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Journal of Hazardous Materials Aug 2024Exposure to ozone (O) has been associated with cardiovascular outcomes in humans, yet the underlying mechanisms of the adverse effect remain poorly understood. We aimed...
Exposure to ozone (O) has been associated with cardiovascular outcomes in humans, yet the underlying mechanisms of the adverse effect remain poorly understood. We aimed to investigate the association between O exposure and glycerophospholipid metabolism in healthy young adults. We quantified plasma concentrations of phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) using a UPLC-MS/MS system. Time-weighted personal exposures were calculated to O and co-pollutants over 4 time windows, and we employed orthogonal partial least squares discriminant analysis to discern differences in lipids profiles between high and low O exposure. Linear mixed-effects models and mediation analysis were utilized to estimate the associations between O exposure, lipids, and cardiovascular physiology indicators. Forty-three healthy adults were included in this study, and the mean (SD) time-weighted personal exposures to O was 9.08 (4.06) ppb. With shorter exposure durations, O increases were associated with increasing PC and lysoPC levels; whereas at longer exposure times, the opposite relationship was shown. Furthermore, two specific lipids, namely lysoPC a C26:0 and lysoPC a C17:0, showed significantly positive mediating effects on associations of long-term O exposure with pulse wave velocity and systolic blood pressure, respectively. Alterations in specific lipids may underlie the cardiovascular effects of O exposure.
Topics: Humans; Ozone; Male; Female; Adult; Air Pollutants; Young Adult; Lysophosphatidylcholines; Glycerophospholipids; Environmental Exposure; Phosphatidylcholines
PubMed: 38876019
DOI: 10.1016/j.jhazmat.2024.134870 -
Medicine Jun 2024Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study Observational Study
BACKGROUND
Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a combination of donepezil and choline alfoscerate, slowed cognitive decline in Alzheimer disease. This study aims to replicate the effect by combining donepezil with other nootropics currently used in South Korea.
METHODS
The 119 patients with cognitive decline who were eligible to use donepezil, with an mini-mental state examination (MMSE) score of 26 or less, were assigned to: donepezil alone (DO); donepezil and choline alfoscerate (DN); donepezil and acetyl-l-carnitine (DA); or donepezil and ginkgo biloba extract (DG). Cognitive evaluations such as MMSE, clinical dementia rating, Alzheimer disease assessment scale-cognitive subscale (ADAS-Cog), and Alzheimer disease assessment scale-noncognitive subscale were performed at the 12th and 24th weeks from the baseline time point.
RESULTS
At the 12th week, the MMSE score increased 3.52% in the DN group, whereas it increased by 1.36% in the DO group. In the DA + DG group, it decreased by 2.17%. At the 24th week, the MMSE score showed an increase of 1.07% in the DO group and 1.61% in the DN group, but decreased by 5.71% in the DA + DG group. ADAS-Cog decreased by 0.9% in the DO group, while it improved by 13.9% in the DN group at the 12th week. At the 24th week, ADAS-Cog showed improvement in the DN group by 18.5%, whereas it improved by 9.4% in the DO group. Alzheimer disease assessment scale-noncognitive subscale also revealed better performance in the DN group than in the DO group at the 12th and 24th weeks.
CONCLUSION
Choline alfoscerate exhibits additional cognitive improvement in both cognitive and noncognitive domains, supporting the findings of the ASCOMALVA trial.
Topics: Humans; Donepezil; Male; Female; Aged; Double-Blind Method; Drug Therapy, Combination; Glycerylphosphorylcholine; Nootropic Agents; Ginkgo biloba; Indans; Alzheimer Disease; Piperidines; Plant Extracts; Republic of Korea; Acetylcarnitine; Cognitive Dysfunction; Mental Status and Dementia Tests; Treatment Outcome; Aged, 80 and over; Cognition; Ginkgo Extract
PubMed: 38875437
DOI: 10.1097/MD.0000000000038067 -
Soft Matter Jun 2024Deformation of the cell membrane is well understood from the viewpoint of protein interactions and free energy balance. However, the various dynamic properties of the...
Deformation of the cell membrane is well understood from the viewpoint of protein interactions and free energy balance. However, the various dynamic properties of the membrane, such as lipid packing and hydrophobicity, and their relationship with cell membrane deformation are unknown. Therefore, the deformation of 1,2-dipalmitoyl--3-phosphocholine (DPPC) and oleic acid (OA) giant unilamellar vesicles (GUVs) was induced by heating and cooling cycles, and time-lapse analysis was conducted based on the membrane hydrophobicity and physical parameters of "single-parent" and "daughter" vesicles. Fluorescence ratiometric analysis by simultaneous dual-wavelength detection revealed the variation of different hydrophilic GUVs and enabled inferences of the "daughter" vesicle composition and the "parent" membrane's local composition during deformation; the "daughter" vesicle composition of OA was lower than that of the "parents", and lateral movement of OA was the primary contributor to the formation of the "daughter" vesicles. Thus, our findings and the newly developed methodology, named quantitative membrane property-morphology relation (QmPMR) analysis, would provide new insights into cell deformation and accelerate research on both deformation and its related events, such as budding and birthing.
