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Breast cancer is the most prevalent cancer in women. Metabolic abnormalities, particularly increased lipid synthesis and uptake, impact the onset and progression of the disease. However, the influence of lipid metabolism in breast cancer varies according to the disease stage and patient's hormone status. In postmenopausal patients, obesity is associated with a higher risk and poor prognosis of luminal tumors, while in premenopausal individuals, it is correlated to BRCA mutated tumors. In fact, the tumor's lipid profile may be used to distinguish between HER2+, luminal and BRCA-mutated tumors. Moreover, drug resistance was associated with increased fatty acid synthesis and alterations in membrane composition, impacting its fluidity and spatial subdomains such as lipid rafts. Here, we discuss the subtype-specific lipid metabolism alterations found in breast cancer and the potentiality of its modulation in a clinical setting.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/metabolismo , Lipídeos , Obesidade/complicações , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Transdução de SinaisRESUMO
Lipidomics is a discipline that focuses on the identification and quantification of lipids. Although a part of the larger omics field, lipidomics requires specific approaches for the analysis and biological interpretation of datasets. This article presents a series of activities for introducing undergraduate microbiology students to lipidomic analysis through tools from the web-based platform MetaboAnalyst. The students perform a complete lipidomic workflow, which includes experiment design, data processing, data normalization, and statistical analysis of molecular phospholipid species obtained from barley roots exposed to Fusarium macroconidia. The input data are provided by the teacher, but students also learn about the methods through which they were originally obtained (untargeted liquid chromatography coupled with mass spectrometry). The ultimate aim is for students to understand the biological significance of phosphatidylcholine acyl editing. The chosen methodology allows users who are not proficient in statistics to make a comprehensive analysis of quantitative lipidomic datasets. We strongly believe that virtual activities based on the analysis of such datasets should be incorporated more often into undergraduate courses, in order to improve students' data-handling skills for omics sciences.
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Hordeum , Lipidômica , Humanos , Lipidômica/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas , Lipídeos/análiseRESUMO
Due to the high prevalence and clinical relevance, scorpionism is a critical public health issue in several Brazilian regions. Tityus serrulatus, commonly known as the Brazilian yellow scorpion, is the most venomous genus found in Brazilian fauna and associated with severe clinical manifestations such as localized pain, hypertension, sweating, tachycardia and complex hyperinflammatory responses. In general, T. serrulatus venom contains a complex mixture of active compounds, including proteins, peptides, and amino acids. Although knowledge of the protein fractions of scorpion venom is available, venom lipid components are not yet comprehensively known. The aim of the present study was to determine and characterize the lipid constituents/profile of the T. serratus venom utilizing liquid chromatography coupled with high-resolution mass spectrometry. Lipid species (164 in total) belonging to 3 different lipid categories, glycerophospholipids, sphingolipids, and glycerolipids, were identified. A further search on MetaCore/MetaDrug platform, which is based upon a manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism, and toxicity information, exhibited several metabolic pathways for 24 of previously identified lipid species, including activation of nuclear factor kappa B and oxidative stress pathways. Further several bioactive compounds, such as plasmalogens, lyso-platelet-activating factors, and sphingomyelins, associated with systemic responses triggered by T. serrulatus envenomation were detected. Finally, lipidomic data presented provide advanced and valuable information to better comprehend the mechanisms underlying the complex pathophysiology induced by T. serrulatus envenomation.
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Venenos de Escorpião , Animais , Venenos de Escorpião/toxicidade , Venenos de Escorpião/química , Escorpiões , Brasil , Lipidômica , LipídeosRESUMO
BACKGROUND: Recurrent Pregnancy Loss (RPL) and Recurrent Implantation Failure (RIF) are highly heterogeneous condition and many of the mechanisms involved still require elucidation. The aim was to analyze the lipidomic profile in plasma of women with RPL and RIF before and after receiving the Lipid Emulsion Therapy (LET) containing 10% fish oil (SMOFlipid® 20%). METHODS: This study included twenty-six women with RPL or RIF from immunological or inflammatory causes, with elevated natural killer cell levels and divided into a Pregnancy Loss or a Live Birth group according to the outcome. The women received intravenous LET and sample collecting was done before the first, third and fifth dose of LET in the pregnant women. Ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF MS) and multivariate statistical methods were performed to evaluate the profile of phospholipids present in the women's plasma. RESULTS: An increase of phosphatidylcholines (PC) 40:8 and 36:5 levels with predominance of n6 polyunsaturated fatty acids (PUFA) was observed in plasma lipids of the Pregnancy Loss Group compared to Live Birth Group. We also observed an increase in the relative abundance of n3 PUFA-PC species (42:10 and 36:6) and LysoPC 15:0 with the long term use of LET. CONCLUSION: The greater availability of n3 PUFA in plasma of the pregnant women stemming from LET use can be considered advantageous regarding the alteration of the phospholipid profile and its postulated anti-inflammatory and immunomodulatory role.
