-
Scientific Reports May 2024Filamentous fungi are eukaryotic microorganisms that differentiate into diverse cellular forms. Recent research demonstrated that phospholipid homeostasis is crucial for...
Filamentous fungi are eukaryotic microorganisms that differentiate into diverse cellular forms. Recent research demonstrated that phospholipid homeostasis is crucial for the morphogenesis of filamentous fungi. However, phospholipids involved in the morphological regulation are yet to be systematically analyzed. In this study, we artificially controlled the amount of phosphatidylcholine (PC), a primary membrane lipid in many eukaryotes, in a filamentous fungus Aspergillus oryzae, by deleting the genes involved in PC synthesis or by repressing their expression. Under the condition where only a small amount of PC was synthesized, A. oryzae hardly formed aerial hyphae, the basic structures for asexual development. In contrast, hyphae were formed on the surface or in the interior of agar media (we collectively called substrate hyphae) under the same conditions. Furthermore, we demonstrated that supplying sufficient choline to the media led to the formation of aerial hyphae from the substrate hyphae. We suggested that acyl chains in PC were shorter in the substrate hyphae than in the aerial hyphae by utilizing the strain in which intracellular PC levels were controlled. Our findings suggested that the PC levels regulate hyphal elongation and differentiation processes in A. oryzae and that phospholipid composition varied depending on the hyphal types.
Topics: Hyphae; Phosphatidylcholines; Aspergillus oryzae; Choline; Gene Expression Regulation, Fungal; Fungal Proteins
PubMed: 38778216
DOI: 10.1038/s41598-024-62580-4 -
Current Opinion in Cell Biology Jun 2024Phosphoinositide 3-kinases regulate many cellular functions, including migration, growth, proliferation, and cell survival. Early studies equated the inhibition of Class... (Review)
Review
Phosphoinositide 3-kinases regulate many cellular functions, including migration, growth, proliferation, and cell survival. Early studies equated the inhibition of Class I PI3Ks with loss of; phosphatidylinositol 3,4,5-trisphosphate (PIP3), but over time, it was realised that these; treatments also depleted phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2). In recent years, the; use of better tools and an improved understanding of its metabolism have allowed for the; identification of specific roles of PI(3,4)P2. This includes the production of PI(3,4)P2 and the; activation of its effector Akt2 in response to growth factor signalling. In contrast, a lysosomal pool of PI(3,4)P2 is a negative regulator of mTORC1 during growth factor deprivation. A growing body of literature also demonstrates that PI(3,4)P2 controls many dynamic plasmalemmal processes. The significance of PI(3,4)P in cell biology is increasingly evident.
Topics: Humans; Animals; Phosphatidylinositol Phosphates; Signal Transduction; Phosphatidylinositol 3-Kinases; Lysosomes
PubMed: 38776601
DOI: 10.1016/j.ceb.2024.102372 -
Journal of Proteome Research Jun 2024The metabolites and microbiota in tongue coating display distinct characteristics in certain digestive disorders, yet their relationship with colorectal cancer (CRC)...
The metabolites and microbiota in tongue coating display distinct characteristics in certain digestive disorders, yet their relationship with colorectal cancer (CRC) remains unexplored. Here, we employed liquid chromatography coupled with tandem mass spectrometry to analyze the lipid composition of tongue coating using a nontargeted approach in 30 individuals with colorectal adenomas (CRA), 32 with CRC, and 30 healthy controls (HC). We identified 21 tongue coating lipids that effectively distinguished CRC from HC (AUC = 0.89), and 9 lipids that differentiated CRC from CRA (AUC = 0.9). Furthermore, we observed significant alterations in the tongue coating lipid composition in the CRC group compared to HC/CRA groups. As the adenoma-cancer sequence progressed, there was an increase in long-chain unsaturated triglycerides (TG) levels and a decrease in phosphatidylethanolamine plasmalogen (PE-P) levels. Furthermore, we noted a positive correlation between -acyl ornithine (NAOrn), sphingomyelin (SM), and ceramide phosphoethanolamine (PE-Cer), potentially produced by members of the phylum. The levels of inflammatory lipid metabolite 12-HETE showed a decreasing trend with colorectal tumor progression, indicating the potential involvement of tongue coating microbiota and tumor immune regulation in early CRC development. Our findings highlight the potential utility of tongue coating lipid analysis as a noninvasive tool for CRC diagnosis.
Topics: Humans; Colorectal Neoplasms; Lipidomics; Male; Female; Tongue; Middle Aged; Tandem Mass Spectrometry; Phosphatidylethanolamines; Aged; Chromatography, Liquid; Lipids; Triglycerides; Adenoma; Sphingomyelins; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Plasmalogens; Case-Control Studies; Ethanolamines; Ceramides; Adult
PubMed: 38775738
DOI: 10.1021/acs.jproteome.4c00063 -
Cell Reports May 2024Motor proteins transport diverse membrane-bound vesicles along microtubules inside cells. How specific lipids, particularly rare lipids, on the membrane recruit and...
