Length and saturation of choline plasmalogens alter the aggregation rate of α-synuclein but not the toxicity of amyloid fibrils.

Plasmalogens comprise a large fraction of the total phospholipids in plasma membranes. These molecules modulate membrane fluidity, produce inflammatory mediators mitigating effects of metabolic stresses. A growing body of evidence suggests that an onset of Parkinson's disease (PD), a severe neurodegenerative pathology, can be triggered by metabolic changes in plasma membranes. However, the role of plasmalogens in the aggregation of α-synuclein (α-syn), an expected molecular cause of PD, remains unclear. In this study we examine the effect of choline plasmalogens (CPs), unique phospholipids that have a vinyl ether linkage at the sn-1 position of glycerol, on the aggregation rate of α-syn. We found that the length and saturation of fatty acids (FAs) in CPs change rates of protein aggregation. We also found drastic changes in the morphology of α-syn fibrils formed in the presence of different CPs compared to α-syn fibrils grown in the lipid-free environment. At the same time, we did not observe substantial changes in the secondary structure and toxicity of α-syn fibrils formed in the presence of different CPs. These results indicate that the length and saturation of FAs in CPs present in the plasma membrane can alter α-syn stability and modulate its aggregation properties, which, in turn can accelerate or delay the onset of PD.

Plasmalogen, a glycerophospholipid crucial for Streptococcus mutans acid tolerance and colonization.

Plasmalogen is a specific glycerophospholipid present in both animal and bacterial organisms. It plays a crucial function in eukaryotic cellular processes and is closely related to several human diseases, including neurological disorders and cancers. Nonetheless, the precise biological role of plasmalogen in bacteria is not well understood. In this study, we identified SMU_438c as the enzyme responsible for plasmalogen production in Streptococcus mutans under anaerobic conditions. The heterologous expression of SMU_438c in a plasmalogen-negative strain, Streptococcus sanguinis, resulted in the production of plasmalogen, indicating that this enzyme is sufficient for plasmalogen production. Additionally, the plasmalogen-deficient S. mutans exhibited significantly lower acid tolerance and diminished its colonization in Drosophila flies compared to the wild-type strain and complemented strain. In summary, our data suggest that plasmalogen plays a vital role in bacterial stress tolerance and in vivo colonization. IMPORTANCE: This study sheds light on the biological role of plasmalogen, a specific glycerophospholipid, in bacteria, particularly in Streptococcus mutans. Plasmalogens are known for their significant roles in eukaryotic cells and have been linked to human diseases like neurological disorders and cancers. The enzyme SMU_438c, identified as essential for plasmalogen production under anaerobic conditions, was crucial for acid tolerance and in vivo colonization in Drosophila by S. mutans, underscoring its importance in bacterial stress response and colonization. These findings bridge the knowledge gap in bacterial physiology, highlighting plasmalogen's role in microbial survival and offering potential insights into microbial pathogenesis and host-microbe interactions.

Protective effect of scallop-derived plasmalogen against vascular dysfunction, via the pSTAT3/PIM1/NFATc1 axis, in a novel mouse model of Alzheimer's disease with cerebral hypoperfusion.

A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

Phosphatidylcholine-Plasmalogen-Oleic Acid Reduces BACE1 Expression in Human SH-SY5Y Cells.

Plasmalogens are a family of glycerophospholipids containing one vinyl-ether bond at the sn-1 position in the glycerol backbone, and play important roles in cellular homeostasis including neural transmission. Therefore, reductions of plasmalogens have been associated with neurodegenerative disorders, such as Alzheimer's disease (AD). To evaluate the potential protective effects of plasmalogens against the pathology of AD, protein expression levels of key factors in amyloid precursor protein (APP) metabolic processes were examined using human neuroblastoma SH-SY5Y cells. Here, phosphatidylcholine-plasmalogen-oleic acid (PC-PLS-18) was shown to reduce protein expression levels of ß-site APP cleaving enzyme 1 (BACE1), clusterin, and Tau, factors involved in the amyloid ß-associated pathogenesis of AD. Thus, PC-PLS-18 may have preventive effects against AD by delaying the onset risk for a certain period.

Simultaneous Intake of Chlorella and Ascidian Ethanolamine Plasmalogen Accelerates Activation of BDNF-TrkB-CREB Signaling in Rats.