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Aborto Habitual , Ácidos Graxos Ômega-3 , Humanos , Feminino , Gravidez , Fosfolipídeos , Aborto Habitual/terapia , Aborto Habitual/etiologia , Ácidos Graxos Ômega-3/uso terapêutico , Emulsões Gordurosas Intravenosas , Cromatografia LíquidaRESUMO
The impact of cocoa lipid content on chocolate quality has been extensively described. Nevertheless, few studies have elucidated the cocoa lipid composition and their bioactive properties, focusing only on specific lipids. In the present study the lipidome of fine-flavor cocoa fermentation was analyzed using LC-MS-QTOF and a Machine Learning model to assess potential bioactivity was developed. Our results revealed that the cocoa lipidome, comprised mainly of fatty acyls and glycerophospholipids, remains stable during fine-flavor cocoa fermentations. Also, several Machine Learning algorithms were trained to explore potential biological activity among the identified lipids. We found that K-Nearest Neighbors had the best performance. This model was used to classify the identified lipids as bioactive or non-bioactive, nominating 28 molecules as potential bioactive lipids. None of these compounds have been previously reported as bioactive. Our work is the first untargeted lipidomic study and systematic effort to investigate potential bioactivity in fine-flavor cocoa lipids.
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Cacau , Chocolate , Fermentação , Lipidômica , Lipídeos , PaladarRESUMO
Sudden infant death syndrome (SIDS) represents the leading cause of death in under one year of age in developing countries. Even in our century, its etiology is not clear, and there is no biomarker that is discriminative enough to predict the risk of suffering from it. Therefore, in this work, taking a public dataset on the lipidomic profile of babies who died from this syndrome compared to a control group, a univariate analysis was performed using the Mann-Whitney U test, with the aim of identifying the characteristics that enable discriminating between both groups. Those characteristics with a p-value less than or equal to 0.05 were taken; once these characteristics were obtained, classification models were implemented (random forests (RF), logistic regression (LR), support vector machine (SVM) and naive Bayes (NB)). We used seventy percent of the data for model training, subjecting it to a cross-validation (k = 5) and later submitting to validation in a blind test with 30% of the remaining data, which allows simulating the scenario in real life-that is, with an unknown population for the model. The model with the best performance was RF, since in the blind test, it obtained an AUC of 0.9, specificity of 1, and sensitivity of 0.8. The proposed model provides the basis for the construction of a SIDS risk prediction computer tool, which will contribute to prevention, and proposes lines of research to deal with this pathology.
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Introduction: Cardiovascular disease (CVD) is the leading cause of mortality worldwide and is the leading cause of death in the US. Lipid dysregulation is a well-known precursor to metabolic diseases, including CVD. There is a growing body of literature that suggests MRI-derived epicardial fat volume, or epicardial adipose tissue (EAT) volume, is linked to the development of coronary artery disease. Interestingly, epicardial fat is also actively involved in lipid and energy homeostasis, with epicardial adipose tissue having a greater capacity for release and uptake of free fatty acids. However, there is a scarcity of knowledge on the influence of plasma lipids on EAT volume. Aim: The focus of this study is on the identification of novel lipidomic species associated with CMRI-derived measures of epicardial fat in Mexican American individuals. Methods: We performed lipidomic profiling on 200 Mexican American individuals. High-throughput mass spectrometry enabled rapid capture of precise lipidomic profiles, providing measures of 799 unique species from circulating plasma samples. Because of our extended pedigree design, we utilized a standard quantitative genetic linear mixed model analysis to determine whether lipids were correlated with EAT by formally testing for association between each lipid species and the CMRI epicardial fat phenotype. Results: After correction for multiple testing using the FDR approach, we identified 135 lipid species showing significant association with epicardial fat. Of those, 131 lipid species were positively correlated with EAT, where increased circulating lipid levels were correlated with increased epicardial fat. Interestingly, the top 10 lipid species associated with an increased epicardial fat volume were from the deoxyceramide (Cer(m)) and triacylglycerol (TG) families. Deoxyceramides are atypical and neurotoxic sphingolipids. Triacylglycerols are an abundant lipid class and comprise the bulk of storage fat in tissues. Pathologically elevated TG and Cer(m) levels are related to CVD risk and, in our study, to EAT volume. Conclusion: Our results indicate that specific lipid abnormalities such as enriched saturated triacylglycerols and the presence of toxic ceramides Cer(m) in plasma of our individuals could precede CVD with increased EAT volume.
