Sphingomyelin Levels Research Articles

Characteristics of sphingomyelin metabolism in the MCF7 and BT474 radiotherapy‑resistant HER2‑positive breast cancer cell lines.

Breast cancer is the most common cancer globally in terms of incidence. This cancer is classified into subtypes based on histological or immunological characteristics. HER2-positive cases account for 15-25% of breast cancer cases, and one of the first events in breast carcinogenesis is HER2 upregulation. Furthermore, HER2 expression increases the detection rate of metastatic or recurrent breast cancers by 50-80%. The epidermal growth factor receptor family includes HER2, which is a transmembrane receptor protein. In our previous case report, patients who were resistant to anti-HER2 monoclonal antibody therapy, chemotherapy and radiotherapy had higher concentrations of phospholipid metabolites such as phosphatidylcholine and sphingomyelin (SM), which was associated with cancer recurrence progression. To better understand the relationship between radiotherapy resistance and SM expression, breast cancer cell lines with and without HER2 expression (MCF7 and BT474) after exposure to ionizing radiation (IR) were examined. In the cell culture supernatant, similar levels of SM in MCF7 cells were identified after 1-4 Gy exposure. However, SM levels in BT474 cells were upregulated compared with those of in the control group. Intracellular SM levels were upregulated in BT474 cells exposed to 1 and 4 Gy compared with the non-irradiated control group. Furthermore, significantly increased mRNA expression levels of sphingomyelin synthase 2 (SGMS2) in BT474 cells exposed to IR were observed compared with those in nonirradiated cells; however, the SGMS2 levels in MCF7 cells did not differ significantly among the 0, 2 and 4 Gy groups. These findings suggested that a higher dose of IR induced the secretion of SM and its associated gene expression in HER2-positive breast cancer cells.

Diagnostic Value of Menstrual Blood Lipidomics in Endometriosis: A Pilot Study.

Endometriosis is a prevalent chronic inflammatory disease characterized by a considerable delay between initial symptoms and diagnosis through surgery. The pressing need for a timely, non-invasive diagnostic solution underscores the focus of current research efforts. This study examines the diagnostic potential of the menstrual blood lipidome. The lipid profile of 39 samples (23 women with endometriosis and 16 patients in a control group) was acquired using reverse-phase high-performance liquid chromatography-mass spectrometry with LipidMatch processing and identification. Profiles were normalized based on total ion counts. Significant differences in lipids were determined using the Mann-Whitney test. Lipids for the diagnostic model, based on logistic regression, were selected using a combination of variance importance projection filters and Akaike information criteria. Levels of ceramides, sphingomyelins, cardiolipins, triacylglycerols, acyl- and alkenyl-phosphatidylethanolamines, and alkenyl-phosphatidylcholines increased, while acyl- and alkyl-phosphatidylcholines decreased in cases of endometriosis. Plasmenylphosphatidylethanolamine PE P-16:0/18:1 and cardiolipin CL 16:0_18:0_22:5_22:6 serve as marker lipids in the diagnostic model, exhibiting a sensitivity of 81% and specificity of 85%. The diagnostic approach based on dried spots of menstrual blood holds promise as an alternative to traditional non-invasive methods for endometriosis screening.

Development and validation of a HPLC-UV method for the quantification of major phospholipids in milk

Phospholipids have gained increased interest in the past decades because of their numerous health benefits. Due to the amphiphilic nature of phospholipids, their quantitative analysis requires lengthy procedures. Hydrophilic interaction liquid chromatography (HILIC) with UV detector was used in the present study to effectively separate the major classes of phospholipids found in milk. Phospholipids were effectively separated on a diol-HILIC column using a gradient elution method using acetonitrile and 10 mM ammonium acetate (pH 5 adjusted using acetic acid). Good chromatographic separation of major phospholipid classes: phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM) was possible at 203 nm. The developed method was validated for both phospholipid standards and milk fat. The correlation coefficient for phospholipids using a linear regression equation for 1–50 μg/mL standard solutions and milk fat were >0.99 and >0.98, respectively. The relative standard deviation for intra-day and inter-day repeatability of phospholipids were less than 6 %, and recoveries fell within the 75-120% range. The developed method was applied for the quantification of phospholipids (PC, PE, and SM) in milk from indigenous and crossbred cattle. Gir, Sahiwal, and Karan Fries cows had no significant difference in PE and PC, while Gir cows exhibited significantly higher levels of SM.