Brain-derived neurotrophic factor (BDNF) plays an important role in neurogenesis, synaptic plasticity, and cognition. BDNF is a neurotrophin that binds to tropomyosin receptor kinase B (TrkB), a specific receptor on target cell surfaces; it acts on neuronal formation, development, growth, and repair via transcription factors, such as cAMP response element-binding protein (CREB), and it is involved in learning and memory. BDNF expression is decreased in patients with Alzheimer's disease (AD). Exercise and the intake of several different foods or ingredients can increase BDNF expression, as confirmed with lutein, xanthophylls (polar carotenoids), and ethanolamine plasmalogen (PlsEtn), which are present at high levels in the brain. This study examined the effects of combining lutein and PlsEtn using lutein-rich Chlorella and ascidian extracts containing high levels of PlsEtn bearing docosahexaenoic acid, which is abundant in the human brain, on the activation of the BDNF-TrkB-CREB signaling pathway in the hippocampus of Sprague-Dawley rats. Although activation of the BDNF-TrkB-CREB signaling pathway in the hippocampus was not observed in Chlorella or ascidian PlsEtn monotherapy, activation was observed with combination therapy at an equal dose. The results of this study suggest that the combination of Chlorella and ascidian PlsEtn may have a preventive effect against dementia, including AD.

Neuroprotective effect of plasmalogens on AlCl3-induced Alzheimer's disease zebrafish via acting on the regulatory network of ferroptosis, apoptosis and synaptic neurotransmission release with oxidative stress as the center.

Plasmalogens (Pls) are considered to play a potential role in the treatment of neurodegenerative diseases. In the present study, an Alzheimer's disease (AD) model of zebrafish induced by AlCl3 was established to investigate whether the marine-derived Pls could alleviate cognitive impairments of AD zebrafish. Behavioral tests were carried out to assess the athletic ability. The transcriptional profiles of zebrafish in the control, AD model and AD_PLS group were compared and analyzed to determine the potential mechanisms of dietary Pls on AD. The study found that Pls could reverse athletic impairment in the AD zebrafish model, and the expression levels of genes related to ferroptosis, synaptic dysfunction and apoptosis were significantly altered between experimental groups. Further analysis showed that all of these genes were associated with oxidative stress (OS). These data suggest that healthy protective role of marine-derived Pls on AD zebrafish may result from inhibition of ferroptosis and neuronal apoptosis, restoring synaptic neurotransmission release, and reducing neuroinflammation. Among them, Oxidative stress is acted as the center to connect different regulation pathways. This study provides evidence to support the essential roles of OS in pathogenesis of AD, and the application of Pls in relieving AD.

CSE triggers ferroptosis via SIRT4-mediated GNPAT deacetylation in the pathogenesis of COPD.

BACKGROUND: It is now understood that ferroptosis plays a significant role in the progression of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke extract (CSE). However, the mechanisms underlying this relationship remain largely unclear. METHODS: In this study, we established a COPD mouse model through exposure to cigarette smoke particulates, followed by H&E staining, analysis of bronchoalveolar lavage fluid, and immunohistochemistry assay. A549 cells were exposed to increasing concentrations of CSE, with the addition of the ferroptosis activator erastin or the inhibitor Fer-1. Cell viability, LDH (lactate dehydrogenase) release, inflammatory cytokines, total ROS (reactive oxygen species), and lipid ROS were measured using the corresponding assay kits. The acetylation level of GNPAT was determined through immunoprecipitation. We assessed the expression levels of molecules involved in plasmalogen biosynthesis (FAR1, AGPS, and GNPAT), GPX4, and SIRT4 using quantitative real-time PCR, western blot analysis, and immunofluorescence staining. RESULTS: CSE-induced lung tissue damage was initially observed, accompanied by oxidative stress, ferroptosis, and increased plasmalogen biosynthesis molecules (FAR1, AGPS, and GNPAT). CSE also induced ferroptosis in A549 cells, resulting in reduced cell viability, GSH, and GPX4 levels, along with increased LDH, ROS, MDA (malondialdehyde) levels, oxidized lipids, and elevated FAR1, AGPS, and GNPAT expression. Knockdown of GNPAT mitigated CSE-induced ferroptosis. Furthermore, we found that CSE regulated the acetylation and protein levels of GNPAT by modulating SIRT4 expression. Importantly, the overexpression of GNPAT countered the inhibitory effects of SIRT4 on ferroptosis. CONCLUSIONS: Our study revealed GNPAT could be deacetylated by SIRT4, providing novel insights into the mechanisms underlying the relationship between CSE-induced ferroptosis and COPD.

