, Biointerfaces Jul 2024Lipid-based drug delivery systems offer the potential to enhance bioavailability, reduce dosing frequency, and improve patient adherence. In aqueous environment,...
Lipid-based drug delivery systems offer the potential to enhance bioavailability, reduce dosing frequency, and improve patient adherence. In aqueous environment, initially dry lipid depots take up water and form liquid crystalline phases. Variation of lipid composition, depot size and hydration-induced phase transitions will plausibly affect the diffusion in and out of the depot. Lipid depots of soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO) mixtures were hydrated for varying time durations in a phosphate-buffered saline (PBS) buffer and then analyzed with Karl Fischer titration, magnetic resonance imaging (MRI) and gravimetrically. Mathematical modeling of the swelling process using diffusion equations, was used to estimate the parameters of diffusion. Both composition of lipid mixture and depot size affect swelling kinetics… The diffusion parameters obtained in Karl Fischer titration and MRI (with temporal and spatial resolution respectively) are in good agreement. Remarkably, the MRI results show a gradient of water content within the depot even after the end of diffusion process. Apparently contradicting the first Fick's law in its classical form, these results find an explanation using the generalized Fick's law that considers the gradient of chemical potential rather than concentration as the driving force of diffusion.
Topics: Phosphatidylcholines; Glycine max; Kinetics; Diffusion; Water; Magnetic Resonance Imaging; Diglycerides
PubMed: 38754200
DOI: 10.1016/j.colsurfb.2024.113955 -
Sphingosine-1-phosphate promotes liver fibrosis in metabolic dysfunction-associated steatohepatitis.PloS One 2024Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive...
AIM
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most prevalent liver diseases and is characterized by steatosis and the accumulation of bioactive lipids. This study aims to understand the specific lipid species responsible for the progression of liver fibrosis in MASH.
METHODS
Changes in bioactive lipid levels were examined in the livers of MASH mice fed a choline-deficient diet (CDD). Additionally, sphingosine kinase (SphK)1 mRNA, which generates sphingosine 1 phosphate (S1P), was examined in the livers of patients with MASH.
RESULTS
CDD induced MASH and liver fibrosis were accompanied by elevated levels of S1P and increased expression of SphK1 in capillarized liver sinusoidal endothelial cells (LSECs) in mice. SphK1 mRNA also increased in the livers of patients with MASH. Treatment of primary cultured mouse hepatic stellate cells (HSCs) with S1P stimulated their activation, which was mitigated by the S1P receptor (S1PR)2 inhibitor, JTE013. The inhibition of S1PR2 or its knockout in mice suppressed liver fibrosis without reducing steatosis or hepatocellular damage.
CONCLUSION
S1P level is increased in MASH livers and contributes to liver fibrosis via S1PR2.
Topics: Animals; Sphingosine; Lysophospholipids; Liver Cirrhosis; Mice; Hepatic Stellate Cells; Phosphotransferases (Alcohol Group Acceptor); Humans; Sphingosine-1-Phosphate Receptors; Fatty Liver; Male; Mice, Knockout; Mice, Inbred C57BL; Liver; Choline Deficiency; Endothelial Cells; Receptors, Lysosphingolipid; Pyrazoles; Pyridines
PubMed: 38753743
DOI: 10.1371/journal.pone.0303296 -
Cell Reports May 2024Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this...
Cardiac dysfunction, an early complication of endotoxemia, is the major cause of death in intensive care units. No specific therapy is available at present for this cardiac dysfunction. Here, we show that the N-terminal gasdermin D (GSDMD-N) initiates mitochondrial apoptotic pore and cardiac dysfunction by directly interacting with cardiolipin oxidized by complex II-generated reactive oxygen species (ROS) during endotoxemia. Caspase-4/11 initiates GSDMD-N pores that are subsequently amplified by the upregulation and activation of NLRP3 inflammation through further generation of ROS. GSDMD-N pores form prior to BAX and VDAC1 apoptotic pores and further incorporate into BAX and VDAC1 oligomers within mitochondria membranes to exacerbate the apoptotic process. Our findings identify oxidized cardiolipin as the definitive target of GSDMD-N in mitochondria of cardiomyocytes during endotoxin-induced myocardial dysfunction (EIMD), and modulation of cardiolipin oxidation could be a therapeutic target early in the disease process to prevent EIMD.