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In plants, lipid metabolism and remodelling are key mechanisms for survival under temperature stress. The present study attempted to compare the lipid profile in barley roots both under chilling stress treatment and in the subsequent recovery to stress. Lipids were obtained through a single-extraction method with a polar solvent mixture, followed by mass spectrometry analysis. The results indicate that lipid metabolism was significantly affected by chilling. Most of the glycerolipids analysed returned to control values during short- and long-term recovery, whereas several representative phosphatidic acid (PA) molecular species were edited during long-term recovery. Most of the PA molecular species that increased in the long-term had the same acyl chains as the phosphatidylcholine (PC) species that decreased. C34:2 and C36:4 underwent the most remarkable changes. Given that the mechanisms underlying the acyl-editing of PC in barley roots remain elusive, we also evaluated the contribution of lysophosphatidylcholine acyltransferases (HvLPCAT) and phospholipase A (HvPLA). In line with the aforementioned results, the expression of the HvLPCAT and HvPLA genes was up-regulated during recovery from chilling. The differential acyl-editing of PA during recovery, which involves the remodelling of PC, might therefore be a regulatory mechanism of cold tolerance in barley.
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Hordeum , Temperatura Baixa , Hordeum/genética , Metabolismo dos Lipídeos , Ácidos Fosfatídicos , Raízes de Plantas/genéticaRESUMO
Mammalian cells synthesize H2S from sulfur-containing amino acids and are also exposed to exogenous sources of this signaling molecule, notably from gut microbes. As an inhibitor of complex IV in the electron transport chain, H2S can have a profound impact on metabolism, suggesting the hypothesis that metabolic reprogramming is a primary mechanism by which H2S signals. In this study, we report that H2S increases lipogenesis in many cell types, using carbon derived from glutamine rather than from glucose. H2S-stimulated lipid synthesis is sensitive to the mitochondrial NAD(P)H pools and is enabled by reductive carboxylation of α-ketoglutarate. Lipidomics analysis revealed that H2S elicits time-dependent changes across several lipid classes, e.g., upregulating triglycerides while downregulating phosphatidylcholine. Direct analysis of triglyceride concentration revealed that H2S induces a net increase in the size of this lipid pool. These results provide a mechanistic framework for understanding the effects of H2S on increasing lipid droplets in adipocytes and population studies that have pointed to a positive correlation between cysteine (a substrate for H2S synthesis) and fat mass.
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Glutamina , Sulfeto de Hidrogênio , NAD , Metabolismo Energético , Lipogênese , Mitocôndrias/metabolismo , Transdução de SinaisRESUMO
Soil-transmitted helminths, including hookworms and whipworms, infect billions of people worldwide. Their capacity to penetrate and migrate through their hosts' tissues is influenced by the suite of molecules produced by the infective developmental stages. To facilitate a better understanding of the immunobiology and pathogenicity of human hookworms and whipworms, we investigated the metabolomes of the infective stage of Nippostrongylus brasiliensis third-stage larvae (L3) which penetrate the skin and Trichuris muris eggs which are orally ingested, using untargeted liquid chromatography-mass spectrometry (LC-MS). We identified 55 polar metabolites through Metabolomics Standard Initiative level-1 (MSI-I) identification from N. brasiliensis and T. muris infective stages, out of which seven were unique to excretory/secretory products (ESPs) of N. brasiliensis L3. Amino acids were a principal constituent (33 amino acids). Additionally, we identified 350 putative lipids, out of which 28 (all known lipids) were unique to N. brasiliensis L3 somatic extract and four to T. muris embryonated egg somatic extract. Glycerophospholipids and glycerolipids were the major lipid groups. The catalogue of metabolites identified in this study shed light on the biology, and possible therapeutic and diagnostic targets for the treatment of these critical infectious pathogens. Moreover, with the growing body of literature on the therapeutic utility of helminth ESPs for treating inflammatory diseases, a role for metabolites is likely but has received little attention thus far.