Sexual dimorphism in the gonad lipidome of blue mussels (Mytilus sp.): New insights from a global lipidomics approach.

Blue mussels (Mytilus sp.) are an economically important species for European aquaculture. Their importance as a food source is expected to increase in the coming net-zero society due to their low environmental footprint; however, their production is affected by anthropogenic stressors and climate change. During reproduction, lipids are key molecules for mussels as they are the main source of energy on which newly hatched embryos depend in the first days of their development. In this work, blue mussels of different origins are analysed, focusing on the differences in lipid composition between the ovary (BMO) and the testis (BMT). The lipidome of blue mussel gonads (BMG) is studied here by combining traditional lipid profiling methods, such as fatty acid and lipid class analysis, with untargeted liquid chromatography-mass spectrometry (LC-MS) lipidomics. The approach used here enabled the identification of 770 lipid molecules from 23 different lipid classes in BMG. BMT, which consists of billions of spermatocytes, had greater amounts of cell membrane and membrane lipid components such as FA18:0, C20 polyunsaturated fatty acids (PUFA), free sterols (ST), ceramide phosphoethanolamines (CerPE), ceramide aminoethylphosphonates (CAEP), cardiolipins (CL), glycerophosphocholines (PC), glycerophosphoethanolamines (PE) and glycerophosphoserines (PS). In BMO, saturated fatty acids (FA14:0 and FA16:0), monounsaturated fatty acids (MUFA) and other storage components such as C18-PUFA accumulated in triradylglycerolipids (TG) and alkyldiacylglycerols (neutral plasmalogens, TG O-), which, together with terpenes, wax esters and cholesterol esters, make up most of oocytes yolk reserves. BMO also had higher levels of ceramides (Cer) and generally alkyl/alkenyl glycerophospholipids (mainly plasmanyl/plasmenyl PC), suggesting a role for these lipids in vitellogenesis. Non-methylene interrupted dienoic fatty acids (NMID FA), typically found in plasmalogens, were the only membrane-forming PUFA predominantly detected in BMO. The results of this study are of great importance for clarifying the lipid composition of BMG and provide an important basis for future studies on the reproductive physiology of these organisms.

Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice.

Mitochondrial function is vital for energy metabolism in thermogenic adipocytes. Impaired mitochondrial bioenergetics in brown adipocytes are linked to disrupted thermogenesis and energy balance in obesity and aging. Phospholipid cardiolipin (CL) and phosphatidic acid (PA) jointly regulate mitochondrial membrane architecture and dynamics, with mitochondria-associated endoplasmic reticulum membranes (MAMs) serving as the platform for phospholipid biosynthesis and metabolism. However, little is known about the regulators of MAM phospholipid metabolism and their connection to mitochondrial function. We discover that LCN2 is a PA binding protein recruited to the MAM during inflammation and metabolic stimulation. Lcn2 deficiency disrupts mitochondrial fusion-fission balance and alters the acyl-chain composition of mitochondrial phospholipids in brown adipose tissue (BAT) of male mice. Lcn2 KO male mice exhibit an increase in the levels of CLs containing long-chain polyunsaturated fatty acids (LC-PUFA), a decrease in CLs containing monounsaturated fatty acids, resulting in mitochondrial dysfunction. This dysfunction triggers compensatory activation of peroxisomal function and the biosynthesis of LC-PUFA-containing plasmalogens in BAT. Additionally, Lcn2 deficiency alters PA production, correlating with changes in PA-regulated phospholipid-metabolizing enzymes and the mTOR signaling pathway. In conclusion, LCN2 plays a critical role in the acyl-chain remodeling of phospholipids and mitochondrial bioenergetics by regulating PA production and its function in activating signaling pathways.

Ether-lipids and cellular signaling: A differential role of alkyl- and alkenyl-ether-lipids?

