Metabolites, Volume 11, Issue 10 (October 2021) – 65 articles

Bovine milk is a significant source of sphingolipids, dietary compounds that can exert anti-inflammatory actions, and which can modulate the host’s microbiome. Because sphingolipid synthesis can be modified by diet, we hypothesized that dietary conditions which reduced FFA availability may result in reduced sphingolipid synthesis. Twelve ruminally cannulated cows (120 ± 52 DIM; 35.5 ± 8.9 kg of milk/d; mean ± SD) were randomly assigned to treatment in a crossover design with 21-d periods. Treatments were (1) High starch (HS), (2) Control. The HS diet contained 29% starch, 24% NDF, and 2.8% fatty acids (FA), whereas the Control diet contained 20% starch, 31% NDF, and 2.3% FA. Plasma and milk samples were obtained on d 21 of each period and sphingolipids were quantified using targeted metabolomics. Univariate and multivariate analyses of generalized log-transformed and Pareto-scaled data included ANOVA (fixed effects of treatment) and discriminant analysis. The lipidomics analysis detected 71 sphingolipids across plasma and milk fat, including sphinganines (n = 3), dihydro-ceramides (n = 8), ceramides (Cer; n = 15), sphingomyelins (SM; n = 17), and glycosylated ceramides (n = 28). Followed by Cer, SM were the most abundant sphingolipids detected in milk and plasma, with a preponderance of 16:0-, 23:0-, and 24:0-carbon sidechains. Although no effects of HS diets were observed on plasma sphingolipids, we detected consistent reductions in the concentrations of several milk Cer (e.g., 22:0- and 24:0-Cer) and SM (17:0- and 23:0-SM) in response to HS. Discriminant analysis revealed distinct metabolite separation of HS and Control groups, with several Cer and SM being distinctively predictive of dietary treatment. We conclude that HS diets can reduce the secretion of milk Cer and SM, even in the absence of changes in circulating sphingolipids. Full article

Quantitative trait loci (QTLs) E and M are major soybean alleles that confer resistance to leaf-chewing insects, and are particularly effective in combination. Flavonoids and/or isoflavonoids are classes of plant secondary metabolites that previous studies agree are the causative agents of resistance of these QTLs. However, all previous studies have compared soybean genotypes that are of dissimilar genetic backgrounds, leaving it questionable what metabolites are a result of the QTL rather than the genetic background. Here, we conducted a non-targeted mass spectrometry approach without liquid chromatography to identify differences in metabolite levels among QTLs E, M, and both (EM) that were introgressed into the background of the susceptible variety Benning. Our results found that E and M mainly confer low-level, global differences in distinct sets of metabolites. The isoflavonoid daidzein was the only metabolite that demonstrated major increases, specifically in insect-treated M and EM. Interestingly, M confers increased daidzein levels in response to insect, whereas E restores M’s depleted daidzein levels in the absence of insect. Since daidzein levels do not parallel levels of resistance, our data suggest a novel mechanism that the QTLs confer resistance to insects by mediating changes in hundreds of metabolites, which would be difficult for the insect to evolve tolerance. Collective global metabolite differences conferred by E and M might explain the increased resistance of EM. Full article

Traditionally, nutritional epidemiology is the study of the relationship between diet and health and disease in humans at the population level. Commonly, the exposure of interest is food intake. In recent years, nutritional epidemiology has moved from a “black box” approach to a systems approach where genomics, metabolomics and proteomics are providing novel insights into the interplay between diet and health. In this context, metabolomics is emerging as a key tool in nutritional epidemiology. The present review explores the use of metabolomics in nutritional epidemiology. In particular, it examines the role that food-intake biomarkers play in addressing the limitations of self-reported dietary intake data and the potential of using metabolite measurements in assessing the impact of diet on metabolic pathways and physiological processes. However, for full realisation of the potential of metabolomics in nutritional epidemiology, key challenges such as robust biomarker validation and novel methods for new metabolite identification need to be addressed. The synergy between traditional epidemiologic approaches and metabolomics will facilitate the translation of nutritional epidemiologic evidence to effective precision nutrition. Full article

