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BMC Gastroenterology May 2024Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes...
BACKGROUND
Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date.
METHODS
The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC.
RESULTS
Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels.
CONCLUSION
Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.
Topics: Humans; Cholangitis, Sclerosing; Gastrointestinal Microbiome; Lipidomics; Mendelian Randomization Analysis; Male; Genome-Wide Association Study; Female; Phosphatidylcholines; Dysbiosis; Middle Aged; Adult
PubMed: 38720308
DOI: 10.1186/s12876-024-03246-3 -
Scientific Reports May 2024Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration...
Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.
Topics: Animals; Multiple Sclerosis; Receptors, Lysophosphatidic Acid; Remyelination; Humans; Mice; Neuroinflammatory Diseases; Oligodendroglia; Brain; Cell Differentiation; Encephalomyelitis, Autoimmune, Experimental; Mice, Inbred C57BL; Myelin Sheath; Lysophospholipids; Blood-Brain Barrier
PubMed: 38719983
DOI: 10.1038/s41598-024-61369-9 -
Frontiers in Immunology 2024Anti-PD-1/PD-L1 inhibitors therapy has become a promising treatment for hepatocellular carcinoma (HCC), while the therapeutic efficacy varies significantly among effects...
INTRODUCTION
Anti-PD-1/PD-L1 inhibitors therapy has become a promising treatment for hepatocellular carcinoma (HCC), while the therapeutic efficacy varies significantly among effects for individual patients are significant difference. Unfortunately, specific predictive biomarkers indicating the degree of benefit for patients and thus guiding the selection of suitable candidates for immune therapy remain elusive.no specific predictive biomarkers are available indicating the degree of benefit for patients and thus screening the preferred population suitable for the immune therapy.
METHODS
Ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS) considered is an important method for analyzing biological samples, since it has the advantages of high rapid, high sensitivity, and high specificity. Ultra-high-pressure liquid chromatography-mass spectrometry (UHPLC-MS) has emerged as a pivotal method for analyzing biological samples due to its inherent advantages of rapidity, sensitivity, and specificity. In this study, potential metabolite biomarkers that can predict the therapeutic effect of HCC patients receiving immune therapy were identified by UHPLC-MS.
RESULTS
A partial least-squares discriminant analysis (PLS-DA) model was established using 14 glycerophospholipid metabolites mentioned above, and good prediction parameters (R2 = 0.823, Q2 = 0.615, prediction accuracy = 0.880 and p < 0.001) were obtained. The relative abundance of glycerophospholipid metabolite ions is closely related to the survival benefit of HCC patients who received immune therapy.
DISCUSSION
This study reveals that glycerophospholipid metabolites play a crucial role in predicting the efficacy of immune therapy for HCC.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Chromatography, High Pressure Liquid; Male; Immune Checkpoint Inhibitors; Biomarkers, Tumor; B7-H1 Antigen; Female; Middle Aged; Programmed Cell Death 1 Receptor; Mass Spectrometry; Aged; Metabolomics; Glycerophospholipids
PubMed: 38707906
DOI: 10.3389/fimmu.2024.1370771 -
Experimental and Molecular Pathology Jun 2024Lipidome perturbation occurring during meta-inflammation is associated to left ventricle (LV) remodeling though the activation of the NLRP3 inflammasome, a key regulator...
Circulating perturbation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is associated to cardiac remodeling and NLRP3 inflammasome in cardiovascular patients with insulin resistance risk.
Lipidome perturbation occurring during meta-inflammation is associated to left ventricle (LV) remodeling though the activation of the NLRP3 inflammasome, a key regulator of chronic inflammation in obesity-related disorders. Little is known about phosphatidylcholine (PC) and phosphatidylethanolamine (PE) as DAMP-induced NLRP3 inflammasome. Our study is aimed to evaluate if a systemic reduction of PC/PE molar ratio can affect NLRP3 plasma levels in cardiovascular disease (CVD) patients with insulin resistance (IR) risk. Forty patients from IRCCS Policlinico San Donato were enrolled, and their blood samples were drawn before heart surgery. LV geometry measurements were evaluated by echocardiography and clinical data associated to IR risk were collected. PC and PE were quantified by ESI-MS/MS. Circulating NLRP3 was quantified by an ELISA assay. Our results have shown that CVD patients with IR risk presented systemic lipid impairment of PC and PE species and their ratio in plasma was inversely associated to NLRP3 levels. Interestingly, CVD patients with IR risk presented LV changes directly associated to increased levels of NLRP3 and a decrease in PC/PE ratio in plasma, highlighting the systemic effect of meta-inflammation in cardiac response. In summary, PC and PE can be considered bioactive mediators associated to both the NLRP3 and LV changes in CVD patients with IR risk.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidylcholines; Inflammasomes; Male; Female; Insulin Resistance; Middle Aged; Phosphatidylethanolamines; Cardiovascular Diseases; Ventricular Remodeling; Aged
PubMed: 38703553
DOI: 10.1016/j.yexmp.2024.104895 -
Acta Naturae 2024This study examines the pathological processes and conditions arising from an experimental modeling of II-IIIA degree thermal burns in laboratory animals. These...