Ether-lipids (EL) are specific lipids bearing a characteristic sn-1 ether bond. Depending on the ether or vinyl-ether nature of this bond, they are present as alkyl- or alkenyl-EL, respectively. Among EL, alkenyl-EL, also referred as plasmalogens in the literature, attract most of the scientific interest as they are the predominant EL species in eukaryotic cells, thus less is known about alkyl-EL. EL have been implicated in various signaling pathways and alterations in their quantity are frequently observed in pathologies such as neurodegenerative and cardiovascular diseases or cancer. However, it remains unknown whether both alkyl- and alkenyl-EL play the same roles in these processes. This review summarizes the roles and mechanisms of action of EL in cellular signaling and tries to discriminate between alkyl- and alkenyl-EL. We also focus on the involvement of EL-mediated alterations of cellular signaling in diseases and discuss the potential interest for EL in therapy.

Marine Plasmalogens: A Gift from the Sea with Benefits for Age-Associated Diseases.

Aging increases oxidative and inflammatory stress caused by a reduction in metabolism and clearance, thus leading to the development of age-associated diseases. The quality of our daily diet and exercise is important for the prevention of these diseases. Marine resources contain various valuable nutrients, and unique glycerophospholipid plasmalogens are found abundantly in some marine invertebrates, including ascidians. One of the major classes, the ethanolamine class (PlsEtn), exists in a high ratio to phospholipids in the brain and blood, while decreased levels have been reported in patients with age-associated diseases, including Alzheimer's disease. Animal studies have shown that the administration of marine PlsEtn prepared from marine invertebrates improved PlsEtn levels in the body and alleviated inflammation. Animal and human studies have reported that marine PlsEtn ameliorates cognitive impairment. In this review, we highlight the biological significance, relationships with age-associated diseases, food functions, and healthcare materials of plasmalogens based on recent knowledge and discuss the contribution of marine plasmalogens to health maintenance in aging.

Fetal sex differences in placental LCPUFA ether and plasmalogen phosphatidylethanolamine and phosphatidylcholine contents in pregnancies complicated by obesity.

BACKGROUND: We have previously reported that maternal obesity reduces placental transport capacity for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA), a preferred form for transfer of DHA (omega 3) to the fetal brain, but only in male fetuses. Phosphatidylethanolamine (PE) and phosphatidylcholine (PC), have either sn-1 ester, ether or vinyl ether (plasmalogen) linkages to primarily unsaturated and monounsaturated fatty acids and DHA or arachidonic acid (ARA, omega 6) in the sn-2 position. Whether ether and plasmalogen PC and PE metabolism in placenta impacts transfer to the fetus is unexplored. We hypothesized that ether and plasmalogen PC and PE containing DHA and ARA are reduced in maternal-fetal unit in pregnancies complicated by obesity and these differences are dependent on fetal sex. METHODS: In maternal, umbilical cord plasma and placentas from obese women (11 female/5 male infants) and normal weight women (9 female/7 male infants), all PC and PE species containing DHA and ARA were analyzed by LC-MS/MS. Placental protein expression of enzymes involved in phospholipid synthesis, were determined by immunoblotting. All variables were compared between control vs obese groups and separated by fetal sex, in each sample using the Benjamini-Hochberg false discovery rate adjustment to account for multiple testing. RESULTS: Levels of ester PC containing DHA and ARA were profoundly reduced by 60-92% in male placentas of obese mothers, while levels of ether and plasmalogen PE containing DHA and ARA were decreased by 51-84% in female placentas. PLA2G4C abundance was lower in male placentas and LPCAT4 abundance was lower solely in females in obesity. In umbilical cord, levels of ester, ether and plasmalogen PC and PE with DHA were reduced by 43-61% in male, but not female, fetuses of obese mothers. CONCLUSIONS: We found a fetal sex effect in placental PE and PC ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

