RESUMO
The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.
Assuntos
Membrana Celular , Integrina beta3 , Camundongos Knockout , Regeneração , Animais , Masculino , Camundongos , Membrana Celular/metabolismo , Proliferação de Células , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/patologia , Traumatismos Cardíacos/genética , Integrina beta3/metabolismo , Integrina beta3/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Plasmalogênios/metabolismo , Transdução de SinaisRESUMO
The trabecular meshwork (TM) from primary open-angle glaucoma (POAG) cases has been found to contain decreased levels of intracellular plasmalogens. Plasmalogens are a subset of lipids involved in diverse cellular processes such as intracellular signaling, membrane asymmetry, and protein regulation. Proper plasmalogen biosynthesis is regulated by rate-limiting enzyme fatty acyl-CoA reductase (Far1). ATPase phospholipid transporting 8B2 (ATP8B2) is a type IV P-type ATPase responsible for the asymmetric distribution of plasmalogens between the intracellular and extracellular leaflets of the plasma membranes. Here we describe the methodology for extraction and culturing of TM cells from corneal tissue and subsequent downregulation of ATP8B2 using siRNA transfection. Further quantification and downstream effects of ATP8B2 gene knockdown will be analyzed utilizing immunoblotting techniques.
Assuntos
Glaucoma de Ângulo Aberto , Plasmalogênios , Malha Trabecular , Malha Trabecular/metabolismo , Malha Trabecular/citologia , Humanos , Plasmalogênios/metabolismo , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/patologia , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/genética , RNA Interferente Pequeno/genética , Regulação para Baixo , Células Cultivadas , Técnicas de Silenciamento de GenesRESUMO
Plasmalogens are vinyl-ether glycerophospholipids critical for the structure and function of neuronal membranes. Deficient plasmalogen levels are associated with neurodegenerative diseases, particularly Alzheimer's disease (AD), which has led to the hypothesis that plasmalogen deficiency might drive disease onset and progression. However, the lack of a suitable animal model with late-onset plasmalogen deficiency has prevented testing of this hypothesis. The goal of this project was therefore to develop and characterize a mouse model capable of undergoing a plasmalogen deficiency only in adulthood, mirroring the chronic decline thought to occur in AD. We report here the creation of a novel animal model containing a tamoxifen-inducible knockout of the Gnpat gene encoding the first step in the plasmalogen biosynthetic pathway. Tamoxifen treatment in adult animals resulted in a significant reduction of plasmalogens in both the circulation and tissues as early as four weeks. By four months, changes in behavior and nerve function were observed, with strong correlations between residual brain plasmalogen levels, hyperactivity, and latency. The model will be useful for further elucidating the role of plasmalogens in AD and evaluating plasmalogen therapies.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Plasmalogênios , Animais , Plasmalogênios/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Camundongos , Encéfalo/metabolismo , Camundongos Knockout , Masculino , Tamoxifeno/farmacologia , Camundongos Endogâmicos C57BL , FemininoRESUMO
Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring's brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.
Assuntos
Encéfalo , Endocanabinoides , Ácidos Graxos , Ácido Linoleico , Plasmalogênios , Feminino , Animais , Masculino , Gravidez , Ratos , Encéfalo/metabolismo , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Endocanabinoides/sangue , Endocanabinoides/metabolismo , Ácido Linoleico/sangue , Plasmalogênios/sangue , Plasmalogênios/metabolismo , Efeitos Tardios da Exposição Pré-Natal/sangue , Caracteres Sexuais , Fatores SexuaisRESUMO
Background: Polycystic ovary syndrome with insulin resistance (PCOS-IR) is the most common endocrine and metabolic disease in women of reproductive age, and low fertility in PCOS patients may be associated with oocyte quality; however, the molecular mechanism through which PCOS-IR affects oocyte quality remains unknown. Methods: A total of 22 women with PCOS-IR and 23 women without polycystic ovary syndrome (control) who underwent in vitro fertilization and embryo transfer were recruited, and clinical information pertaining to oocyte quality was analyzed. Lipid components of follicular fluid (FF) were detected using high-coverage targeted lipidomics, which identified 344 lipid species belonging to 19 lipid classes. The exact lipid species associated with oocyte quality were identified. Results: The number (rate) of two pronuclear (2PN) zygotes, the number (rate) of 2PN cleaved embryos, and the number of high-quality embryos were significantly lower in the PCOS-IR group. A total of 19 individual lipid classes and 344 lipid species were identified and quantified. The concentrations of the 19 lipid species in the normal follicular fluid (control) ranged between 10-3 mol/L and 10-9 mol/L. In addition, 39 lipid species were significantly reduced in the PCOS-IR group, among which plasmalogens were positively correlated with oocyte quality. Conclusions: This study measured the levels of various lipids in follicular fluid, identified a significantly altered lipid profile in the FF of PCOS-IR patients, and established a correlation between poor oocyte quality and plasmalogens in PCOS-IR patients. These findings have contributed to the development of plasmalogen replacement therapy to enhance oocyte quality and have improved culture medium formulations for oocyte in vitro maturation (IVM).