This study examines the pathological processes and conditions arising from an experimental modeling of II-IIIA degree thermal burns in laboratory animals. These conditions are characterized by skin structure defects, diminished skin functions, especially the barrier function, and damage to skin derivatives like hair follicles and sebaceous glands. We compared the effect of liposomes composed of soybean lecithin of 90% phosphatidylcholine content and liposomes composed of lecithin of 26% phosphatidylcholine content on the epidermis, dermis and its capillaries, hair follicles, and the sebaceous glands of the laboratory animals 24 h after experimental modeling of II-IIIA degree thermal skin burns. We discuss the dependency of liposome effects on the skin and its derivatives on the fatty acid composition of the lecithin used, with particular focus on phosphatidylinositol, phosphatidic acids, as well as oleic and linoleic acids.
PubMed: 38698959
DOI: 10.32607/actanaturae.27329 -
Nature Communications May 2024The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and...
The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc). When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.
Topics: Humans; Large Neutral Amino Acid-Transporter 1; Phosphatidylethanolamines; Lipoylation; Lysosomes; Cell Membrane; Amino Acid Transport System y+; HEK293 Cells; Protein Multimerization; Protein Binding; Mass Spectrometry; Mutagenesis, Site-Directed; Hydrogen-Ion Concentration; Membrane Proteins; Fusion Regulatory Protein 1, Heavy Chain; Adaptor Proteins, Signal Transducing
PubMed: 38697966
DOI: 10.1038/s41467-024-47948-4 -
Journal of Oleo Science 2024This study was to investigate the effects of Smilax China L. saponins (SCS) on non-alcoholic fatty liver disease (NAFLD). Rats were fed a high-fat diet (HFD) for 8 weeks...
This study was to investigate the effects of Smilax China L. saponins (SCS) on non-alcoholic fatty liver disease (NAFLD). Rats were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by SCS treatment for 8 weeks. The effect of SCS on liver injury was observed by H&E staining and the regulative mechanism of SCS on lipid formation was exposed by detecting Oil red O, insulin resistance (IR), and fatty acids synthesis (FAS). Furthermore, transcriptomics and metabolomics were performed to analyze the potential targets. The experimental results indicated that SCS exerted a positive curative effect in alleviating HFD-induced overweight, hepatic injury, steatosis, and lipid formation and accumulation in rats, and the preliminary mechanism studies showed that SCS could alleviate IR, inhibit FAS expression, and reduce Acetyl-CoA levels. Besides, the integrative analysis of transcriptomics and metabolomics exposed the targets of SCS to regulate lipid production likely being the sphingolipid metabolism and glycerophospholipid metabolism pathways. This study demonstrates that SCS significantly ameliorates lipid metabolic disturbance in rats with NAFLD by relieving insulin resistance, inhibiting the FAS enzymes, and regulating the sphingolipid and glycerophospholipid metabolism pathways.
Topics: Animals; Smilax; Saponins; Non-alcoholic Fatty Liver Disease; Male; Insulin Resistance; Metabolomics; Diet, High-Fat; Transcriptome; Lipid Metabolism; Rats; Rats, Sprague-Dawley; Sphingolipids; Glycerophospholipids; Liver; Disease Models, Animal
PubMed: 38692892
DOI: 10.5650/jos.ess23167 -
Journal of the American Chemical Society May 2024The nanoscopic layer of water that directly hydrates biological membranes plays a critical role in maintaining the cell structure, regulating biochemical processes, and...
The nanoscopic layer of water that directly hydrates biological membranes plays a critical role in maintaining the cell structure, regulating biochemical processes, and managing intermolecular interactions at the membrane interface. Therefore, comprehending the membrane structure, including its hydration, is essential for understanding the chemistry of life. While cholesterol is a fundamental lipid molecule in mammalian cells, influencing both the structure and dynamics of cell membranes, its impact on the structure of interfacial water has remained unknown. We used surface-specific vibrational sum-frequency generation spectroscopy to study the effect of cholesterol on the structure and hydration of monolayers of the lipids 1,2-dipalmitoyl--glycero-3-phosphocholine (DPPC), 1,2-dioleoyl--glycero-3-phosphocholine (DOPC), and egg sphingomyelin (SM). We found that for the unsaturated lipid DOPC, cholesterol intercalates in the membrane without significantly changing the orientation of the lipid tails and the orientation of the water molecules hydrating the headgroups of DOPC. In contrast, for the saturated lipids DPPC and SM, the addition of cholesterol leads to clearly enhanced packing and ordering of the hydrophobic tails. It is also observed that the orientation of the water hydrating the lipid headgroups is enhanced upon the addition of cholesterol. These results are important because the orientation of interfacial water molecules influences the cell membranes' dipole potential and the strength and specificity of interactions between cell membranes and peripheral proteins and other biomolecules. The lipid nature-dependent role of cholesterol in altering the arrangement of interfacial water molecules offers a fresh perspective on domain-selective cellular processes, such as protein binding.