Green and white asparagus are quite different crops but can be harvested from the same plant. They have distinct morphological differences due to their mode of cultivation and they are characterised by having contrasting appearance and flavour. Significant chemical differences are therefore expected. Spears from three varieties of both green and white forms, harvested in two consecutive seasons were analysed using headspace GC-MS and LC-MS with an untargeted metabolomic workflow. Mainly C₅ and C₈ alcohols and aldehydes, and phenolic compounds were more abundant in green spears, whereas benzenoids, monoterpenes, unsaturated aldehydes and steroidal saponins were more abundant in white ones. Previously reported key asparagus volatiles and non-volatiles were detected at similar or not significantly different levels in the two asparagus types. Spatial metabolomics revealed also that many volatiles with known positive aroma attributes were significantly more abundant in the upper parts of the spears and showed a decreasing trend towards the base. These findings provide valuable insights into the metabolome of raw asparagus, the contrasts between green and white spears as well as the different chemical distributions along the stem. Full article

Open microalgal ponds used in industrial biomass production are susceptible to a number of biotic and abiotic environmental stressors (e.g., grazers, pathogens, pH, temperature, etc.) resulting in pond crashes with high economic costs. Identification of signature chemicals to aid in rapid, non-invasive, and accurate identification of the stressors would facilitate targeted and effective treatment to save the algal crop from a catastrophic crash. Specifically, we were interested in identifying volatile organic compounds (VOCs) that can be used to as an early diagnostic for algal crop damage. Cultures of Microchloropsis gaditana were subjected to two forms of algal crop damage: (1) active grazing by the marine rotifer, Brachionus plicatilis, or (2) repeated freeze–thaw cycles. VOCs emitted above the headspace of these algal cultures were collected using fieldable solid phase microextraction (SPME) fibers. An untargeted analysis and identification of VOCs was conducted using gas chromatography-mass spectrometry (GC-MS). Diagnostic VOCs unique to each algal crop damage mechanism were identified. Active rotifer grazing of M. gaditana was characterized by the appearance of carotenoid degradation products, including β-cyclocitral and various alkenes. Freeze–thaw algae produced a different set of VOCs, including palmitoleic acid. Both rotifer grazing and freeze–thawed algae produced β-ionone as a VOC, possibly suggesting a common stress-induced cellular mechanism. Importantly, these identified VOCs were all absent from healthy algal cultures of M. gaditana. Early detection of biotic or abiotic environmental stressors will facilitate early diagnosis and application of targeted treatments to prevent algal pond crashes. Thus, our work further supports the use of VOCs for monitoring the health of algal ponds to ultimately enhance algal crop yields for production of biofuel. Full article

Citrate is a crucial energy sensor that plays a central role in cellular metabolic homeostasis. The solute carrier family 13 member 5 (SLC13A5), a sodium-coupled citrate transporter highly expressed in the mammalian liver with relatively low levels in the testis and brain, imports citrate from extracellular spaces into the cells. The perturbation of SLC13A5 expression and/or activity is associated with non-alcoholic fatty liver disease, obesity, insulin resistance, cell proliferation, and early infantile epileptic encephalopathy. SLC13A5 has been proposed as a promising therapeutic target for the treatment of these metabolic disorders. In the liver, the inductive expression of SLC13A5 has been linked to several xenobiotic receptors such as the pregnane X receptor and the aryl hydrocarbon receptor as well as certain hormonal and nutritional stimuli. Nevertheless, in comparison to the heightened interest in understanding the biological function and clinical relevance of SLC13A5, studies focusing on the regulatory mechanisms of SLC13A5 expression are relatively limited. In this review, we discuss the current advances in our understanding of the molecular mechanisms by which the expression of SLC13A5 is regulated. We expect this review will provide greater insights into the regulation of the SLC13A5 gene transcription and the signaling pathways involved therein. Full article

I’m Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels. Full article

Volatile organic compounds (VOCs) have been proposed in the last two decades as biomarkers for disease detection and therapeutic monitoring. Model in vitro experiments with established cell lines are fundamental to clarify whether given VOCs originate from normal human cells or pathogens, including transformed cancer cells. Due to the trace concentrations of target metabolites, adsorptive enrichment is needed before gas chromatography-mass spectrometry (GC-MS) analysis, with solid-phase microextraction (SPME) being perfectly suited for this purpose. Here, a modification of SPME, the thin-film microextraction (TFME) technique, is proposed for analysis of cellular VOCs, which utilizes a planar mesh coated with stationary phase to increase the extraction phase volume and active surface area. In this study, four different adsorbents were compared: carboxen, divinylbenzene, hydrophobic−lipophilic balanced and polydimethylsiloxane. Amongst them, HLB sheets using poly(divinylbenzene-co-N-vinyl-pyrrolidone) skeleton structure proved to be the most versatile, enabling the most sensitive analysis of VOCs with a broad polarity and volatility. For HLB, sampling type (internal static headspace, external bi-directional headspace), extraction temperature and extraction time were also examined. An established method was successfully applied to analyze metabolites produced by A549 cells revealing five volatiles at significantly higher (additionally benzaldehyde at lower) levels in cell culture medium compared to the cell-free reference medium headspace. Full article