Docosahexaenoic acid (DHA) is a critical omega 3 long chain polyunsaturated fatty acid (LCPUFA) for fetal brain development. We have recently reported that maternal obesity reduces placental transport capacity for LysophosPhatidylCholine-DHA (LPC-DHA), a preferred form for transfer of DHA to the fetal brain, but only in male fetuses. Other important lipids, the plasmalogen phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are considered DHA reservoirs, but its roles in the maternal­fetal unit are largely unexplored. We examined these lipid species in maternal and fetal circulation and in placental tissue to uncover potential novel roles for ether and plasmalogen lipids in the regulation of placenta delivery of these vital nutrients in pregnancies complicated by obesity depending of fetal sex. We demonstrated for the first time, that female fetuses of obese mothers decrease placental ether and plasmalogen PE containing DHA and arachidonic acid (ARA, omega 6), and show a high fetal­placental adaptability and placental reserve capacity that can maintain the PC-LCPUFA synthesis and the transfer of these crucial species to the fetus to preserve brain development. Our study also demonstrated that male fetuses, in response to maternal obesity, reduce the placental ester PC species containing DHA and ARA and reduce the ether and plasmalogen PE reservoir of DHA and ARA in fetal circulation. Our findings support a fetal sex effect in placental ester, ether and plasmalogen PE and PC containing DHA in response to maternal obesity which appears to reflect an ability of female placentas to adapt to maintain optimal fetal DHA transfer in maternal obesity.

A new test method for biochemical analysis of plasmalogens in dried blood spots and erythrocytes from patients with peroxisomal disorders.

Measurement of plasmalogens is useful for the biochemical diagnosis of rhizomelic chondrodysplasia punctata (RCDP) and is also informative for Zellweger spectrum disorders (ZSD). We have developed a test method for the simultaneous quantitation of C16:0, C18:0, and C018:1 plasmalogen (PG) species and their corresponding fatty acids (FAs) in dried blood spots (DBS) and erythrocytes (RBC) by using capillary gas chromatography-mass spectrometry. Normal reference ranges for measured markers and 10 calculated ratios were established by the analysis of 720 and 473 unaffected DBS and RBC samples, respectively. Determination of preliminary disease ranges was made by using 45 samples from 43 unique patients: RCDP type 1 (DBS: 1 mild, 17 severe; RBC: 1 mild, 6 severe), RCDP type 2 (DBS: 2 mild, 1 severe; RBC: 2 severe), RCDP type 3 (DBS: 1 severe), RCDP type 4 (RBC: 2 severe), and ZSD (DBS: 3 severe; RBC: 2 mild, 7 severe). Postanalytical interpretive tools in Collaborative Laboratory Integrated Reports (CLIR) were used to generate an integrated score and a likelihood of disease. In conjunction with a review of clinical phenotype, phytanic acid, and very long-chain FA test results, the CLIR analysis allowed for differentiation between RCDP and ZSD. Data will continue to be gathered to improve CLIR analysis as more samples from affected patients with variable disease severity are analyzed. The addition of DBS analysis of PGs may allow for at-home specimen collection and second-tier testing for newborn screening programs.

Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome.

After five waves of coronavirus disease 2019 (COVID-19) outbreaks, it has been recognized that a significant portion of the affected individuals developed long-term debilitating symptoms marked by chronic fatigue, cognitive difficulties ("brain fog"), post-exertional malaise, and autonomic dysfunction. The onset, progression, and clinical presentation of this condition, generically named post-COVID-19 syndrome, overlap significantly with another enigmatic condition, referred to as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Several pathobiological mechanisms have been proposed for ME/CFS, including redox imbalance, systemic and central nervous system inflammation, and mitochondrial dysfunction. Chronic inflammation and glial pathological reactivity are common hallmarks of several neurodegenerative and neuropsychiatric disorders and have been consistently associated with reduced central and peripheral levels of plasmalogens, one of the major phospholipid components of cell membranes with several homeostatic functions. Of great interest, recent evidence revealed a significant reduction of plasmalogen contents, biosynthesis, and metabolism in ME/CFS and acute COVID-19, with a strong association to symptom severity and other relevant clinical outcomes. These bioactive lipids have increasingly attracted attention due to their reduced levels representing a common pathophysiological manifestation between several disorders associated with aging and chronic inflammation. However, alterations in plasmalogen levels or their lipidic metabolism have not yet been examined in individuals suffering from post-COVID-19 symptoms. Here, we proposed a pathobiological model for post-COVID-19 and ME/CFS based on their common inflammation and dysfunctional glial reactivity, and highlighted the emerging implications of plasmalogen deficiency in the underlying mechanisms. Along with the promising outcomes of plasmalogen replacement therapy (PRT) for various neurodegenerative/neuropsychiatric disorders, we sought to propose PRT as a simple, effective, and safe strategy for the potential relief of the debilitating symptoms associated with ME/CFS and post-COVID-19 syndrome.

