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Frontiers in Oncology 2024Multiple myeloma (MM), a malignant disease of plasma cells originating in the bone marrow, is influenced significantly by genetic factors. Although plasma liposomes have...
BACKGROUND
Multiple myeloma (MM), a malignant disease of plasma cells originating in the bone marrow, is influenced significantly by genetic factors. Although plasma liposomes have been linked to MM, the nature of their potential causal relationship remains to be elucidated. This study aims to explore this relationship using Mendelian randomization (MR) analysis.
METHODS
Liposome-associated genetic instrumental variables (IVs) were identified from plasma lipidomics data of 7,174 Finnish individuals within a Genome-Wide Association Study (GWAS) pooled database. A MM pooled dataset was sourced from a GWAS meta-analysis encompassing 150,797 individuals, including 598 MM patients and 218,194 controls. These IVs underwent MR analysis, adhering to strict criteria for correlation, independence, and the exclusion of confounders. The inverse variance weighted (IVW) method, MR-Egger method, weighted median (WM) method, and simple median were utilized for MR analysis assessment, alongside Cochran's Q test, MR-Egger intercept, MR-Pleiotropy Residual Sum and Outlier (MR-RESSO) method, and leave-one-out analysis for evaluating heterogeneity, multiplicity, and instrumental bias.
RESULTS
The study identified 88 significant, independent single nucleotide polymorphisms (SNPs) as IVs for MR analysis, each with an F-statistic value above 10, indicating robustness against weak instrument bias. IVW analysis revealed associations between six plasma liposome components and MM risk (p < 0.05). Phosphatidylinositol (16:0_18:1) serum levels (odds ratio [OR] = 1.769, 95% confidence interval [CI]: 1.132-2.763, p = 0.012) and triacylglycerol (56:4) levels (p = 0.026, OR = 1.417, 95% CI: 1.042-1.926) were positively correlated with the risk of multiple myeloma development. Phosphatidylethanolamine (18:0_20:4) (p = 0.004, 95% CI: 0.621-0.916, OR = 0.754), phosphatidylcholine (18:2_20:4) (p = 0.004, OR = 0.680, 95% CI: 0.519-0.889), sterol ester (27:1/18:3) levels (p = 0.013, OR = 0.677, 95% CI: 0.498-0.922), and phosphatidylcholine (O-18:2_20:4) levels (OR = 0.710, 95% CI: 0.517-0.913, p = 0.033) were negatively associated with the risk of developing multiple myeloma. The Cochran's Q test did not detect statistical method heterogeneity, nor did the MR-RESSO test or the MR-Egger intercept detect horizontal pleiotropy; leave-one-out analyses confirmed the absence of bias from individual SNPs.
CONCLUSIONS
Our findings suggest a complex relationship between plasma liposome components and MM risk. Elevated serum levels of triacylglycerol and phosphatidylinositol are positively associated with MM risk, while certain phospholipids and sterol esters offer a protective effect. This study provides valuable insights into the clinical relevance of liposomes in the pathology of multiple myeloma.
PubMed: 38933448
DOI: 10.3389/fonc.2024.1404744 -
Pharmaceutics Jun 2024Glycerophospholipids have hydrophobic and hydrophilic moieties. Previous studies suggest that phospholipids with different moieties have different effects on rodent...
Glycerophospholipids have hydrophobic and hydrophilic moieties. Previous studies suggest that phospholipids with different moieties have different effects on rodent behavior; however, the relationship between chemical structures and behavioral effects remains unclear. To clarify the functions of phospholipid moieties, we injected male rats with phospholipids with different moieties and conducted behavioral tests. Exploratory activity was reduced by phosphatidylethanolamine (PE)(18:0/22:6) but not PE(18:0/18:0) or PE(18:0/20:4). Conversely, exploratory activity was increased by plasmanyl PE(16:0/22:6), which harbors an alkyl-ether linkage, but not by phosphatidylcholine (PC)(16:0/22:6) or plasmanyl PC(16:0/22:6). Docosahexaenoic acid (DHA)(22:6) and an alkyl-ether linkage in PE were thus postulated to be involved in exploratory activity. Anxiety-like behavior was reduced by plasmenyl PC(18:0/20:4), which harbors a vinyl-ether linkage, but not by PC(18:0/20:4) or plasmanyl PC(18:0/20:4), suggesting the anxiolytic effects of vinyl-ether linkage. The activation of social interaction was suppressed by PE(18:0/18:0), PE(18:0/22:6), PC(16:0/22:6), plasmanyl PE(16:0/22:6), and plasmanyl PC(16:0/22:6) but not by PE(18:0/20:4), plasmenyl PE(18:0/20:4), or plasmanyl PC(18:0/22:6). DHA may suppress social interaction, whereas arachidonic acid(20:4) or a combination of alkyl-ether linkage and stearic acid(18:0) may restore social deficits. Our findings indicate the characteristic effects of different phospholipid moieties on rat behavior, and may help to elucidate patterns between chemical structures and their effects.
