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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 -
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 -
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 -
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 -
Metabolism: Clinical and Experimental Jun 2024Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG...
BACKGROUND AND AIM
Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments.
METHODS
We generated a transgenic mouse model overexpressing human DGKδ2 under the myosin light chain promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG mice and wild-type littermates fed chow or high-fat diet (HFD). Mice were also provided free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes.
RESULTS
DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance and increased skeletal muscle glycogen content. DGKδ TG mice were protected against HFD-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulated the beneficial effects of exercise on metabolic outcomes. DGKδ overexpression and exercise had a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle revealed common gene ontology signatures of exercise and DGKδ overexpression that were related to lipid storage, extracellular matrix, and glycerophospholipids biosynthesis pathways.
CONCLUSION
Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.
PubMed: 38843995
DOI: 10.1016/j.metabol.2024.155939 -
Life Science Alliance Aug 2024Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT)...
Lipid composition is conserved within sub-cellular compartments to maintain cell function. Lipidomic analyses of liver, muscle, white and brown adipose tissue (BAT) mitochondria revealed substantial differences in their glycerophospholipid (GPL) and free cholesterol (FC) contents. The GPL to FC ratio was 50-fold higher in brown than white adipose tissue mitochondria. Their purity was verified by comparison of proteomes with ER and mitochondria-associated membranes. A lipid signature containing PC and FC, calculated from the lipidomic profiles, allowed differentiation of mitochondria from BAT of mice housed at different temperatures. Elevating FC in BAT mitochondria prevented uncoupling protein (UCP) 1 function, whereas increasing GPL boosted it. Similarly, overexpression facilitating mitochondrial FC import inhibited UCP1 function in primary brown adipocytes, whereas a knockdown promoted it. We conclude that the mitochondrial GPL/FC ratio is key for BAT function and propose that targeting it might be a promising strategy to promote UCP1 activity.
Topics: Animals; Uncoupling Protein 1; Mice; Adipose Tissue, Brown; Cholesterol; Mitochondria; Lipidomics; Organ Specificity; Mice, Inbred C57BL; Adipose Tissue, White; Glycerophospholipids; Male; Lipid Metabolism
PubMed: 38843936
DOI: 10.26508/lsa.202402828 -
Hepatology Communications Jun 2024Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether...
BACKGROUND
Abnormal phospholipid metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) development and progression. We aimed to clarify whether genetic variants of phospholipid metabolism modify these relationships.
METHODS
This case-control study consecutively recruited 600 patients who underwent MRI-based proton density fat fraction examination (240 participants with serum metabonomics analysis, 128 biopsy-proven cases) as 3 groups: healthy control, nonobese MASLD, and obese MASLD, (n = 200 cases each). Ten variants of phospholipid metabolism-related genes [phospholipase A2 Group VII rs1805018, rs76863441, rs1421378, and rs1051931; phospholipase A2 receptor 1 (PLA2R1) rs35771982, rs3828323, and rs3749117; paraoxonase-1 rs662 and rs854560; and ceramide synthase 4 (CERS4) rs17160348)] were genotyped using SNaPshot.
RESULTS
The T-allele of CERS4 rs17160348 was associated with a higher risk of both obese and nonobese MASLD (OR: 1.95, 95% CI: 1.20-3.15; OR: 1.76, 95% CI: 1.08-2.86, respectively). PLA2R1 rs35771982-allele is a risk factor for nonobese MASLD (OR: 1.66, 95% CI: 1.11-1.24), moderate-to-severe steatosis (OR: 3.24, 95% CI: 1.96-6.22), and steatohepatitis (OR: 2.61, 95% CI: 1.15-3.87), while the paraoxonase-1 rs854560 T-allele (OR: 0.50, 95% CI: 0.26-0.97) and PLA2R1 rs3749117 C-allele (OR: 1.70, 95% CI: 1.14-2.52) are closely related to obese MASLD. After adjusting for sphingomyelin level, the effect of the PLA2R1 rs35771982CC allele on MASLD was attenuated. Furthermore, similar effects on the association between the CERS4 rs17160348 C allele and MASLD were observed for phosphatidylcholine, phosphatidic acid, sphingomyelin, and phosphatidylinositol.