Assuntos
Fertilização in vitro , Líquido Folicular , Resistência à Insulina , Lipidômica , Oócitos , Plasmalogênios , Síndrome do Ovário Policístico , Humanos , Feminino , Síndrome do Ovário Policístico/metabolismo , Líquido Folicular/metabolismo , Líquido Folicular/química , Oócitos/metabolismo , Adulto , Lipidômica/métodos , Plasmalogênios/metabolismo , Plasmalogênios/análise , Fertilização in vitro/métodos , Lipídeos/análise , Infertilidade Feminina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Transferência Embrionária , Estudos de Casos e ControlesRESUMO
Plasmalogens are a special class of glycerophospholipids characterized by a vinyl ether bond (-C = C-O-) at the sn-1 position of the glycerol backbone. Altered plasmalogen profiles have been observed in neurodegenerative diseases and cancers. Profiling of plasmalogens requires specifying the vinyl ether bond and differentiating them from various types of isobars and isomers. Herein, by coupling C = C derivatization via offline Paternò-Büchi reaction with liquid chromatography-tandem mass spectrometry, we have developed a sensitive workflow for analysis of plasmalogens from biological samples. Using bovine heart lipid extract as a model system, we profiled more than 100 distinct structures of plasmenylethanolamines (PE-Ps) and plasmenylcholines (PC-Ps) at the C = C location level, far exceeding previous reports. Analysis of human glioma and normal brain tissue samples revealed elevated n-10 C = C isomers of PE-Ps in the glioma tissue samples. These findings suggest that the developed workflow holds potential in aiding the study of altered metabolism of plasmalogens in clinical samples.
Assuntos
Plasmalogênios , Espectrometria de Massas em Tandem , Plasmalogênios/análise , Plasmalogênios/química , Espectrometria de Massas em Tandem/métodos , Animais , Bovinos , Humanos , Glioma/metabolismo , Glioma/química , Cromatografia Líquida/métodos , Miocárdio/química , Miocárdio/metabolismoRESUMO
BACKGROUND: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle. METHODS: We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men). We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years). FINDINGS: In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21-0.43), 0.39 (95% CI 0.25-0.61) and 0.42 (95% CI 0.30-0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively, and a 34% lower mortality risk (HR = 0.66; 95% CI 0.56-0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score. INTERPRETATION: The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimise the practical implementation of the Pls Score in clinical and population settings. FUNDING: National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).
Assuntos
Biomarcadores , Plasmalogênios , Humanos , Plasmalogênios/sangue , Plasmalogênios/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/metabolismo , Austrália/epidemiologia , Estudos Cross-Over , Adulto , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Idoso , Fosfatidiletanolaminas/metabolismo , Estilo de Vida , Fatores de Risco CardiometabólicoRESUMO
The quality of Pacific oyster (Crassostrea gigas) can be affected by many factors during depuration, in which temperature is the major element. In this study, we aim to determine the quality and plasmalogen changes in C. gigas depurated at different temperatures. The quality was significantly affected by temperature, represented by varying survival rate, glycogen content, total antioxidant capacity, alkaline phosphatase activity between control and stressed groups. Targeted MS analysis demonstrated that plasmalogen profile was significantly changed during depuration with PUFA-containing plasmalogen species being most affected by temperature. Proteomics analysis and gene expression assay further verified that plasmalogen metabolism is regulated by temperature, specifically, the plasmalogen synthesis enzyme EPT1 was significantly downregulated by high temperature and four plasmalogen-related genes (GPDH, PEDS, Pex11, and PLD1) were transcriptionally regulated. The positive correlations between the plasmalogen level and quality characteristics suggested plasmalogen could be regarded as a quality indicator of oysters during depuration.