PubMed: 38931883
DOI: 10.3390/pharmaceutics16060762 -
BMC Microbiology Jun 2024Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8)...
Multi-drug-resistant Staphylococcus aureus infections necessitate novel antibiotic development. D-3263, a transient receptor potential melastatin member 8 (TRPM8) agonist, has potential antineoplastic properties. Here, we reported the antibacterial and antibiofilm activities of D-3263. Minimum inhibitory concentrations (MICs) against S. aureus, Enterococcus faecalis and E. faecium were ≤ 50 µM. D-3263 exhibited bactericidal effects against clinical methicillin-resistant S. aureus (MRSA) and E. faecalis strains at 4× MIC. Subinhibitory D-3263 concentrations effectively inhibited S. aureus and E. faecalis biofilms, with higher concentrations also clearing mature biofilms. Proteomic analysis revealed differential expression of 29 proteins under 1/2 × MIC D-3263, influencing amino acid biosynthesis and carbohydrate metabolism. Additionally, D-3263 enhanced membrane permeability of S. aureus and E. faecalis. Bacterial membrane phospholipids phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CL) dose-dependently increased D-3263 MICs. Overall, our data suggested that D-3263 exhibited potent antibacterial and antibiofilm activities against S. aureus by targeting the cell membrane.
Topics: Biofilms; Anti-Bacterial Agents; Microbial Sensitivity Tests; Staphylococcus aureus; Enterococcus faecalis; Methicillin-Resistant Staphylococcus aureus; Bacterial Proteins; Proteomics; Humans; Cell Membrane; Cell Membrane Permeability
PubMed: 38926818
DOI: 10.1186/s12866-024-03377-3 -
Cell Reports Jun 2024Polymyxins are often the only effective antibiotics against the "Critical" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii...
Polymyxins are often the only effective antibiotics against the "Critical" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by "undetectable" polymyxin-dependent A. baumannii.
PubMed: 38923457
DOI: 10.1016/j.celrep.2024.114410 -
Membranes May 2024The Danshen terpenoid cryptotanshinone (CPT) is gaining enormous interest in light of its various outstanding biological activities. Among those, CPT has been shown to...
The Danshen terpenoid cryptotanshinone (CPT) is gaining enormous interest in light of its various outstanding biological activities. Among those, CPT has been shown to interact with cell membranes and, for instance, to have antibacterial activity. Several works have shown that CPT alone, or in combination with other drugs, can effectively act as an antibiotic against various infectious bacteria. Some authors have related the mechanism underlying this action to CPT-membrane interaction. This work shows that CPT readily partitions into phosphatidylcholine membranes, but there is a limiting capacity of accommodation of ca. 1 mol CPT to 3 mol phospholipid. The addition of CPT to unilamellar liposomes composed of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) causes membrane permeabilization, as shown by fluorescent probe leakage. This process has been kinetically studied, as well as its modulation by incorporation of phosphatidylethanolamine or phosphatidylglycerol, as a model for pathogenic cell membranes. The thermotropic behavior of 1,2-dimyristoylphosphatidylcholine (DMPC) model membranes is weakly affected by CPT, but the terpenoid causes significant dehydration of the polar region of the bilayer and weak disordering of the acyl chain palisade, as observed in Fourier-transform infrared spectroscopy (FTIR) results. Small-angle X-ray scattering (SAXS) shows that CPT increases DMPC bilayer thickness, which could be due to localization near the phospholipid/water interface. Molecular dynamics (MD) simulations show that the lateral diffusion coefficient of the phospholipid increases with the presence of CPT. CPT extends from the polar head region to the center of the bilayer, being centered between the carbonyl groups and the unsaturated region of the POPC, where there is greater overlap. Interestingly, the free energy profiles of a water molecule crossing the lipid membrane show that the POPC membrane becomes more permeable in the presence of CPT. In summary, our results show that CPT perturbs the physicochemical properties of the phospholipid membrane and compromises its barrier function, which could be of relevance to explain part of its antimicrobial or anticancer activities.