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Malassezia yeasts are lipid dependent and part of the human and animal skin microbiome. However, they are also associated with a variety of dermatological conditions and even cause systemic infections. How these yeasts can live as commensals on the skin and switch to a pathogenic stage has long been a matter of debate. Lipids are important cellular molecules, and understanding the lipid metabolism and composition of Malassezia species is crucial to comprehending their biology and host-microbe interaction. Here, we investigated the lipid composition of Malassezia strains grown to the stationary phase in a complex Dixon medium broth. In this study, we perform a lipidomic analysis of a subset of species; in addition, we conducted a gene prediction analysis for the detection of lipid metabolic proteins. We identified 18 lipid classes and 428 lipidic compounds. The most commonly found lipids were triglycerides (TAG), sterol (CH), diglycerides (DG), fatty acids (FAs), phosphatidylcholine (PC), phosphatidylethanolamine (PE), ceramides, cholesteryl ester (CE), sphingomyelin (SM), acylcarnitine, and lysophospholipids. Particularly, we found a low content of CEs in Malassezia furfur, atypical M. furfur, and Malassezia pachydermatis and undetectable traces of these components in Malassezia globosa, Malassezia restricta, and Malassezia sympodialis. Remarkably, uncommon lipids in yeast, like diacylglyceryltrimethylhomoserine and FA esters of hydroxyl FAs, were found in a variable concentration in these Malassezia species. The latter are bioactive lipids recently reported to have antidiabetic and anti-inflammatory properties. The results obtained can be used to discriminate different Malassezia species and offer a new overview of the lipid composition of these yeasts. We could confirm the presence and the absence of certain lipid-biosynthesis genes in specific species. Further analyses are necessary to continue disclosing the complex lipidome of Malassezia species and the impact of the lipid metabolism in connection with the host interaction.
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Malassezia , Animais , Humanos , Lipidômica , Lipídeos , Malassezia/genética , Saccharomyces cerevisiaeRESUMO
In this era of precision medicine, there is an increasingly urgent need for highly sensitive tests for detecting tumors such as colon cancer (CC), a silent disease where the first symptoms may take 10-15 years to appear. Mass spectrometry-based lipidomics is an emerging tool for such clinical diagnosis. We used ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry operating in high energy collision spectral acquisition mode (MSE) mode (UPLC-QTOF-MSE) and gas chromatography (GC) to investigate differences between the plasmatic lipidic composition of CC patients and control (CTR) subjects. Key enzymes in lipidic metabolism were investigated using immuno-based detection assays. Our partial least squares discriminant analysis (PLS-DA) resulted in a suitable discrimination between CTR and CC plasma samples. Forty-two statistically significant discriminating lipids were putatively identified. Ether lipids showed a prominent presence and accordingly, a decrease in glyceronephosphate O-acyltransferase (GNPAT) enzyme activity was found. A receiver operating characteristic (ROC) curve built for three plasmalogens of phosphatidylserine (PS), named PS(P-36:1), PS(P-38:3) and PS(P-40:5), presented an area under the curve (AUC) of 0.998, and sensitivity and specificity of 100 and 85.7% respectively. These results show significant differences in CC patients' plasma lipid composition that may be useful in discriminating them from CTR individuals with a special role for plasmalogens.
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Sepsis is a severe disease with a high mortality rate. Identification and treatment in the initial hours of the disease improve outcomes. Some biomarkers like procalcitonin and C-reactive protein are used for diagnosis and to access sepsis prognosis and they can help in clinical decision-making, but none has sufficient specificity or sensitivity to be routinely employed in clinical practice. This review seeks to evaluate lipid metabolism alterations in patients with sepsis and the possibility of using the respective metabolites as biomarkers of the disease. A search of the main electronic biomedical databases was conducted for the 20-year period ending in February 2020, focused on primary research articles on biomarkers in sepsis. The keywords included sepsis, septic shock, biomarker, metabolomic, lipidomic and lysophosphatidylcoline.. It concludes that altered lipid profiles, along with the progress of the disease should provide new insights, enabling a better understanding of the pathogenic mechanisms and making it possible to design new early diagnosis and therapeutic procedures for sepsis.