Assuntos
Crassostrea , Plasmalogênios , Temperatura , Animais , Plasmalogênios/metabolismo , Plasmalogênios/análise , Crassostrea/genética , Crassostrea/metabolismo , Frutos do Mar/análise , Proteômica/métodos , Antioxidantes/metabolismo , Antioxidantes/análise , Fosfatase Alcalina/metabolismo , Qualidade dos AlimentosRESUMO
The metabolites and microbiota in tongue coating display distinct characteristics in certain digestive disorders, yet their relationship with colorectal cancer (CRC) remains unexplored. Here, we employed liquid chromatography coupled with tandem mass spectrometry to analyze the lipid composition of tongue coating using a nontargeted approach in 30 individuals with colorectal adenomas (CRA), 32 with CRC, and 30 healthy controls (HC). We identified 21 tongue coating lipids that effectively distinguished CRC from HC (AUC = 0.89), and 9 lipids that differentiated CRC from CRA (AUC = 0.9). Furthermore, we observed significant alterations in the tongue coating lipid composition in the CRC group compared to HC/CRA groups. As the adenoma-cancer sequence progressed, there was an increase in long-chain unsaturated triglycerides (TG) levels and a decrease in phosphatidylethanolamine plasmalogen (PE-P) levels. Furthermore, we noted a positive correlation between N-acyl ornithine (NAOrn), sphingomyelin (SM), and ceramide phosphoethanolamine (PE-Cer), potentially produced by members of the Bacteroidetes phylum. The levels of inflammatory lipid metabolite 12-HETE showed a decreasing trend with colorectal tumor progression, indicating the potential involvement of tongue coating microbiota and tumor immune regulation in early CRC development. Our findings highlight the potential utility of tongue coating lipid analysis as a noninvasive tool for CRC diagnosis.
Assuntos
Neoplasias Colorretais , Lipidômica , Fosfatidiletanolaminas , Espectrometria de Massas em Tandem , Língua , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/microbiologia , Lipidômica/métodos , Masculino , Feminino , Língua/microbiologia , Língua/metabolismo , Língua/patologia , Língua/química , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem/métodos , Fosfatidiletanolaminas/metabolismo , Fosfatidiletanolaminas/análise , Idoso , Cromatografia Líquida , Lipídeos/análise , Lipídeos/química , Triglicerídeos/metabolismo , Triglicerídeos/análise , Adenoma/metabolismo , Adenoma/microbiologia , Esfingomielinas/análise , Esfingomielinas/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/química , Plasmalogênios/análise , Plasmalogênios/metabolismo , Plasmalogênios/química , Estudos de Casos e Controles , Etanolaminas/metabolismo , Etanolaminas/análise , Etanolaminas/química , Ceramidas/metabolismo , Ceramidas/análise , AdultoRESUMO
Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.
Assuntos
Homeostase , Metabolismo dos Lipídeos , Bainha de Mielina , Oligodendroglia , Selenoproteínas , Animais , Humanos , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Peroxidação de Lipídeos , Camundongos Knockout , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fosfatidiletanolaminas/metabolismo , Éteres Fosfolipídicos/metabolismo , Plasmalogênios/metabolismo , Selenoproteínas/metabolismo , Selenoproteínas/genética , Paraplegia Espástica Hereditária/metabolismo , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologiaRESUMO
Sea cucumber phospholipids, including the plasmalogen (PlsEtn) and plasmanylcholine (PakCho), have been shown to play a regulatory role in lipid metabolism disorders, but their mechanism of action remains unclear. Therefore, high-fat diet (HFD) and palmitic acid were used to establish lipid accumulation models in mice and HepG2 cells, respectively. Results showed that PlsEtn can reduce lipid deposition both in vivo and in vitro. HFD stimulation abnormally activated lipophagy through the phosphorylation of the AMPK/ULK1 pathway. The lipophagy flux monitor revealed abnormalities in the fusion stage of lipophagy. Of note, only PlsEtn stimulated the dynamic remodeling of the autophagosome membrane, which was indicated by the significantly decreased LC3 II/I ratio and p62 level. In all experiments, the effect of PlsEtn was significantly higher than that of PakCho. These findings elucidated the mechanism of PlsEtn in alleviating lipid accumulation, showed that it might be a lipophagy enhancer, and provided new insights into the high-value utilization of sea cucumber as an agricultural resource.