Diet-Related Lipidomic Signatures and Changed Type 2 Diabetes Risk in a Randomized Controlled Feeding Study With Mediterranean Diet and Traditional Chinese or Transitional Diets.

OBJECTIVE: Few trials studied the links of food components in different diets with their induced lipidomic changes and related metabolic outcomes. Thus, we investigated specific lipidomic signatures with habitual diets and modified diabetes risk by using a trial and a cohort. RESEARCH DESIGN AND METHODS: We included 231 Chinese with overweight and prediabetes in a randomized feeding trial with Mediterranean, traditional, or transitional diets (control diet) from February to September 2019. Plasma lipidomic profiles were measured at baseline, third month, and sixth month by high-throughput targeted liquid chromatography-mass spectrometry. Associations of the identified lipids with habitual dietary intakes were examined in another lipidomic database of a Chinese cohort (n = 1,117). The relationships between diet-induced changes of lipidomic species and diabetes risk factors were further investigated through both individual lipids and relevant modules in the trial. RESULTS: Out of 364 lipidomic species, 26 altered across groups, including 12 triglyceride (TAG) fractions, nine plasmalogens, four phosphatidylcholines (PCs), and one phosphatidylethanolamine. TAG fractions and PCs were associated with habitual fish intake while plasmalogens were associated with red meat intake in the cohort. Of the diet-related lipidomic metabolites, 10 TAG fractions and PC(16:0/22:6) were associated with improved Matsuda index (ß = 0.12 to 0.42; PFDR < 0.030). Two plasmalogens were associated with deteriorated fasting glucose (ß = 0.29 to 0.31; PFDR < 0.014). Similar results were observed for TAG and plasmalogen related modules. CONCLUSIONS: These fish- and red meat-related lipidomic signatures sensitively reflected different diets and modified type 2 diabetes risk factors, critical for optimizing dietary patterns.

Dynamic changes and importance of plasma concentrations of ether phospholipids, of which the majority are plasmalogens, in postpartum Holstein dairy cows.

CONTEXT: Ethanolamine plasmalogens (EPls) and choline plasmalogens (CPls) are classes of ethanolamine ether phospholipids (ePE) and choline ether phospholipids (ePC), respectively. EPls play crucial roles in maternal and breastfed infant bodies and stimulate gonadotropin secretion by gonadotrophs. AIMS: To estimate changes in and importance of plasma concentrations of EPls and CPls, utilising newly developed enzymatic fluorometric assays for ePE and ePC in postpartum Holstein cows. METHODS: Plasma samples were collected from 3weeks before expected parturition until approximately 8weeks after parturition (16 primiparous and 38 multiparous cows) for analysis. KEY RESULTS: Plasma concentrations of ePE and ePC, most of which are plasmalogens, declined before and increased after parturition and stabilised near the day of the first postpartum ovulation (1stOV). From weeks 2 to 3 after parturition, third-parity cows exhibited ePE concentrations that were higher than those of other parity cows. The days from parturition to 1stOV correlated with days from parturition to conception. On the day of 1stOV, milk yield correlated with plasma concentration of both ePE and ePC, while ePC concentration correlated negatively with milk fat percentage. At the early luteal phase after 1stOV, plasma ePE concentration correlated with plasma anti-Müllerian hormone concentration (r =0.39, P <0.01), and plasma ePC concentration correlated with plasma follicle-stimulating hormone concentration (r =0.43, P <0.01). CONCLUSION: The concentrations of ePE and ePC changed dramatically around parturition and 1stOV, and the concentrations correlated with important parameters for milk production and reproduction. IMPLICATIONS: The blood plasmalogen may play important roles in postpartum dairy cows.

Dietary Eicosapentaenoic Acid Containing Phosphoethanolamine Plasmalogens Remodels the Lipidome of White Adipose Tissue and Suppresses High-Fat Diet Induced Obesity in Mice.