Topics: Cholesterol; Water; Cell Membrane; Phosphatidylcholines; Sphingomyelins; 1,2-Dipalmitoylphosphatidylcholine
PubMed: 38687869
DOI: 10.1021/jacs.4c00474 -
Lung Jun 2024Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the...
PURPOSE
Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults. In ARDS extensive inflammation and leakage of fluid into the alveoli lead to dysregulation of pulmonary surfactant metabolism and function. Altered surfactant synthesis, secretion, and breakdown contribute to the clinical features of decreased lung compliance and alveolar collapse. Lung function in ARDS could potentially be restored with surfactant replacement therapy, and synthetic surfactants with modified peptide analogues may better withstand inactivation in ARDS alveoli than natural surfactants.
METHODS
This study aimed to investigate the activity in vitro and the bolus effect (200 mg phospholipids/kg) of synthetic surfactant CHF5633 with analogues of SP-B and SP-C, or natural surfactant Poractant alfa (Curosurf, both preparations Chiesi Farmaceutici S.p.A.) in a severe ARDS model (the ratio of partial pressure arterial oxygen and fraction of inspired oxygen, P/F ratio ≤ 13.3 kPa) induced by hydrochloric acid instillation followed by injurious ventilation in adult New Zealand rabbits. The animals were ventilated for 4 h after surfactant treatment and the respiratory parameters, histological appearance of lung parenchyma and levels of inflammation, oxidative stress, surfactant dysfunction, and endothelial damage were evaluated.
RESULTS
Both surfactant preparations yielded comparable improvements in lung function parameters, reductions in lung injury score, pro-inflammatory cytokines levels, and lung edema formation compared to untreated controls.
CONCLUSIONS
This study indicates that surfactant replacement therapy with CHF5633 improves lung function and lung architecture, and attenuates inflammation in severe ARDS in adult rabbits similarly to Poractant alfa. Clinical trials have so far not yielded conclusive results, but exogenous surfactant may be a valid supportive treatment for patients with ARDS given its anti-inflammatory and lung-protective effects.
Topics: Animals; Rabbits; Respiratory Distress Syndrome; Pulmonary Surfactants; Lung; Phospholipids; Disease Models, Animal; Biological Products; Pulmonary Surfactant-Associated Protein B; Oxidative Stress; Pulmonary Surfactant-Associated Protein C; Male; Bronchoalveolar Lavage Fluid; Peptide Fragments; Phosphatidylcholines
PubMed: 38684519
DOI: 10.1007/s00408-024-00689-z -
Frontiers in Bioscience (Landmark... Apr 2024The effect of the daily consumption of a low-fat yogurt (150 g) enriched with Platelet-Activating Factor receptor (PAF-R) antagonists, or the plain one, on gut... (Randomized Controlled Trial)
Randomized Controlled Trial
Does Yogurt Enriched with Platelet-Activating Factor Inhibitors from Olive Oil By-Products Affect Gut Microbiota and Faecal Metabolites in Healthy Overweight Subjects? (A randomized, parallel, three arm trial.).
OBJECTIVE
The effect of the daily consumption of a low-fat yogurt (150 g) enriched with Platelet-Activating Factor receptor (PAF-R) antagonists, or the plain one, on gut microbiota and faecal metabolites was investigated in healthy overweight subjects.
METHODS
A randomized, three-arm, double-blind, placebo-controlled, parallel-group study was performed that lasted 8 weeks. Blood and stools were collected and analyzed before and after the intervention.
RESULTS
Our findings revealed that the intake of the enriched yogurt resulted in a significant increase in the levels of spp., group and Firmicutes-to-Bacteroidetes (F/B) ratio. On the other hand, a significant increase in the levels of and group was detected after the intake of the plain yogurt. The increase in the levels of group was inversely associated with the plasma catabolic enzyme of PAF, namely LpPLA2 (lipoprotein-associated phospholipase A2), a cardiovascular risk marker that has been linked with inflammation and atherosclerosis. Moreover, in the enriched with PAF-R antagonists yogurt group, the increased levels of group were also associated with lower PAF action assessed as human platelet-rich plasma (PRP) aggregation. Additionally, a higher % increase in molar ratio of Branched Short Chain Fatty Acids (BSCFAs) was detected for both yogurt groups after the 8 week-intervention compared to control. The consumption of the enriched yogurt also resulted in a significant drop in faecal caproic levels and a trend for lower ratio of butyrate to total volatile fatty acids (VFAs) compared to baseline levels.
CONCLUSION
Yogurt consumption seems to favorably affect gut microbiota while its enrichment with PAF-R antagonists from olive oil by-products, may provide further benefits in healthy overweight subjects.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov (NCT02259205).
Topics: Humans; Yogurt; Gastrointestinal Microbiome; Overweight; Olive Oil; Feces; Male; Female; Adult; Double-Blind Method; Middle Aged; Platelet Activating Factor; Receptors, G-Protein-Coupled; Platelet Membrane Glycoproteins
PubMed: 38682205
DOI: 10.31083/j.fbl2904159