The effect of gut microbiome and plasma metabolome on systemic sclerosis: a bidirectional two-sample Mendelian randomization study.

Cellular and molecular biology, combined with research on the human microbiome and metabolome, have provided new insights into the pathogenesis of systemic sclerosis (SSc). However, most studies on gut microbiota (GM) and metabolome in SSc are observational studies. The impact of confounding factors and reverse causation leads to different insights. To shed light on this matter, we utilized Mendelian randomization (MR) to determine the causal effect of GM/metabolites on SSc. Based on summary-level data from genome-wide association studies, bidirectional Two-sample MR was conducted involving 196 GM, 1400 plasma metabolism, and 9,095 SSc. Inverse Variance Weighting (IVW) was mainly used for effect estimation. Forward MR analysis found that three GM and two plasma metabolites are causally related to SSc. IVW results showed Victivallaceae (family) (OR, 1.469; 95%CI, 1.099-1.963; p = 0.009) and LachnospiraceaeUCG004 (genus) (OR, 1.548; 95%CI, 1.020-2.349; p = 0.04) were risk factor of SSc. Conversely, Prevotella7 (genus) (OR, 0.759; 95%CI, 0.578-0.997; p = 0.048)was a protective factor of SSc. The results on plasma metabolites indicated that Pregnenediol disulfate (C21H34O8S2) levels (OR, 1.164; 95%CI, 1.006-1.347; p = 0.041)was a risk factor of SSc, while Sphingomyelin (d18:1/19:0, d19:1/18:0) levels (OR, 0.821; 95%CI, 0.677-0.996; p = 0.045)was a protective factor of SSc. Reverse MR analysis did not find causally relationship between SSc and the above GM/plasma metabolites. Our results revealed the causally effect between GM/plasma metabolites and SSc. These findings provided new insights into the mechanism of SSc. In particular, we demonstrated Prevotella7 was a protective factor of SSc despite its controversial role in SSc in previous researches.

Circulating Lipid Profiles Associated With Resistance to Androgen Deprivation Therapy in Localized Prostate Cancer.

Intense androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs) before radical prostatectomy (RP) produced favorable pathologic responses in approximately 20% of patients. The molecular reason for the low rate of response remains unclear. Lipid metabolism is known to influence androgen receptor signaling and ARPI efficacy. The aim of the study was to identify circulating lipid profiles associated with ADT/ARPI resistance in localized prostate cancer. Two independent experimental approaches were used. Experiment 1: Post hoc analysis of the association between plasma lipidomic profiles and ADT/ARPI response was performed on patients (n = 104) from two phase II trials of neoadjuvant ADT/ARPI. Response to ADT/ARPI was defined by pathologic response. Experiment 2: Patient-derived tumor explants from RP (n = 105) were cultured in enzalutamide for 48 hours. Explant response to enzalutamide was evaluated against pre-RP plasma lipidomic profiles (n = 105) and prostate tissue lipidomic profiles (n = 36). Response was defined by Ki67 (cell proliferation marker) fold difference between enzalutamide and vehicle-treated explants. In both experiments, associations between lipid profiles and ADT/ARPI response were analyzed by latent class analysis. Pretreatment plasma lipid profiles classified each experimental cohort into two groups with differences in ADT/ARPI response rates. The response rates of the groups were 9.6% versus 29% in experiment 1 (chi-squared test P = .012) and 49% versus 70% in experiment 2 (chi-squared test P = .037). In both experiments, the group with a higher incidence of ADT/ARPI resistance had higher plasma levels of sphingomyelin, glycosylceramides, free fatty acids, acylcarnitines, cholesterol esters, and alkyl/alkenyl-phosphatidylcholine and lower plasma levels of triacylglycerols, diacylglycerols, and phosphoethanolamine (t-test P < .05). Pretreatment circulating lipid profiles are associated with ADT/ARPI resistance in localized cancer in both human cohorts and explant models.