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Biomarcadores/sangue , Lipidômica , Sepse/sangue , Atenção à Saúde , Humanos , Inflamação/sangue , Inflamação/patologia , Redes e Vias MetabólicasRESUMO
Oils and fats are important raw materials in food products, animal feed, cosmetics, and pharmaceuticals among others. The market today is dominated by oils derive, d from African palm, soybean, oilseed and animal fats. Colombia's Amazon region has endemic palms such as Euterpe precatoria (açai), Oenocarpus bataua (patawa), and Mauritia flexuosa (buriti) which grow in abundance and produce a large amount of ethereal extract. However, as these oils have never been used for any economic purpose, little is known about their chemical composition or their potential as natural ingredients for the cosmetics or food industries. In order to fill this gap, we decided to characterize the lipids present in the fruits of these palms. We began by extracting the oils using mechanical and solvent-based approaches. The oils were evaluated by quantifying the quality indices and their lipidomic profiles. The main components of these profiles were triglycerides, followed by diglycerides, fatty acids, acylcarnitine, ceramides, ergosterol, lysophosphatidylcholine, phosphatidyl ethanolamine, and sphingolipids. The results suggest that solvent extraction helped increase the diglyceride concentration in the three analyzed fruits. Unsaturated lipids were predominant in all three fruits and triolein was the most abundant compound. Characterization of the oils provides important insights into the way they might behave as potential ingredients of a range of products. The sustainable use of these oils may have considerable economic potential.
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Fracionamento Químico/métodos , Frutas/metabolismo , Lipidômica , Óleos de Plantas/isolamento & purificação , Óleos de Plantas/metabolismoRESUMO
A obesidade é um dos principais fatores etiológicos do desenvolvimento da resistência à insulina, e ambos são responsáveis, em parte, pelo aumento do estresse oxidativo e diabete mellitus tipo 2. Vários estudos têm mostrado os benefícios de uma dieta rica em vegetais e frutas, devido à ação dos compostos bioativos sobre os parâmetros clínicos e estresse oxidativo. O objetivo deste estudo foi verificar os efeitos dos sucos de laranja, obtido das variedades Pera e Moro, sobre os marcadores bioquímicos e de estresse oxidativo, em indivíduos com resistência à insulina, classificados através do índice HOMA-IR. Os voluntários foram suplementados durante 15 dias com os sucos de laranja em um ensaio crossover, com washout de 40 dias. Nos dias 0 e 16 de cada ensaio, foram registrados parâmetros antropométricos e de consumo alimentar, e coletadas amostras de sangue e urina pra análises bioquímicas e de estresse oxidativo. A composição de flavonoides entre as variedades de suco foi similar, diferindo no conteúdo de ácido ascórbico e antocianinas do suco de laranja Moro. Não foram observadas mudanças nos parâmetros de estresse oxidativo após a administração dos sucos de laranja, com exceção do 8-OHdG urinário, um marcador de dano oxidativo ao DNA que apresentou-se reduzido após ambas as intervenções. Dados clínicos não foram significativamente modificados, entretanto, observou-se grande variabilidade interindividual nos valores de pressão arterial e lipídios séricos. A partir desta premissa, foi realizada a análise lipidômica do plasma com amostras do ensaio com o suco de laranja cv. Pera e observaram-se reduções significativas nos triglicérides, principalmente aqueles compostos de ácidos graxos saturados ou monoinsaturados, ou contendo ao menos uma cadeia de ácido linoleico, além do aumento de espécies de acilcarnitinas de cadeia longa. O consumo de ambos os sucos de laranja parece exercer um efeito protetor contra o dano oxidativo ao DNA, provavelmente por ação não-enzimática. A análise lipidômica do plasma sugere que o suco de laranja cv. Pera pode modular o metabolismo de lipídios, relacionados à lipogênese de novo e beta-oxidação