Topics: Cardiolipins; Reactive Oxygen Species; Animals; Endotoxemia; Phosphate-Binding Proteins; Intracellular Signaling Peptides and Proteins; Oxidation-Reduction; Myocytes, Cardiac; Mice; Humans; Mice, Inbred C57BL; Male; Apoptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Mitochondria; Gasdermins
PubMed: 38753484
DOI: 10.1016/j.celrep.2024.114237 -
Langmuir : the ACS Journal of Surfaces... May 2024Diverse collections of lipids self-assemble into domains within biological membranes, and these domains are typically organized in both the transverse and lateral...
Diverse collections of lipids self-assemble into domains within biological membranes, and these domains are typically organized in both the transverse and lateral directions of the membrane. The ability of the membrane to link these domains across the membrane's interior grants cells control over features on the external cellular surface. Numerous hypothesized factors drive the cross-membrane (or transverse) coupling of lipid domains. In this work we seek to isolate these transverse lipid-lipid influences in a simple model system using droplet interface bilayers (DIBs) to better understand the associated mechanics. DIBs enable symmetric and asymmetric combinations of domain-forming lipid mixtures within a model bilayer, and the evolving energetics of the membrane may be tracked using drop-shape analysis. We find that symmetric distributions of domain-forming lipids produce long-lasting, gradual shifts in the DIB membrane energetics that are not observed in asymmetric distributions of the lipids where the domain-forming lipids are only within one leaflet. The approach selected for this work provides experimental measurement of the mismatch penalty associated with antiregistered lipid domains as well as measurements of the influence of rafts on DIB behaviors with suggestions for their future use as a model platform.
Topics: Lipid Bilayers; Membrane Microdomains; Phosphatidylcholines
PubMed: 38753461
DOI: 10.1021/acs.langmuir.4c00958 -
MSphere Jun 2024Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant . In the rare...
UNLABELLED
Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistant . In the rare event of failed daptomycin therapy, the source of resistance is often attributable to mutations directly within the membrane phospholipid biosynthetic pathway of or in the regulatory systems that control cell envelope response and membrane homeostasis. Here we describe the structural changes to the cell envelope in a daptomycin-resistant isolate of strain N315 that has acquired mutations in the genes most commonly reported associated with daptomycin resistance: , , and . In addition to the decreased phosphatidylglycerol (PG) levels that are the hallmark of daptomycin resistance, the mutant with high-level daptomycin resistance had increased branched-chain fatty acids (BCFAs) in its membrane lipids, increased membrane fluidity, and increased cell wall thickness. However, the successful utilization of isotope-labeled straight-chain fatty acids (SCFAs) in lipid synthesis suggested that the aberrant BCFA:SCFA ratio arose from upstream alteration in fatty acid synthesis rather than a structural preference in PgsA. Transcriptomics studies revealed that expression of pyruvate dehydrogenase () was suppressed in the daptomycin-resistant isolate, which is known to increase BCFA levels. While complementation with an additional copy of had no effect, complementation of the mutation resulted in increased PG formation, reduction in cell wall thickness, restoration of normal BCFA levels, and increased daptomycin susceptibility. Collectively, these results demonstrate that contributes to daptomycin resistance through its influence on membrane fluidity and cell wall thickness, in addition to phosphatidylglycerol levels.
IMPORTANCE
The cationic lipopeptide antimicrobial daptomycin has become an essential tool for combating infections with that display reduced susceptibility to β-lactams or vancomycin. Since daptomycin's activity is based on interaction with the negatively charged membrane of , routes to daptomycin-resistance occur through mutations in the lipid biosynthetic pathway surrounding phosphatidylglycerols and the regulatory systems that control cell envelope homeostasis. Therefore, there are many avenues to achieve daptomycin resistance and several different, and sometimes contradictory, phenotypes of daptomycin-resistant , including both increased and decreased cell wall thickness and membrane fluidity. This study is significant because it demonstrates the unexpected influence of a lipid biosynthesis gene, , on membrane fluidity and cell wall thickness in with high-level daptomycin resistance.