Visualization of renal rotenone accumulation after oral administration and in situ detection of kidney injury biomarkers via MALDI mass spectrometry imaging.

The examination of drug accumulation within complex biological systems offers valuable insights into the molecular aspects of drug metabolism and toxicity. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is an innovative methodology that enables the spatial visualization and quantification of biomolecules as well as drug and its metabolites in complex biological system. Hence, this method provides valuable insights into the metabolic profile and any molecular changes that may occur as a result of drug treatment. The renal system is particularly vulnerable to adverse effects of drug-induced harm and toxicity. In this study, MALDI MSI was utilized to examine the spatial distribution of drug and renal metabolites within kidney tissues subsequent to a single oral dosage of the anticancer compound rotenone. The integration of ion mobility spectrometry with MALDI MSI enhanced the data acquisition and analysis, resulting to improved mass resolution. Subsequently, the MS/MS fragment ions of rotenone reference drug were detected and characterized using MALDI HDMS/MS imaging. Notably, drug accumulation was observed in the cortical region of the representative kidney tissue sections treated with rotenone. The histological examination of treated kidney tissues did not reveal any observable changes. Differential ion intensity of renal endogenous metabolites was observed between untreated and rotenone-treated tissues. In the context of treated kidney tissues, the ion intensity level of sphingomyelin (D18:1/16:0), a sphingolipid indicator of glomerular cell injury and renal damage, was found to be elevated significantly compared to untreated kidney tissues. Conversely, the ion intensities of choline, glycero-3-phosphocholine (GPC), inosine, and a lysophosphatidylcholine LysoPC(18:0) exhibited a significant decrease. The results of this study demonstrate the potential of MALDI MSI as a novel technique for investigating the in situ spatial distribution of drugs and renal endogenous molecules while preserving the anatomical integrity of the kidney tissue. This technique can be used to study drug-induced metabolism and toxicity in a dynamic manner.

Deciphering the lipid–cancer nexus: comprehensive Mendelian randomization analysis of the associations between lipid profiles and digestive system cancer susceptibility

BackgroundDigestive system cancers represent a significant global health challenge and are attributed to a combination of demographic and lifestyle changes. Lipidomics has emerged as a pivotal area in cancer research, suggesting that alterations in lipid metabolism are closely linked to cancer development. However, the causal relationship between specific lipid profiles and digestive system cancer risk remains unclear.MethodsUsing a two-sample Mendelian randomization (MR) approach, we elucidated the causal relationships between lipidomic profiles and the risk of five types of digestive system cancer: stomach, liver, esophageal, pancreatic, and colorectal cancers. The aim of this study was to investigate the effect impact of developing lipid profiles on the risk of digestive system cancers utilizing data from public databases such as the GWAS Catalog and the UK Biobank. The inverse‒variance weighted (IVW) method and other strict MR methods were used to evaluate the potential causal links. In addition, we performed sensitivity analyses and reverse MR analyses to ensure the robustness of the results.ResultsSignificant causal relationships were identified between certain lipidomic traits and the risk of developing digestive system cancers. Elevated sphingomyelin (d40:1) levels were associated with a reduced risk of developing gastric cancer (odds ratio (OR) = 0.68, P < 0.001), while elevated levels of phosphatidylcholine (16:1_20:4) increased the risk of developing esophageal cancer (OR = 1.31, P = 0.02). Conversely, phosphatidylcholine (18:2_0:0) had a protective effect against colorectal cancer (OR = 0.86, P = 0.036). The bidirectional analysis did not suggest reverse causality between cancer risk and lipid levels. Strict MR methods demonstrated the robustness of the above causal relationships.ConclusionOur findings underscore the significant causal relationships between specific lipidomic traits and the risk of developing various digestive system cancers, highlighting the potential of lipid profiles in informing cancer prevention and treatment strategies. These results reinforce the value of MR in unraveling complex lipid-cancer interactions, offering new avenues for research and clinical application.