Obesity is one of the main etiological factors of insulin resistance development, and both are responsible, in part, for the increase on oxidative stress and Diabetes mellitus type 2 development. Several studies have showed the benefits of a diet rich in vegetables and fruits, due to the action of bioactive compounds on biochemical and oxidative stress parameters. The aim of this study was to study the effects of orange juices obtained by varieties Pera and Moro on oxidative stress and clinical biomarkers, in obese subjects with insulin resistance, classified through the HOMA-IR index. The volunteers consumed both orange juices for 15 days with in a crossover design, with 40-day washout period. On days 0 and 16 of each trial, anthropometric and food consumption parameters were registered, and blood and urine samples were collected to analyze biochemical parameters and oxidative stress biomarkers. The flavonoids content of both juices was similar, but only orange juice from Moro variety contained anthocyanins and higher ascorbic acid content. No changes in oxidative stress markers were found after juice administration, except for urinary 8-OHdG, an oxidative DNA damage marker, which was reduced after both interventions. Clinical data were not significantly modified, but a high interindividual difference was observed in blood pressure and serum lipids. From this point of view, plasma lipidomic analysis was performed with samples of clinical trial with orange juice cv. Pera and showed significant decrease in triglycerides, mainly those with saturated or monounsaturated fatty acids, or containing at least one linoleic acid (related with inflammatory processes), besides the increase of long chain acylcarnitines. The intake of both orange juices appears to have a protective effect against DNA damage, probably by non-enzymatic action. Plasma lipidomic analysis suggests that Pera orange juice can modulate lipid metabolism related to de novo lipogenesis and fatty acid beta-oxidation
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Resistência à Insulina , Estresse Oxidativo , Citrus sinensis/efeitos adversos , Sucos de Frutas e Vegetais/efeitos adversos , Obesidade/classificaçãoRESUMO
BACKGROUND: Sepsis remains the primary cause of death from infection, despite advances in modern medicine. The identification of reliable diagnostic biomarkers for the early detection of this disease is critical and may reduce the mortality rate as it could allow early treatment. The purpose of this study was to describe the changes in the plasma and red cells blood lipidome profiling of patients diagnosed with sepsis and septic shock with the aim to identify potentially useful metabolic markers. METHODS: Lipids from plasma and erythrocytes from septic patients (n = 20) and healthy controls (n = 20) were evaluated by electrospray ionization quadrupole time-of-flight mass spectrometry, and the fatty acid composition of the phospholipids fraction of erythrocytes was determined by gas chromatography. The data were treated with multivariate data analysis, including principal component analysis and (orthogonal) partial least squares discriminant analysis. RESULTS: Potential biomarkers including lysophosphatidylcholines (lyso-PCs) and sphingomyelin (SMs) with specific fatty acid chains were identified. Both Lyso-PCs and SMs were downregulated, whereas the saturated and unsaturated phosphatidylcholines (PCs) were upregulated in the plasma and erythrocytes of septic patients. An increase in oleic acid (C18:1 n-9) accompanied by a decrease in the unsaturation index as well as in the levels on n-3 polyunsaturated fatty acids was observed in erythrocytes phospholipids patients as compared with healthy controls. CONCLUSIONS: These results suggest that lipidome profiling has great potential in discovering potential clinical biomarkers for sepsis and helping to understand its underlying mechanisms.
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The plasmalogens are a class of glycerophospholipids which contain a vinyl-ether and an ester bond at the sn-1 and sn-2 positions, respectively, in the glycerol backbone. They constitute 10 mol% of the total mass of phospholipids in humans, mainly as membrane structure components. Plasmalogens are important for the organization and stability of lipid raft microdomains and cholesterol-rich membrane regions involved in cellular signaling. In addition to their structural roles, a subset of ether lipids are thought to function as endogenous antioxidants and emerging studies suggest that they are involved in cell differentiation and signaling pathways. Although the clinical significance of plasmalogens is linked to peroxisomal disorders, the pathophysiological roles and their possible metabolic pathways are not fully understood since they present unique structural attributes for the different tissue types. Studies suggest that changes in plasmalogen metabolism may contribute to the development of various types of cancer. Here, we review the molecular characteristics of plasmalogens in order to significantly increase our understanding of the plasmalogen molecule and its involvement in gastrointestinal cancers as well as other types of cancers.