Motor proteins transport diverse membrane-bound vesicles along microtubules inside cells. How specific lipids, particularly rare lipids, on the membrane recruit and activate motors is poorly understood. To address this, we prepare spherical supported lipid bilayers (SSLBs) consisting of a latex bead enclosed within a membrane of desired lipid composition. SSLBs containing phosphatidic acid recruit dynein when incubated with Dictyostelium fractions but kinesin-1 when incubated with rat brain fractions. These SSLBs allow controlled biophysical investigation of membrane-bound motors along with their regulators at the single-cargo level in vitro. Optical trapping of single SSLBs reveals that motor-specific inhibitors can "lock" a motor to a microtubule, explaining the paradoxical arrest of overall cargo transport by such inhibitors. Increasing their size causes SSLBs to reverse direction more frequently, relevant to how large cargoes may navigate inside cells. These studies are relevant to understand how unidirectional or bidirectional motion of vesicles might be generated.
PubMed: 38771696
DOI: 10.1016/j.celrep.2024.114252 -
Communications Biology May 2024Glycerophosphocholine (GPC) is an important precursor for intracellular choline supply in phosphatidylcholine (PC) metabolism. GDE5/Gpcpd1 hydrolyzes GPC into choline...
Glycerophosphocholine (GPC) is an important precursor for intracellular choline supply in phosphatidylcholine (PC) metabolism. GDE5/Gpcpd1 hydrolyzes GPC into choline and glycerol 3-phosphate; this study aimed to elucidate its physiological function in vivo. Heterozygous whole-body GDE5-deficient mice reveal a significant GPC accumulation across tissues, while homozygous whole-body knockout results in embryonic lethality. Skeletal muscle-specific GDE5 deletion (Gde5 skKO) exhibits reduced passive force and improved fatigue resistance in electrically stimulated gastrocnemius muscles in vivo. GDE5 deficiency also results in higher glycolytic metabolites and glycogen levels, and glycerophospholipids alteration, including reduced levels of phospholipids that bind polyunsaturated fatty acids (PUFAs), such as DHA. Interestingly, this PC fatty acid compositional change is similar to that observed in skeletal muscles of denervated and Duchenne muscular dystrophy mouse models. These are accompanied by decrease of GDE5 expression, suggesting a regulatory role of GDE5 activity for glycerophospholipid profiles. Furthermore, a DHA-rich diet enhances contractile force and lowers fatigue resistance, suggesting a functional relationship between PC fatty acid composition and muscle function. Finally, skinned fiber experiments show that GDE5 loss increases the probability of the ryanodine receptor opening and lowers the maximum Ca-activated force. Collectively, GDE5 activity plays roles in PC and glucose/glycogen metabolism in skeletal muscle.
Topics: Animals; Muscle, Skeletal; Mice; Phosphatidylcholines; Mice, Knockout; Muscle Contraction; Male; Mice, Inbred C57BL; Phosphoric Diester Hydrolases
PubMed: 38769369
DOI: 10.1038/s42003-024-06298-z -
International Journal of Pharmaceutics Jun 2024Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation...
Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation challenge is the poor aqueous solubility of CBD. This study aimed to produce inhalable CBD powders with enhanced solubility and characterise their solid-state properties. CBD was spray freeze dried with mannitol or trehalose dihydrate with and without dipalmitoylphosphatidylcholine (DPPC). All four powders had acceptable yields at > 70 % with porous and spherical particles. The two crystalline mannitol powders contained less residual solvent than both amorphous trehalose ones. The addition of DPPC did not affect the crystallinity and residual solvent level of the powders. Instead, DPPC made the particles more porous, decreased the particle size from 19-23 µm to 11-13 µm, and increased CBD solubility from 0.36 µg/mL to over 2 µg/mL. The two DPPC powders were dispersed from a low resistance RS01 inhaler, showing acceptable aerosol performance with emitted fractions at 91-93 % and fine particle fractions < 5 µm at 34-43 %. These formulations can be used as a platform to deliver CBD and other cannabinoids by inhalation.
Topics: 1,2-Dipalmitoylphosphatidylcholine; Cannabidiol; Administration, Inhalation; Solubility; Freeze Drying; Particle Size; Powders; Aerosols; Mannitol; Trehalose; Excipients; Porosity; Chemistry, Pharmaceutical
PubMed: 38762165
DOI: 10.1016/j.ijpharm.2024.124235 -
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