Lung cancer metabolomics: a pooled analysis in the Cancer Prevention Studies

BackgroundA better understanding of lung cancer etiology and the development of screening biomarkers have important implications for lung cancer prevention.MethodsWe included 623 matched case–control pairs from the Cancer Prevention Study (CPS) cohorts. Pre-diagnosis blood samples were collected between 1998 and 2001 in the CPS-II Nutrition cohort and 2006 and 2013 in the CPS-3 cohort and were sent for metabolomics profiling simultaneously. Cancer-free controls at the time of case diagnosis were 1:1 matched to cases on date of birth, blood draw date, sex, and race/ethnicity. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression, controlling for confounders. The Benjamini–Hochberg method was used to correct for multiple comparisons.ResultsSphingomyelin (d18:0/22:0) (OR: 1.32; 95% CI: 1.15, 1.53, FDR = 0.15) and taurodeoxycholic acid 3-sulfate (OR: 1.33; 95% CI: 1.14, 1.55, FDR = 0.15) were positively associated with lung cancer risk. Participants diagnosed within 3 years of blood draw had a 55% and 48% higher risk of lung cancer per standard deviation increase in natural log-transformed sphingomyelin (d18:0/22:0) and taurodeoxycholic acid 3-sulfate level, while 26% and 28% higher risk for those diagnosed beyond 3 years, compared to matched controls. Lipid and amino acid metabolism accounted for 47% to 80% of lung cancer-associated metabolites at P < 0.05 across all participants and subgroups. Notably, ever-smokers exhibited a higher proportion of lung cancer-associated metabolites (P < 0.05) in xenobiotic- and lipid-associated pathways, whereas never-smokers showed a more pronounced involvement of amino acid- and lipid-associated metabolic pathways.ConclusionsThis is the largest prospective study examining untargeted metabolic profiles regarding lung cancer risk. Sphingomyelin (d18:0/22:0), a sphingolipid, and taurodeoxycholic acid 3-sulfate, a bile salt, may be risk factors and potential screening biomarkers for lung cancer. Lipid and amino acid metabolism may contribute significantly to lung cancer etiology which varied by smoking status.

Alterations to sphingolipid metabolism from antipsychotic administration in healthy volunteers are restored following the use of cannabidiol

Randomized clinical trials substantiate cannabidiol (CBD) as a next-generation antipsychotic, effective in alleviating positive and negative symptoms associated with psychosis, while minimising the adverse effects seen with established treatments. Although the mechanisms remain debated, CBD is known to induce drug-responsive changes in lipid-based retrograde neurotransmitters. Lipid aberrations are also frequently observed with antipsychotics, which may contribute to their efficacy or increase the risk of undesirables, including metabolic dysfunction, obesity and dyslipidaemia. Our study investigated CBD's impact following lipid responses triggered by interaction with second-generation antipsychotics (SGA) in a randomized phase I safety study. Untargeted mass spectrometry assessed the lipidomic profiles of human sera, collected from 38 healthy volunteers. Serum samples were obtained prior to commencement of any medication (t = 0), 3 days after consecutive administration of one of the five, placebo-controlled, treatment arms designed to achieve steady-state concentrations of each SGA (amisulpride, 150 mg/day; quetiapine, 300 mg/day; olanzapine 10 mg/day; risperidone, 3 mg/day), and after six successive days of SGA treatment combined with CBD (800 mg/day). Receiver operating characteristics (ROC) refined 3712 features to a putative list of 15 lipids significantly altered (AUC > 0.7), classified into sphingolipids (53 %), glycerolipids (27 %) and glycerophospholipids (20 %). Targeted mass spectrometry confirmed reduced sphingomyelin and ceramide levels with antipsychotics, which mapped along their catabolic pathway and were restored by CBD. These sphingolipids inversely correlated with body weight after olanzapine, quetiapine, and risperidone treatment, where CBD appears to have arrested or attenuated these effects. Herein, we propose CBD may alleviate aberrant sphingolipid metabolism and that further investigation into sphingolipids as markers for monitoring side effects of SGAs and efficacy of CBD is warranted.

Phospholipid metabolism-related genotypes of PLA2R1 and CERS4 contribute to nonobese MASLD.