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Antineoplásicos/farmacologia , Neoplasias Gastrointestinais/etiologia , Plasmalogênios/metabolismo , Plasmalogênios/farmacologia , Antineoplásicos/química , Biomarcadores Tumorais/metabolismo , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Metabolismo dos Lipídeos , Éteres Fosfolipídicos/farmacologiaRESUMO
BACKGROUND & AIMS: Currently there is no FDA-approved therapy for nonalcoholic steatohepatitis (NASH). Increased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio can induce endoplasmic reticulum (ER) stress and mitochondrial dysfunction that characterize NASH. Our recent study with n-3 PUFA showed improvement in individual histologic parameters like steatosis, ballooning and lobular inflammation. We hypothesized that n-3 PUFA therapy mediated improvement in histologic parameters is modulated by lipidomic and proteomic changes. METHODS: We therefore evaluated hepatic proteomic and plasma lipidomic profiles before and after n-3 PUFA therapy in subjects with NASH. In a double-blind, randomized, placebo-controlled trial, patients with NASH received 6-month treatment with n-3 PUFA (0.945 g/day [64% alpha-linolenic (ALA), 21% eicosapentaenoic (EPA), and 16% docosahexaenoic (DHA) acids]). Paired liver biopsy and plasma collected before and after-n-3 PUFA therapy were assessed using mass spectrometry and gas chromatography for hepatic proteomics and plasma lipidomics. Data were matched to UniProt and LIPID MAPS database, respectively. Cytoscape software was used to analyze functional pathways. Twenty-seven NASH patients with paired liver histology and plasma before and after n-3 PUFA treatment were studied. RESULTS: Treatment with n-3 PUFA significantly increased ALA, EPA, and glycerophospholipids, and decreased arachidonic acid (p < 0.05 for all). Further, proteomic markers of cell matrix, lipid metabolism, ER stress and cellular respiratory pathways were also modulated. Interestingly, these alterations reflected functional changes highly suggestive of decreased cellular lipotoxicity potential; reduced ER proteasome degradation of proteins and induction of chaperones; and a shift in cell energy homeostasis towards mitochondrial beta-oxidation. CONCLUSION: Six-month treatment with omega-3 PUFAs significantly improved hepatic proteomic and plasma lipidomic markers of lipogenesis, endoplasmic reticulum stress and mitochondrial functions in patients with NASH.
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Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/uso terapêutico , Lipogênese/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado , Masculino , Pessoa de Meia-Idade , ProteômicaRESUMO
BACKGROUND: Rectal adenocarcinoma (RAC) is a common malignant tumor of the digestive tract and survival is highly dependent upon stage of disease at diagnosis. Lipidomic strategy can be used to identify potential biomarkers for establishing early diagnosis or therapeutic programs for RAC. OBJECTIVE: To evaluate the lipoperoxidation biomarkers and lipidomic signature in the plasma of patients with RAC (n = 23) and healthy controls (n = 18). METHODS: Lipoperoxidation was evaluated based on malondialdehyde (MDA) and F2-isoprostane levels and the lipidomic profile obtained by gas chromatography and high resolution mass spectrometry (ESI-q-TOF) associated with a multivariate statistical technique. RESULTS: The most abundant ions identified in the RAC patients were those of protonated phosphatidylcholine and phosphatidylethanolamine. It was found that a lisophosphatidylcholine (LPC) plasmalogen containing palmitoleic acid [LPC (P-16:1)], with highest variable importance projection score, showed a tendency to be lower in the cancer patients. A reduction of n - 3 polyunsaturated fatty acids was observed in the plasma of these patients. MDA levels were higher in patients with advanced cancer (stages III/IV) than in the early stages groups and the healthy group (p < 0.05). No differences in F2-isoprostane levels were observed among these groups. CONCLUSION: This study shows that the reduction in plasma levels of LPC plasmalogens associated with an increase in MDA levels may indicate increased oxidative stress in these patients and identify the metabolite LPC (P-16:1) as a putatively novel lipid signature for RAC.
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Objective To describe the protocol of the SURgically induced Metabolic effects on the Human GastroIntestinal Tract (SURMetaGIT) study, a clinical pan-omics study exploring the gastrointestinal tract as a central organ driving remission of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGB). The main points considered in the study's design and challenges faced in its application are detailed. Methods This observational, longitudinal, prospective study involved collection of gastrointestinal biopsy specimens, faeces, urine, and blood from 25 obese women with T2DM who were candidates for RYGB (20 patients for omics assessment and 5 for omics validation). These collections were performed preoperatively and 3 and 24 months postoperatively. Gastrointestinal transcriptomics; faecal metagenomics and metabolomics; plasma proteomics, lipidomics, and metabolomics; and biochemical, nutritional, and metabolic data were assessed to identify their short- and long-term correlations with T2DM remission. Results Data were collected from 20 patients before and 3 months after RYGB. These patients have nearly completed the 2-year follow-up assessments. The five additional patients are currently being selected for omics data validation. Conclusion The multi-integrated pan-omics approach of the SURMetaGIT study enables integrated analysis of data that will contribute to the understanding of molecular mechanisms involved in T2DM remission after RYGB.