Topics: Unilamellar Liposomes; Oleic Acid; Hydrophobic and Hydrophilic Interactions; 1,2-Dipalmitoylphosphatidylcholine; Cell Membrane
PubMed: 38873752
DOI: 10.1039/d4sm00253a -
Scientific Reports Jun 2024Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations...
Barth syndrome (BTHS) is a lethal rare genetic disorder, which results in cardiac dysfunction, severe skeletal muscle weakness, immune issues and growth delay. Mutations in the TAFAZZIN gene, which is responsible for the remodeling of the phospholipid cardiolipin (CL), lead to abnormalities in mitochondrial membrane, including alteration of mature CL acyl composition and the presence of monolysocardiolipin (MLCL). The dramatic increase in the MLCL/CL ratio is the hallmark of patients with BTHS, which is associated with mitochondrial bioenergetics dysfunction and altered membrane ultrastructure. There are currently no specific therapies for BTHS. Here, we showed that cardiac mitochondria isolated from TAFAZZIN knockdown (Taz) mice presented abnormal ultrastructural membrane morphology, accumulation of vacuoles, pro-fission conditions and defective mitophagy. Interestingly, we found that in vivo treatment of Taz mice with a CL-targeted small peptide (named SS-31) was able to restore mitochondrial morphology in tafazzin-deficient heart by affecting specific proteins involved in dynamic process and mitophagy. This agrees with our previous data showing an improvement in mitochondrial respiratory efficiency associated with increased supercomplex organization in Taz mice under the same pharmacological treatment. Taken together our findings confirm the beneficial effect of SS-31 in the amelioration of tafazzin-deficient dysfunctional mitochondria in a BTHS animal model.
Topics: Animals; Barth Syndrome; Mitophagy; Disease Models, Animal; Mice; Acyltransferases; Cardiolipins; Mitochondria, Heart; Transcription Factors; Lysophospholipids; Mice, Knockout; Oligopeptides
PubMed: 38871974
DOI: 10.1038/s41598-024-64368-y -
The multifunction effector Vice stimulates macropinocytosis and interferes with the ESCRT machinery.Proceedings of the National Academy of... Jun 2024Intracellular bacterial pathogens divert multiple cellular pathways to establish their niche and persist inside their host. , the causative agent of Q fever, secretes...
Intracellular bacterial pathogens divert multiple cellular pathways to establish their niche and persist inside their host. , the causative agent of Q fever, secretes bacterial effector proteins via its Type 4 secretion system to generate a -containing vacuole (CCV). Manipulation of lipid and protein trafficking by these effectors is essential for bacterial replication and virulence. Here, we have characterized the lipid composition of CCVs and found that the effector Vice interacts with phosphoinositides and membranes enriched in phosphatidylserine and lysobisphosphatidic acid. Remarkably, eukaryotic cells ectopically expressing Vice present compartments that resemble early CCVs in both morphology and composition. We found that the biogenesis of these compartments relies on the double function of Vice. The effector protein initially localizes at the plasma membrane of eukaryotic cells where it triggers the internalization of large vacuoles by macropinocytosis. Then, Vice stabilizes these compartments by perturbing the ESCRT machinery. Collectively, our results reveal that Vice is an essential effector protein capable of hijacking two major cellular pathways to shape the bacterial replicative niche.
Topics: Endosomal Sorting Complexes Required for Transport; Pinocytosis; Bacterial Proteins; Coxiella burnetii; Vacuoles; Humans; HeLa Cells; Cell Membrane; Animals; Phosphatidylinositols
PubMed: 38870060
DOI: 10.1073/pnas.2315481121 -
International Journal of Systematic and... Jun 2024A Gram-stain-negative, aerobic, non-spore-forming, nonmotile, rod-shaped, and yellow-pigmented bacterium, designated strain JXAS1, was isolated from a freshwater sample...
A Gram-stain-negative, aerobic, non-spore-forming, nonmotile, rod-shaped, and yellow-pigmented bacterium, designated strain JXAS1, was isolated from a freshwater sample collected from Poyang Lake in China. Phylogenetic analysis based on 16S rRNA gene sequence revealed that the isolate belonged to the genus , being closest to DSM 6368 (98.61 %). The genome size of strain JXAS1 was 4.66 Mb with DNA G+C content 35.7 mol%. The average nucleotide identity and DNA-DNA hybridization values between strain JXAS1 and its closest relatives were below the threshold values of 95 and 70 %, respectively. The strain contained menaquinone 6 (MK-6) as the predominant menaquinone and the major polar lipids were phosphatidylethanolamine, one unidentified glycolipid, and one unidentified polar lipid. The major fatty acids (>5 %) were iso-C, summed feature 3 (C 7 and/or C 6), C, iso-C 3OH, iso-C 3OH, and summed feature 9 (iso-C 9 and/or 10-methyl C). Based on phylogenetic, genotypic, and phenotypic evidence, the isolated strain represents a new species in the genus , and the name is proposed. The type strain is JXAS1 (=GDMCC 1.1378=KCTC 62719).