Assuntos
Dieta Hiperlipídica , Metabolismo dos Lipídeos , Plasmalogênios , Pepinos-do-Mar , Animais , Dieta Hiperlipídica/efeitos adversos , Plasmalogênios/metabolismo , Pepinos-do-Mar/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Humanos , Células Hep G2 , Masculino , Camundongos Endogâmicos C57BL , Autofagia/efeitos dos fármacosRESUMO
Heart tissue can experience a progressive accumulation of transthyretin (TTR), a small four subunit protein that transports holoretinol binding protein and thyroxine. This severe pathology is known as transthyretin amyloid cardiomyopathy. Numerous experimental studies indicated that the aggregation rate and toxicity of TTR fibrils could be altered by the presence of lipids; however, the role of plasmalogens in this process remains unknown. In this study, we investigate the effect of choline plasmalogens (CPs) with different lengths and saturations of fatty acids (FAs) on TTR aggregation. We found that CPs with saturated and unsaturated FAs strongly suppressed TTR aggregation. We also found that CPs with saturated FAs did not change the morphology of TTR fibrils; however, much thicker fibrillar species were formed in the presence of CPs with unsaturated FAs. Finally, we found that CPs with C16:0, C18:0, and C18:1 FAs substantially lowered the cytotoxicity of TTR fibrils that were formed in their presence.
Assuntos
Plasmalogênios , Pré-Albumina , Pré-Albumina/química , Pré-Albumina/metabolismo , Plasmalogênios/metabolismo , Plasmalogênios/química , Humanos , Amiloide/química , Amiloide/metabolismo , Agregados Proteicos/efeitos dos fármacos , Ácidos Graxos/química , Ácidos Graxos/metabolismoRESUMO
The sea cucumber plasmalogen PlsEtn has been shown to be associated with various chronic diseases related to lipid metabolism. However, the mechanism is unclear. Therefore, the present study used the sea cucumber plasmanylcholine PakCho as a structural contrast to PlsEtn and assessed its effect in 8 week high-fat diet (HFD)-fed mice. The lipidomic approach based on high-resolution mass spectrometry combined with molecular biology techniques was used to evaluate the mechanism of PlsEtn. The results showed that both PlsEtn and PakCho significantly inhibited an increase in mouse body weight and liver total triglyceride and total cholesterol levels caused by HFD. In addition, oil red O staining demonstrated that lipid droplets stored in the liver were degraded. Meanwhile, untargeted lipidomic experiments revealed that total lipids (increased by 42.8 mmol/mg prot; p < 0.05), triglycerides (increased by 38.9 mmol/mg prot; p < 0.01), sphingolipids (increased by 1.5 mmol/mg prot; p < 0.0001), and phospholipids (increased by 2.5 mmol/mg prot; p < 0.05) were all significantly elevated under HFD. PlsEtn resolved lipid metabolism disorders by alleviating the abnormal expression of lipid subclasses. In addition, five lipid molecular species, PE (18:1/20:4), PE (18:1/20:3), PE (18:1/18:3), TG (16:0/16:0/17:0), and TG (15:0/16:0/18:1), were identified as the biomarkers of HFD-induced lipid metabolism disorders. Finally, lipophagy-associated protein expression analysis showed that HFD abnormally activated lipophagy via ULK1 phosphorylation and PlsEtn alleviated lipophagy disorder through lysosomal function promotion. In addition, PlsEtn performed better than PakCho. Taken together, the current study results unraveled the mechanism of PlsEtn in alleviating lipid metabolism disorder and offered a new theoretical foundation for the high-value development of sea cucumber.
Assuntos
Dieta Hiperlipídica , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Plasmalogênios , Pepinos-do-Mar , Triglicerídeos , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos , Pepinos-do-Mar/química , Pepinos-do-Mar/metabolismo , Fígado/metabolismo , Masculino , Plasmalogênios/metabolismo , Triglicerídeos/metabolismo , Humanos , Lipídeos/sangueRESUMO
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.
Assuntos
Neoplasias , Doenças do Sistema Nervoso , Humanos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Plasmalogênios/metabolismo , Streptococcus mutans/metabolismo , Ácidos/metabolismo , Drosophila , BiofilmesRESUMO
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.