SCOPE: Dietary supplementation of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) can alter the lipidome profiles of adipocytes, thereby counteract obesity. DHA/EPA in the form of phospholipids demonstrates higher bioavailability than triglyceride or ethyl ester (EE), but their effects on the lipidome and metabolic changes during obesity are still unknown. METHODS AND RESULTS: High-fat diet-induced obese mice are treated with different molecular forms of EPA, and EPA supplemented as phosphoethanolamine plasmalogens (PlsEtn) has a superior effect on reducing fat mass accumulation than phosphatidylcholine (PC) or EE. The lipidomics analysis indicates that EPA in form of PlsEtn but not PC or EE significantly decreases total PC and sphingomyelin content in white adipose tissue (WAT). Some specific polyunsaturated fatty acid -containing PCs and ether phospholipids are increased in EPA-PlsEtn-fed mice, which may attribute to the upregulation of unsaturated fatty acid biosynthesis and fatty acid elongation reactions in WAT. In addition, the expression of genes related to fatty acid catabolism is also promoted by EPA-PlsEtn supplementation, which may cause the decreased content of saturated and monounsaturated fatty acid-containing PCs. CONCLUSIONS: EPA-PlsEtn supplementation is demonstrated to remodel lipidome and regulate the fatty acid metabolic process in WAT, indicating it may serve as a new strategy for obesity treatment in the future.

Effects of high-sugar, high-cholesterol, and high-fat diet on phospholipid profile of mouse tissues with a focus on the mechanism of plasmalogen synthesis.

High-sugar diet (HSD), high-cholesterol diet (HCD), and high-fat diet (HFD) all modulate the levels of lipids. However, there is a lack of comparative data on the effects of different diets on phospholipids (PLs). Given their important role in physiology and disease, there has been an increasing focus on altered PLs in liver and brain disorders. This study aims to determine the effects of HSD, HCD, and HFD for 14-week feeding on the PL profile of the mouse liver and hippocampus. Quantitative analysis of 116 and 113 PL molecular species in liver and hippocampus tissues revealed that the HSD, HCD, and HFD significantly affected the PLs in liver and hippocampus, especially decreased the levels of plasmenylethanolamine (pPE) and phosphatidylethanolamine (PE). Overall, the impact of HFD on liver PLs was more significant, consistent with the morphological changes in the liver. Compared to HSD and HCD, HFD induced a significant decrease in PC (P-16:0/18:1) and an increase in LPE (18:0) and LPE (18:1) in liver. In the liver of mice fed with different diets, the expression of the key enzymes Gnpat, Agps in the pPE biosynthesis pathway and peroxisome-associated membrane proteins pex14p were decreased. In addition, all diets significantly reduced the expression of Gnpat, pex7p, and pex16p in hippocampus tissue. In conclusion, HSD, HCD, and HFD enhanced lipid accumulation in the liver, led to liver injury, significantly affected the liver and hippocampus PLs, and decreased the expression of genes related to plasmalogen synthesis in mouse liver and hippocampus, which caused severe plasmalogen reduction.

1-O-alkyl-glycerols from Squid Berryteuthis magister Reduce Inflammation and Modify Fatty Acid and Plasmalogen Metabolism in Asthma Associated with Obesity.

Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1-O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.

Utilization of LC-MS/MS and Drift Tube Ion Mobility for Characterizing Intact Oxidized Arachidonate-Containing Glycerophosphatidylethanolamine.

Lipid peroxidation is a key component in the pathogenesis of numerous disease states, where the oxidative damage of lipids frequently leads to membrane dysfunction and subsequent cellular death. Glycerophosphoethanolamine (PE) is the second most abundant phospholipid found in cellular membranes and, when oxidized, has been identified as an executor of ferroptotic cell death. PE commonly exists in the plasmalogen form, where the presence of the vinyl ether bond and its enrichment in polyunsaturated fatty acids make it especially susceptible to oxidative degradation. This results in a multitude of oxidized products complicating identification and often requiring several analytical techniques for interpretation. In the present study, we outline an analytical approach for the structural characterization of intact oxidized products of arachidonate-containing diacyl and plasmalogen PE. Intact oxidized PE structures, including structural and positional isomers, were identified using complementary liquid chromatography techniques, drift tube ion mobility, and high-resolution tandem mass spectrometry. This work establishes a comprehensive method for the analysis of intact lipid peroxidation products and provides an important pathway to investigate how lipid peroxidation initially impacts glycerophospholipids and their role in redox biology.