Topics: Daptomycin; Cell Wall; Membrane Fluidity; Anti-Bacterial Agents; Drug Resistance, Bacterial; Staphylococcus aureus; Microbial Sensitivity Tests; Bacterial Proteins; Cell Membrane; Mutation; Phosphatidylglycerols
PubMed: 38752757
DOI: 10.1128/msphere.00115-24 -
Life Science Alliance Aug 2024Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in , encoding the first step in the synthesis...
Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in , encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in mice there is a failure of the α7β1 integrin complex that is specific to affected muscle. We observed that in hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of .
Topics: Animals; Mice; Vinculin; Mice, Knockout; Muscular Dystrophies; Integrins; Choline Kinase; Sarcolemma; Humans; Focal Adhesions; Cell Membrane; Actinin; Muscle, Skeletal; Phosphatidylinositol 4,5-Diphosphate; Actins; Disease Models, Animal
PubMed: 38749543
DOI: 10.26508/lsa.202301956 -
Journal of Colloid and Interface Science Sep 2024Lamellarity and shape are important factors in the formation of vesicles and determine their role in biological systems and pharmaceutical applications. Cardiolipin (CL)...
Lamellarity and shape are important factors in the formation of vesicles and determine their role in biological systems and pharmaceutical applications. Cardiolipin (CL) is a major lipid in many biological membranes and exerts a great influence on their structural organization due to its particular structure and physico-chemical properties. Here, we used small-angle X-ray and neutron scattering to study the effects of CL with different acyl chain lengths and saturations (CL, CL, CL) on vesicle morphology and lamellarity in membrane models containing mixtures of phosphatidylcholine and phosphatidylethanolamine with different acyl chain lengths and saturations (C and C ). Measurements were performed in the presence of Phosphate Buffer Saline (PBS), at 37°C, to better reflect physiological conditions, which resulted in strong effects on vesicle morphology, depending on the type and amount of CL used. The presence of small quantities of CL (from 2.5%) reduced inter-membrane correlations and increased perturbation of the membrane, an effect which is enhanced in the presence of matched shorter saturated acyl chains, and mainly unilamellar vesicles (ULV) are formed. In extruded vesicles, employed for SANS experiments, flattened vesicles are observed partly due to the hypertonic effect of PBS, but also influenced by the type of CL added. Our experimental data from SAXS and SANS revealed a strong dependence on CL content in shaping the membrane microstructure, with an apparent optimum in the PC:CL mixture in terms of promoting reduced correlations, preferred curvature and elongation. However, the use of PBS caused distinct differences from previously published studies in water in terms of vesicle shape, and highlights the need to investigate vesicle formation under physiological conditions in order to be able to draw conclusions about membrane formation in biological systems.
Topics: Cardiolipins; Liposomes; Scattering, Small Angle; Phosphatidylcholines; Phosphatidylethanolamines; X-Ray Diffraction; Particle Size; Neutron Diffraction
PubMed: 38749223
DOI: 10.1016/j.jcis.2024.04.211 -
Biochemical and Biophysical Research... Jul 2024Aging is a complex, degenerative process associated with various metabolic abnormalities. Ginsenosides (GS) is the main active components of Panax ginseng, which has...
A novel mechanism of major ginsenosides from Panax ginseng against multiple organ aging in middle-aged mice: Phosphatidylcholine-myo-inositol metabolism based on metabolomic analysis.