PubMed: 38921485
DOI: 10.3390/membranes14060118 -
Frontiers in Molecular Biosciences 2024Numerous strategies have been proposed to minimize obesity-associated health effects, among which phytocannabinoids appear to be effective and safe compounds. In...
Numerous strategies have been proposed to minimize obesity-associated health effects, among which phytocannabinoids appear to be effective and safe compounds. In particular, cannabigerol (CBG) emerges as a potent modulator of the composition of membrane phospholipids (PLs), which plays a critical role in the development of insulin resistance. Therefore, here we consider the role of CBG treatment on the composition of PLs fraction with particular emphasis on phospholipid subclasses (e.g., phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI)) in the red gastrocnemius muscle of Wistar rats fed the standard or high-fat, high-sucrose (HFHS) diet. The intramuscular PLs content was determined by gas-liquid chromatography and based on the composition of individual FAs, we assessed the stearoyl-CoA desaturase 1 (SCD1) index as well as the activity of n-3 and n-6 polyunsaturated fatty acids (PUFAs) pathways. Expression of various proteins engaged in the inflammatory pathway, FAs elongation, and desaturation processes was measured using Western blotting. Our research has demonstrated the important association of obesity with alterations in the composition of muscular PLs, which was significantly improved by CBG supplementation, enriching the lipid pools in n-3 PUFAs and decreasing the content of arachidonic acid (AA), which in turn influenced the activity of PUFAs pathways in various PLs subclasses. CBG also inhibited the local inflammation development and profoundly reduced the SCD1 activity. Collectively, restoring the PLs homeostasis of the myocyte membrane by CBG indicates its new potential medical application in the treatment of obesity-related metabolic disorders.
PubMed: 38919749
DOI: 10.3389/fmolb.2024.1401558 -
Scientific Reports Jun 2024Retinoblastoma is one of the most common ocular malignancies in children. Bmi-1, a member of the Polycomb group family of transcriptional repressors, is expressed in a...
Retinoblastoma is one of the most common ocular malignancies in children. Bmi-1, a member of the Polycomb group family of transcriptional repressors, is expressed in a variety of tumors. The purpose of our study was to explore the role of Bmi-1 in retinoblastoma. RT-qPCR and western blot were used for calculating the mRNA and protein levels of Bmi-1 and RKIP. MTT, Wound healing and Transwell assays were performed to measure the proliferation, migration and invasion in retinoblastoma cells. Cell apoptosis was detected by flow cytometry. The volume and mass of transplanted tumors were detected in nude mice. Bmi-1 was over expressed, and RKIP was low expressed in retinoblastoma cells. Bmi-1 promoted cell proliferation, migration and invasion and suppressed cell apoptosis of Y79 and SO-RB50 cells. Downregulation of Bmi-1 and overexpression of RKIP inhibited cell proliferation, migration and invasion, and increased cell apoptosis. The functions of Bmi-1 knockdown on retinoblastoma cells were blocked by RKIP knockdown, but promoted by RKIP. Down-regulated Bmi-1 inhibited xenograft tumor growth, and RKIP exacerbated this inhibitory effect. Bmi-1 served as a potential therapeutic target for improving the efficacy of clinical treatment in retinoblastoma. All the findings revealed the functions of Bmi-1/RKIP axis in retinoblastoma tumorigenesis.
Topics: Humans; Retinoblastoma; Polycomb Repressive Complex 1; Cell Proliferation; Apoptosis; Cell Movement; Animals; Cell Line, Tumor; Mice; Neoplasm Invasiveness; Mice, Nude; Phosphatidylethanolamine Binding Protein; Gene Expression Regulation, Neoplastic; Retinal Neoplasms
PubMed: 38914697
DOI: 10.1038/s41598-024-65011-6 -
Heliyon Jun 2024Renal calculi (RC) represent a prevalent disease of the urinary system characterized by a high incidence rate. The traditional clinical diagnosis of RC emphasizes...