CONCLUSIONS
The mutations in PLA2R1 rs35771982 and CERS4 rs17160348 presented detrimental impact on the risk of occurrence and disease severity in nonobese MASLD through altered phospholipid metabolism.
Topics: Humans; Male; Female; Middle Aged; Case-Control Studies; Genotype; Receptors, Phospholipase A2; Phospholipids; Adult; Obesity; Polymorphism, Single Nucleotide; Fatty Liver; Genetic Predisposition to Disease
PubMed: 38836837
DOI: 10.1097/HC9.0000000000000388 -
BMC Pulmonary Medicine Jun 2024sphingosine-1-phosphate (S1P), a naturally occurring sphingolipid, has been involved in pulmonary interstitial remodeling signaling. However, no study has examined its... (Observational Study)
Observational Study
BACKGROUND
sphingosine-1-phosphate (S1P), a naturally occurring sphingolipid, has been involved in pulmonary interstitial remodeling signaling. However, no study has examined its clinical merits for interstitial lung disease (ILD). This study aimed to investigate the serum level of S1P in ILD patients and its clinical correlation with the severity of disease in the two main types of ILDs: the IPF and the CTD-ILD patients.
METHODS
This retrospective observational pilot study included 67 ILD patients and 26 healthy controls. These patients were stratified into the IPF group (35) and the CTD-ILD group (32). The severity of ILD was evaluated through pulmonary function indicators and the length of hospital stay.
RESULTS
Serum S1P level was statistically higher in ILD patients than in health control (p = 0.002), while the Serum S1P levels in CTD-ILD and IPF patients were comparable. Serum S1P level further showed statistically negative correlation with pulmonary function indexes (TLC% pred, FVC% pred and FEV1% pred) and positive correlation with length of hospital stay (r = -0.38, p = 0.04; r = -0.41, p = 0.02, r = -0.37, p = 0.04; r = 0.42, p = 0.02, respectively) in CTD-ILD patients, although serum S1P level was not significantly correlated with inflammatory indexes. The IPF patients failed to exhibit a significant correlation of serum S1P level with pulmonary function and length of hospital stay.
CONCLUSIONS
Serum S1P level might be a clinically useful biomarker in evaluating the severity of CTD-ILD patients rather than IPF patients.
Topics: Humans; Male; Female; Lung Diseases, Interstitial; Sphingosine; Biomarkers; Lysophospholipids; Middle Aged; Retrospective Studies; Aged; Severity of Illness Index; Pilot Projects; Respiratory Function Tests; Lung; Case-Control Studies; Length of Stay
PubMed: 38835000
DOI: 10.1186/s12890-024-03081-y -
ELife Jun 2024During macroautophagy, cytoplasmic constituents are engulfed by autophagosomes. Lysosomes fuse with closed autophagosomes but not with unclosed intermediate structures....
During macroautophagy, cytoplasmic constituents are engulfed by autophagosomes. Lysosomes fuse with closed autophagosomes but not with unclosed intermediate structures. This is achieved in part by the late recruitment of the autophagosomal SNARE syntaxin 17 (STX17) to mature autophagosomes. However, how STX17 recognizes autophagosome maturation is not known. Here, we show that this temporally regulated recruitment of STX17 depends on the positively charged C-terminal region of STX17. Consistent with this finding, mature autophagosomes are more negatively charged compared with unclosed intermediate structures. This electrostatic maturation of autophagosomes is likely driven by the accumulation of phosphatidylinositol 4-phosphate (PI4P) in the autophagosomal membrane. Accordingly, dephosphorylation of autophagosomal PI4P prevents the association of STX17 to autophagosomes. Furthermore, molecular dynamics simulations support PI4P-dependent membrane insertion of the transmembrane helices of STX17. Based on these findings, we propose a model in which STX17 recruitment to mature autophagosomes is temporally regulated by a PI4P-driven change in the surface charge of autophagosomes.
Topics: Qa-SNARE Proteins; Autophagosomes; Phosphatidylinositol Phosphates; Humans; Molecular Dynamics Simulation; Autophagy
PubMed: 38831696
DOI: 10.7554/eLife.92189