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. 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. 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. 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.

Metabolomic-derived endotypes of age-related macular degeneration (AMD): a step towards identification of disease subgroups.

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with a complex pathophysiology and phenotypic diversity. Here, we apply Similarity Network Fusion (SNF) to cluster AMD patients into putative metabolomics-derived endotypes. Using a discovery cohort of 163 AMD patients from Boston, US, and a validation cohort of 214 patients from Coimbra, Portugal, we identified four distinct metabolomics-derived endotypes with varying retinal structural and functional characteristics, confirmed across both cohorts. Patients clustered into Endotype 1 exhibited a milder form of AMD and were characterized by low levels of amino acids in specific metabolic pathways. Meanwhile, patients clustered into both Endotype 3 and 4 were associated with more severe AMD and exhibited low levels of fatty acid metabolites and elevated levels of sphingomyelins and fatty acid metabolites, respectively. These preliminary findings indicate that metabolomics-derived endotyping may offer a refined strategy for categorizing AMD patients based on their specific pathophysiological underpinnings, rather than relying solely on traditional observational clinical indicators.

Multicentric investigations of the role in the disease severity of accelerated phospholipid changes in COVID-19 patient airway

ContextThe changes in host membrane phospholipids are crucial in airway infection pathogenesis. Phospholipase A2 hydrolyzes host cell membranes, producing lyso-phospholipids and free fatty acids, including arachidonic acid (AA), which contributes significantly to lung inflammation. AimFollow these changes and their evolution from day 1, day 3 to day 7 in airway aspirates of 89 patients with COVID-19-associated acute respiratory distress syndrome and examine whether they correlate with the severity of the disease. The patients were recruited in three French intensive care units. The analysis was conducted from admission to the intensive care unit until the end of the first week of mechanical ventilation. ResultsIn the airway aspirates, we found significant increases in the levels of host cell phospholipids, including phosphatidyl-serine and phosphatidyl-ethanolamine, and their corresponding lyso-phospholipids. This was accompanied by increased levels of AA and its inflammatory metabolite prostaglandin E2 (PGE2). Additionally, enhanced levels of ceramides, sphingomyelin, and free cholesterol were observed in these aspirates. These lipids are known to be involved in cell death and/or apoptosis, whereas free cholesterol plays a role in virus entry and replication in host cells. However, there were no significant changes in the levels of dipalmitoyl-phosphatidylcholine, the major surfactant phospholipid. A correlation analysis revealed an association between mortality risk and levels of AA and PGE2, as well as host cell phospholipids. ConclusionOur findings indicate a correlation between heightened cellular phospholipid modifications and variations in AA and PGE2 with the severity of the disease in patients. Nevertheless, there is no indication of surfactant alteration in the initial phases of the illness.

Untargeted lipidomics analysis in women with morbid obesity and type 2 diabetes mellitus: A comprehensive study.

There is a phenotype of obese individuals termed metabolically healthy obese that present a reduced cardiometabolic risk. This phenotype offers a valuable model for investigating the mechanisms connecting obesity and metabolic alterations such as Type 2 Diabetes Mellitus (T2DM). Previously, in an untargeted metabolomics analysis in a cohort of morbidly obese women, we observed a different lipid metabolite pattern between metabolically healthy morbid obese individuals and those with associated T2DM. To validate these findings, we have performed a complementary study of lipidomics. In this study, we assessed a liquid chromatography coupled to a mass spectrometer untargeted lipidomic analysis on serum samples from 209 women, 73 normal-weight women (control group) and 136 morbid obese women. From those, 65 metabolically healthy morbid obese and 71 with associated T2DM. In this work, we find elevated levels of ceramides, sphingomyelins, diacyl and triacylglycerols, fatty acids, and phosphoethanolamines in morbid obese vs normal weight. Conversely, decreased levels of acylcarnitines, bile acids, lyso-phosphatidylcholines, phosphatidylcholines (PC), phosphatidylinositols, and phosphoethanolamine PE (O-38:4) were noted. Furthermore, comparing morbid obese women with T2DM vs metabolically healthy MO, a distinct lipid profile emerged, featuring increased levels of metabolites: deoxycholic acid, diacylglycerol DG (36:2), triacylglycerols, phosphatidylcholines, phosphoethanolamines, phosphatidylinositols, and lyso-phosphatidylinositol LPI (16:0). To conclude, analysing both comparatives, we observed decreased levels of deoxycholic acid, PC (34:3), and PE (O-38:4) in morbid obese women vs normal-weight. Conversely, we found elevated levels of these lipids in morbid obese women with T2DM vs metabolically healthy MO. These profiles of metabolites could be explored for the research as potential markers of metabolic risk of T2DM in morbid obese women.