Renal calculi (RC) represent a prevalent disease of the urinary system characterized by a high incidence rate. The traditional clinical diagnosis of RC emphasizes imaging and stone composition analysis. However, the significance of metabolic status in RC diagnosis and prevention remains unclear. This study aimed to investigate serum metabolites in RC patients to identify those associated with RC and to develop a metabolite-based diagnostic model. We employed nontargeted metabolomics utilizing ultra-performance liquid chromatography‒mass spectrometry (UPLC‒MS) to compare serum metabolites between RC patients and healthy controls. Our findings demonstrated significant disparities in serum metabolites, particularly in fatty acids and glycerophospholipids, between the two groups. Notably, the glycerophospholipid (GP) metabolic pathway in RC patients was significantly disrupted. Logistic regression models using differentially abundant metabolites revealed that elevated levels of 2-butyl-4-methyl phenol and reduced levels of phosphatidylethanolamine (P-16:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)) had the most substantial effect on RC risk. Overall, our study indicates that RC induces notable alterations in serum metabolites and that the diagnostic model based on these metabolites effectively distinguishes RC. This research offers promising insights and directions for further diagnostic and mechanistic studies on RC.
PubMed: 38912451
DOI: 10.1016/j.heliyon.2024.e32482 -
Lipids in Health and Disease Jun 2024Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals....
BACKGROUND
Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway.
METHODS
We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran's Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings.
RESULTS
The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929-0.972, p = 6.65 × 10), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906-0.971, p = 2.79 × 10), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906-0.969, p = 1.48 × 10) and TAG (56:8) (OR: 0.918, 95% CI: 0.876-0.961, p = 2.72 × 10) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028-1.079, p = 2.11 × 10) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039-1.135, p = 2.47 × 10) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%.
CONCLUSION
Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.
Topics: Dermatitis, Atopic; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Lipids; Triglycerides; Phosphatidylethanolamines; Phosphatidylcholines; Polymorphism, Single Nucleotide
PubMed: 38909247
DOI: 10.1186/s12944-024-02134-9 -
BMC Genomics Jun 2024Global per capita meat consumption continues to rise, especially pork. Meat quality is influenced by the content of intramuscular fat (IMF) as a key factor. The...
BACKGROUND
Global per capita meat consumption continues to rise, especially pork. Meat quality is influenced by the content of intramuscular fat (IMF) as a key factor. The longissimus dorsi muscle of Dahe pigs (DHM, IMF: 7.98% ± 1.96%) and Dahe black pigs (DHBM, IMF: 3.30% ± 0.64%) was studied to explore cellular heterogeneity and differentially expressed genes (DEGs) associated with IMF deposition using single-nucleus RNA sequencing (snRNA-seq). The lipid composition was then analyzed using non-targeted lipidomics.
RESULTS
A total of seven cell subpopulations were identified, including myocytes, fibroblast/fibro/adipogenic progenitors (FAPs), satellite cells, endothelial cells, macrophages, pericytes, and adipocytes. Among them, FAPs and adipocytes were more focused because they could be associated with lipid deposition. 1623 DEGs in the FAPs subpopulation of DHBM were up-regulated compared with DHM, while 1535 were down-regulated. These DEGs enriched in the glycolysis/gluconeogenesis pathway. 109 DEGs were up-regulated and 806 were down-regulated in the adipocyte subpopulation of DHBM compared with DHM, which were mainly enriched in the PPAR signaling pathway and fatty acid (FA) biosynthesis. The expression level of PPARG, ABP4, LEP, and ACSL1 genes in DHM was higher than that in DHBM. Lipidomics reveals porcine lipid composition characteristics of muscle tissue. A total of 41 lipid classes and 2699 lipid species were identified in DHM and DHBM groups. The top ten relative peak areas of lipid classes in DHM and DHBM were triglyceride (TG), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), diglyceride (DG), cardiolipin (CL), ceramides (Cer), Simple Glc series (Hex1Cer), sphingomyelin (phSM), and phosphatidylinositol (PI). The relative peak areas of 35 lipid species in DHM were lower than DHBM, and 28 lipid species that were higher. There was a significant increase in the TG fatty acyl chains C6:0, C17:0, and C11:4, and a significant decrease in C16:0, C18:1, C18:2, and C22:4 in DHBM (p < 0.05).
CONCLUSIONS
C16:0 FA may downregulate the expression level of PPARG gene, which leads to the downregulation of fat metabolism-related genes such as ACSL, PLIN2, and FABP4 in DHBM compared with DHM. This may be the reason that the lipid deposition ability of Dahe pigs is stronger than that of Dahe black pigs, which need further investigation.
Topics: Animals; Swine; Muscle, Skeletal; Lipid Metabolism; Lipidomics; Sequence Analysis, RNA; Single-Cell Analysis; Lipids; Gene Expression Profiling
PubMed: 38902599
DOI: 10.1186/s12864-024-10488-8