Topics: Flavobacterium; Lakes; Phylogeny; China; RNA, Ribosomal, 16S; Base Composition; Fatty Acids; Vitamin K 2; DNA, Bacterial; Bacterial Typing Techniques; Sequence Analysis, DNA; Nucleic Acid Hybridization; Phosphatidylethanolamines; Glycolipids; Phospholipids
PubMed: 38865183
DOI: 10.1099/ijsem.0.006416 -
Nature Communications Jun 2024Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well...
Focal adhesions form liquid-like assemblies around activated integrin receptors at the plasma membrane. How they achieve their flexible properties is not well understood. Here, we use recombinant focal adhesion proteins to reconstitute the core structural machinery in vitro. We observe liquid-liquid phase separation of the core focal adhesion proteins talin and vinculin for a spectrum of conditions and interaction partners. Intriguingly, we show that binding to PI(4,5)P-containing membranes triggers phase separation of these proteins on the membrane surface, which in turn induces the enrichment of integrin in the clusters. We suggest a mechanism by which 2-dimensional biomolecular condensates assemble on membranes from soluble proteins in the cytoplasm: lipid-binding triggers protein activation and thus, liquid-liquid phase separation of these membrane-bound proteins. This could explain how early focal adhesions maintain a structured and force-resistant organization into the cytoplasm, while still being highly dynamic and able to quickly assemble and disassemble.
Topics: Talin; Focal Adhesions; Cell Membrane; Vinculin; Humans; Animals; Phosphatidylinositol 4,5-Diphosphate; Integrins; Cytoplasm; Protein Binding; Phase Separation
PubMed: 38862544
DOI: 10.1038/s41467-024-49222-z -
International Journal of Nanomedicine 2024Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients,...
PURPOSE
Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG-HA and DSPE-PEG-TK-PEG, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration.
METHODS AND RESULTS
PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects.
CONCLUSION
The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.
Topics: Female; Liposomes; Paclitaxel; Ovarian Neoplasms; Diosgenin; Hyaluronic Acid; Cell Line, Tumor; Polyethylene Glycols; Animals; Reactive Oxygen Species; Humans; Apoptosis; Drug Synergism; Cell Proliferation; Cell Movement; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylethanolamines
PubMed: 38859958
DOI: 10.2147/IJN.S455942 -
Analytical Chemistry Jun 2024Lipids are critical modulators of membrane protein structure and function. However, it is challenging to investigate the thermodynamics of protein-lipid interactions...
Lipids are critical modulators of membrane protein structure and function. However, it is challenging to investigate the thermodynamics of protein-lipid interactions because lipids can simultaneously bind membrane proteins at different sites with different specificities. Here, we developed a native mass spectrometry (MS) approach using single and double mutants to measure the relative energetic contributions of specific residues on Aquaporin Z (AqpZ) toward cardiolipin (CL) binding. We first mutated potential lipid-binding residues on AqpZ, and mixed mutant and wild-type proteins together with CL. By using native MS to simultaneously resolve lipid binding to the mutant and wild-type proteins in a single spectrum, we directly determined the relative affinities of CL binding, thereby revealing the relative Gibbs free energy change for lipid binding caused by the mutation. Comparing different mutants revealed that W14 contributes to the tightest CL binding site, with R224 contributing to a lower affinity site. Using double mutant cycling, we investigated the synergy between W14 and R224 sites on CL binding. Overall, this novel native MS approach provides unique insights into the binding of lipids to specific sites on membrane proteins.
Topics: Cardiolipins; Mass Spectrometry; Mutation; Aquaporins; Binding Sites; Protein Binding; Membrane Proteins; Thermodynamics; Models, Molecular; Escherichia coli Proteins
PubMed: 38859611
DOI: 10.1021/acs.analchem.4c01704 -
JCI Insight Jun 2024In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known....
In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.
Topics: Animals; Cadherins; Sphingosine-1-Phosphate Receptors; Mice; Arthritis, Experimental; Antigens, CD; Endothelial Cells; Humans; Arthritis, Rheumatoid; ADAM10 Protein; Amyloid Precursor Protein Secretases; Signal Transduction; Mice, Knockout; Membrane Proteins; Male; Sphingosine; Lysophospholipids; Capillary Permeability; Female
PubMed: 38855867
DOI: 10.1172/jci.insight.171467