Risk factors and lipid metabolism characteristics of early-onset male androgenetic alopecia: A pilot study.

Male androgenetic alopecia (MAA) is a multifactorial disease, with patients presenting at a younger age, which is a risk factor for many metabolic diseases. To explore the risk factors associated with early-onset of MAA and its metabolic characteristics. Forty patients with MAA and 45 healthy controls were collected. The serum levels of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total testosterone (TT), uric acid (UA), and 25-hydroxyvitamin D (25(OH)D) were measured. Meanwhile, lipid metabolites were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). 37.50% MAA patients had metabolic syndrome, compared to 17.78% in control group (p < 0.05). The levels of HDL-C, UA, and 25(OH)D were decreased in patients with MAA compared to healthy controls (p < 0.05). However, there was no significant difference in the level of TT between the two groups. Additionally, there were no significant differences in the levels of HDL-C, UA, 25(OH)D, and TT among different grades of hair loss (p > 0.05). The lipid profile of early-onset MAA differed significantly from healthy controls. In early-onset MAA, the levels of ceramide (Cer) and sphingomyelin (SM) were significantly lower. Cer(d38:5) and TG(15:0/18:1/18:1) may be the biomarkers. Low HDL-C, UA, and 25(OH)D may be the independent risk factors for early-onset MAA. Abnormal lipid metabolism was observed in early-onset MAA, wherein Cer and SM may serve as protective factors.

Alzheimer's disease manifests abnormal sphingolipid metabolism.

Alzheimer's disease (AD) is associated with disturbed metabolism, prompting investigations into specific metabolic pathways that may contribute to its pathogenesis and pathology. Sphingolipids have garnered attention due to their known physiological impact on various diseases. We conducted comprehensive profiling of sphingolipids to understand their possible role in AD. Sphingolipid levels were measured in AD brains, Cerad score B brains, and controls, as well as in induced pluripotent stem (iPS) cells (AD, PS, and control), using liquid chromatography mass spectrometry. AD brains exhibited higher levels of sphingosine (Sph), total ceramide 1-phosphate (Cer1P), and total ceramide (Cer) compared to control and Cerad-B brains. Deoxy-ceramide (Deoxy-Cer) was elevated in Cerad-B and AD brains compared to controls, with increased sphingomyelin (SM) levels exclusively in Cerad-B brains. Analysis of cell lysates revealed elevated dihydroceramide (dhSph), total Cer1P, and total SM in AD and PS cells versus controls. Multivariate analysis highlighted the relevance of Sph, Cer, Cer1P, and SM in AD pathology. Machine learning identified Sph, Cer, and Cer1P as key contributors to AD. Our findings suggest the potential importance of Sph, Cer1P, Cer, and SM in the context of AD pathology. This underscores the significance of sphingolipid metabolism in understanding and potentially targeting mechanisms underlying AD.

Circulating sphingolipids and subclinical brain pathology: the cardiovascular health study.

Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone.

Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.

People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue. MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA). Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis. MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.