Assuntos
Doença de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/química , Plasmalogênios , Amiloide/química , Doença de Parkinson/metabolismoRESUMO
The identification and quantitation of plasmalogen glycerophospholipids is challenging due to their isobaric overlap with plasmanyl ether-linked glycerophospholipids, susceptibility to acid degradation, and their typically low abundance in biological samples. Trimethylation enhancement using diazomethane (TrEnDi) can be used to significantly enhance the signal of glycerophospholipids through the creation of quaternary ammonium groups producing fixed positive charges using 13C-diazomethane in complex lipid extracts. Although TrEnDi requires a strong acid for complete methylation, we report an optimized protocol using 10 mM HBF4 with the subsequent addition of a buffer solution that prevents acidic hydrolysis of plasmalogen species and enables the benefits of TrEnDi to be realized for this class of lipids. These optimized conditions were applied to aliquots of bovine liver extract (BLE) to achieve permethylation of plasmalogen lipids within a complex mixture. Treating aliquots of unmodified and TrEnDi-derivatized BLE samples with 80% formic acid and comparing their liquid chromatography mass spectrometry (LCMS) results to analogous samples not treated with formic acid, enabled the identification of 29 plasmalogen species. On average, methylated plasmalogen species from BLE demonstrated 2.81-fold and 28.1-fold sensitivity gains over unmodified counterparts for phosphatidylcholine and phosphatidylethanolamine plasmalogen species, respectively. Furthermore, the compatibility of employing 13C-TrEnDi and a previously reported iodoacetalization strategy was demonstrated to effectively identify plasmenyl-ether lipids in complex biological extracts at greater levels of sensitivity. Overall, we detail an optimized 13C-TrEnDi derivatization strategy that enables the analysis of plasmalogen glycerophospholipids with no undesired cleavage of radyl groups, boosting their sensitivity in LCMS and LCMS/MS analyses.
Assuntos
Isótopos de Carbono , Diazometano , Glicerofosfolipídeos , Fígado , Plasmalogênios , Animais , Bovinos , Plasmalogênios/química , Plasmalogênios/análise , Isótopos de Carbono/análise , Diazometano/química , Fígado/química , Glicerofosfolipídeos/química , Glicerofosfolipídeos/análise , Metilação , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
Plasmalogens (vinyl-ether phospholipids) are an emergent class of lipid drugs against various diseases involving neuro-inflammation, oxidative stress, mitochondrial dysfunction, and altered lipid metabolism. They can activate neurotrophic and neuroprotective signaling pathways but low bioavailabilities limit their efficiency in curing neurodegeneration. Here, liquid crystalline lipid nanoparticles (LNPs) are created for the protection and non-invasive intranasal delivery of purified scallop-derived plasmalogens. The in vivo results with a transgenic mouse Parkinson's disease (PD) model (characterized by motor impairments and α-synuclein deposition) demonstrate the crucial importance of LNP composition, which determines the self-assembled nanostructure type. Vesicle and hexosome nanostructures (characterized by small-angle X-ray scattering) display different efficacy of the nanomedicine-mediated recovery of motor function, lipid balance, and transcriptional regulation (e.g., reduced neuro-inflammation and PD pathogenic gene expression). Intranasal vesicular and hexosomal plasmalogen-based LNP treatment leads to improvement of the behavioral PD symptoms and downregulation of the Il6, Il33, and Tnfa genes. Moreover, RNA-sequencing and lipidomic analyses establish a dramatic effect of hexosomal nanomedicines on PD amelioration, lipid metabolism, and the type and number of responsive transcripts that may be implicated in neuroregeneration.
Assuntos
Administração Intranasal , Modelos Animais de Doenças , Nanomedicina , Nanopartículas , Doença de Parkinson , Plasmalogênios , Animais , Plasmalogênios/química , Plasmalogênios/farmacologia , Camundongos , Doença de Parkinson/metabolismo , Doença de Parkinson/tratamento farmacológico , Nanopartículas/química , Nanomedicina/métodos , Camundongos Transgênicos , Metabolismo dos Lipídeos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , LipossomosRESUMO
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.
Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Peptídeos beta-Amiloides/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Plasmalogênios , Ácido Aspártico Endopeptidases/metabolismo , Ácido Oleico , Fosfatidilcolinas/farmacologia , Neuroblastoma/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismoRESUMO
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.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Plasmalogênios , Fatores de Transcrição NFI/metabolismo , Inflamassomos/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Remodelação VascularRESUMO
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.