Aging is a complex, degenerative process associated with various metabolic abnormalities. Ginsenosides (GS) is the main active components of Panax ginseng, which has anti-aging effects and improves metabolism. However, the anti-aging effect and the mechanism of GS in middle-aged mice has not been elucidated. In this study, GS after 3-month treatment significantly improved the grip strength, fatigue resistance, cognitive indices, and cardiac function of 15-month-old mice. Meanwhile, GS treatment reduced the fat content and obviously inhibited histone H2AX phosphorylation at Ser 139 (γ-H2AX), a marker of DNA damage in major organs, especially in the heart and liver. Further, the correlation analysis of serum metabolomics combined with aging phenotype suggested that myo-inositol (MI) upregulated by GS was positively correlated with left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), the main indicators of cardiac function. More importantly, liver tissue metabolomic analysis showed that GS increased MI content by promoting the synthesis pathway from phosphatidylcholine (PC) to MI for the inhibition of liver aging. Finally, we proved that MI reduced the percentage of senescence-associated β-galactosidase staining, γ-H2AX immunofluorescence staining, p21 expression, and the production of reactive oxygen species in HO-induced cardiomyocytes. These results suggest that GS can enhance multiple organ functions, especially cardiac function for promoting the healthspan of aging mice, which is mediated by the conversion of PC to MI in the liver and the increase of MI level in the serum. Our study might provide new insights into the potential mechanisms of ginsenosides for prolonging the healthspan of natural aging mice.
Topics: Animals; Panax; Ginsenosides; Aging; Phosphatidylcholines; Metabolomics; Mice; Male; Inositol; Liver; Mice, Inbred C57BL
PubMed: 38749089
DOI: 10.1016/j.bbrc.2024.150027 -
Biochimica Et Biophysica Acta.... Jun 2024The interaction between chiral drugs and biomimetic membranes is of interest in biophysical research and biotechnological applications. There is a belief that the...
The interaction between chiral drugs and biomimetic membranes is of interest in biophysical research and biotechnological applications. There is a belief that the membrane composition, particularly the presence of cholesterol, could play a pivotal role in determining enantiospecific effects of pharmaceuticals. Our study explores this topic focusing on the interaction of ibuprofen enantiomers (S- and R-IBP) with cholesterol-containing model membranes. The effects of S- and R-IBP at 20 mol% on bilayer mixtures of dipalmitoylphosphatidylcholine (DPPC) with 0, 10, 20 and 50 mol% cholesterol were investigated using circular dichroism and spin-label electron spin resonance. Morphological changes due to IBP enantiomers were studied with atomic force microscopy on supported cholesterol-containing DPPC monolayers. The results reveal that IBP isoforms significantly and equally interact with pure DPPC lipid assemblies. Cholesterol content, besides modifying the structure and the morphology of the membranes, triggers the drug enantioselectivity at 10 and 20 mol%, with the enantiomers differently adsorbing on membranes and perturbing them. The spectroscopic and the microscopic data indicate that IBP stereospecificity is markedly reduced at equimolar content of Chol mixed with DPPC. This study provides new insights into the role of cholesterol in modulating enantiospecific effects of IBP in lipid membranes.
Topics: Ibuprofen; Cholesterol; Stereoisomerism; 1,2-Dipalmitoylphosphatidylcholine; Lipid Bilayers; Circular Dichroism; Microscopy, Atomic Force; Biomimetics; Membranes, Artificial
PubMed: 38744417
DOI: 10.1016/j.bbamem.2024.184334 -
The Journal of Physical Chemistry... May 2024Nanoplastic-lipid interaction is vital to understanding the nanoscale mechanism of plastic adsorption and aggregation on a lipid membrane surface. However, a...
Nanoplastic-lipid interaction is vital to understanding the nanoscale mechanism of plastic adsorption and aggregation on a lipid membrane surface. However, a single-particle mechanistic picture of the nanoplastic transport process on a lipid surface remains unclear. Here, we report a salt-dependent non-Gaussian transport mechanism of polystyrene particles on a supported 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer surface. Particle stickiness on the POPC surface increases with salt concentration, where the particles stay longer at the surface and diffuse to shorter distances. Additionally, a non-Gaussian diffusion state dominates the transport process at high salt concentrations. Our current study provides insight into the transport mechanism of polystyrene (PS) particles on supported lipid membranes, which is essential to understanding fundamental questions regarding the adsorption mechanisms of nanoplastics on lipid surfaces.
Topics: Lipid Bilayers; Phosphatidylcholines; Polystyrenes; Sodium Chloride; Surface Properties; Adsorption; Diffusion
PubMed: 38743920
DOI: 10.1021/acs.jpclett.4c00806