Lipid responses to perfluorooctane sulfonate exposure for multiple rat organs

Perfluorooctane sulfonate (PFOS) is a persistent chemical that has long been a threat to human health. However, the molecular effects of PFOS on various organs are not well studied. In this study, male Sprague–Dawley rats were treated with various doses of PFOS through gavage for 21 days. Subsequently, the liver, lung, heart, kidney, pancreas, testis, and serum of the rats were harvested for lipid analysis. We applied a focusing lipidomic analytical strategy to identify key lipid responses of phosphorylcholine-containing lipids, including phosphatidylcholines and sphingomyelins. Partial least squares discriminant analysis revealed that the organs most influenced by PFOS exposure were the liver, kidney, and testis. Changes in the lipid profiles of the rats indicated that after exposure, levels of diacyl-phosphatidylcholines and 22:6-containing phosphatidylcholines in the liver, kidney, and testis of the rats decreased, whereas the level of 20:3-containing phosphatidylcholines increased. Furthermore, levels of polyunsaturated fatty acids-containing plasmenylcholines decreased. Changes in sphingomyelin levels indicated organ-dependent responses. Decreased levels of sphingomyelins in the liver, nonmonotonic dose responses in the kidney, and irregular responses in the testis after PFOS exposure are observed. These lipid responses may be associated with alterations pertaining to phosphatidylcholine synthesis, fatty acid metabolism, membrane properties, and oxidative stress in the liver, kidney, and testis. Lipid responses in the liver could have contributed to the observed increase in liver to body weight ratios. The findings suggest potential toxicity and possible mechanisms associated with PFOS in multiple organs.

Temporal metabolomics state in pregnant rat: Analysis of amniotic fluid, placenta, and maternal plasma at embryonic and fetal time points

IntroductionDuring pregnancy, the dynamic metabolic demands for fetal growth require a continuous supply of essential metabolites. Understanding maternal metabolome changes during gestation is crucial for predicting disease risks in neonates. MethodsThe study aimed to characterize the placental and amniotic fluid (AF) metabolomes during gestation in rats at gestational days GD-13 and 19 reflecting the end of the embryonic and fetal periods, respectively, and the maternal plasma, using metabolomics (LC-MS) and chemometrics. The objective was to highlight, through univariate and multivariate analyses, the complementarity of the data obtained from these different biological matrices. ResultsThe biological matrix had more impact on the metabolome composition than the gestational stage. The placental and AF metabolomes showed specific metabolome evolving over the two gestational stages. Analyzing the three targeted metabolomes revealed evolving pathways in arginine and proline metabolism/glutathione metabolism and phenylalanine metabolism; purine metabolism; and carbohydrate metabolism. Significantly, lipid metabolism in the placenta exhibited substantial changes with higher levels of certain phosphatidylethanolamine and sphingomyelins at GD19 while some cholesteryl esters and some glycosphingolipids levels being in higher levels at GD13. DiscussionThese data highlight the metabolic gradients (mainly in placenta, also in AF, but only a few in plasma) observed through embryonic patterning and organ development during mid-to late gestation.

Exploring the potential effect of electroacupuncture on cardiovascular function and lipid profiles in spontaneously hypertensive rats

BackgroundInvestigating the effects of electroacupuncture (EA) treatment on cardiovascular function and aortic lipid profiles in spontaneously hypertensive rats (SHR) constitutes the foundational focus of this study. The overarching goal is to comprehensively elucidate the alterations brought about by EA treatment and to assess its potential as an alternative therapy for hypertension. MethodsConsecutive EA treatments were administered to SHR, and the effects on systolic blood pressure, cardiac function, and hypertension-related neuronal signals were assessed. Aortic lipid profiles in vehicle-treated SHR and EA-treated SHR groups were analyzed using mass spectrometry-based lipid profiling. Additionally, the expression of Cers2 and GNPAT, enzymes involved in the synthesis of specific aortic lipids, was examined. ResultsThe study demonstrated that consecutive EA treatments restored systolic blood pressure, improved cardiovascular function, and normalized hypertension-related neuronal signals in SHR. Analysis of the aortic lipid profiles revealed distinct differences between the vehicle-treated SHR group and the EA-treated SHR group. Specifically, EA treatment significantly altered the levels of aortic sphingomyelin and phospholipids, including very long-chain fatty acyl-ceramides and ether phosphatidylcholines. These changes in aortic lipid profiles correlated significantly with systolic blood pressure and cardiac function indicators. Furthermore, EA treatment significantly altered the expression of Cers2 and GNPAT. ConclusionsThe findings suggest that EA may influence cardiovascular functions and aortic lipid profiles in SHR.