Fu brick tea (FBT) is one of the major brands of dark tea. Microbial fermentation is considered the key step in the development of the special characteristics of FBT. The systemic corelationship of the microbiome and metabolomics during manufacture of Fu brick tea is not fully understood. In this study, we comprehensively explored the microbiome and metabolite dynamic evolution during the FBT manufacturing processes, and revealed decisive factors for the quality and safety of FBT based on the grouped methods of metabolomics combined with biochemical measurements, microbiome sequencing combined with quantitative polymerase chain reaction (PCR), and multiplex analysis. Both the microbiome and quantitative PCR showed that fungi displayed concentrated distribution characteristics in the primary dark tea samples, while bacterial richness increased during the flowering processes and ripening period. All microorganism species, as well as dominant fungi and bacteria, were identified in the distinct processes periods. A total of 178 metabolites were identified, and 34 of them were characterized as critical metabolites responsible for metabolic changes caused by the corresponding processes. Metabolic analysis showed that most metabolites were decreased during the FBT manufacturing processes, with the exception of gallic acid. Multivariate analysis verified that the critical metabolites were correlated with specific dominant microbial species. All the top fungal species except unclassified_g_ Aspergillus showed positive correlations with six critical metabolites (L-The, epigallocatechin (EGC), Gln, tea polyphenol (TP), tea polysaccharides (TPs) and caffeine). Five of the top bacteria species (Cronobacter, Klebsiella, Pantoea, Pluralibacter, and unclassified_ f_Entero-bacteriaceae) showed positive correlations with epigallocatechins and tea polyphenols, while the other 11 top bacterial species correlated negatively with all the critical metabolites. The content of amino acids, tea polyphenols, tea polysaccharides, and flavonoids was reduced during microbial fermentation. In conclusion, our results reveal that microbial composition is the critical factor in changing the metabolic profile of FBT. This discovery provides a theoretical basis for improving the quality of FBT and enhancing its safety. Full article

Cesarean delivery and formula feeding have both been implicated as important factors associated with perturbations to the infant gut microbiome. To investigate the functional metabolic response of the infant gut microbial milieu to these factors, we profiled the stool metabolomes of 121 infants from a US pregnancy cohort study at approximately 6 weeks of life and evaluated associations with delivery mode and feeding method. Multivariate analysis of six-week stool metabolomic profiles indicated discrimination by both delivery mode and diet. For diet, exclusively breast-fed infants exhibited metabolomic profiles that were distinct from both exclusively formula-fed and combination-fed infants, which were relatively more similar to each other in metabolomic profile. We also identified individual metabolites that were important for differentiating delivery mode groups and feeding groups and metabolic pathways related to delivery mode and feeding type. We conclude based on previous work and this current study that the microbial communities colonizing the gastrointestinal tracts of infants are not only taxonomically, but also functionally distinct when compared according to delivery mode and feeding groups. Further, different sets of metabolites and metabolic pathways define delivery mode and diet metabotypes. Full article

Certain symptoms associated with mild sickness and lethargy have not been categorized as definitive diseases. Confirming such symptoms in captive monkeys (Macaca fascicularis, known as cynomolgus monkeys) can be difficult; however, it is possible to observe and analyze their feces. In this study, we investigated the relationship between stool state and various omics data by considering objective and quantitative values of stool water content as a phenotype for analysis. By examining the food intake of the monkeys and assessing their stool, urine, and plasma, we attempted to obtain a comprehensive understanding of the health status of individual monkeys and correlate it with the stool condition. Our metabolomics data strongly suggested that many lipid-related metabolites were correlated with the stool water content. The lipidomic analysis revealed the involvement of saturated and oxidized fatty acids, metallomics revealed the contribution of selenium (a bio-essential trace element), and intestinal microbiota analysis revealed the association of several bacterial species with the stool water content. Based on our results, we hypothesize that the redox imbalance causes minor health problems. However, it is not possible to make a definite conclusion using multi-omics alone, and other hypotheses could be proposed. Full article

Malassezia are common components of human skin, and as the dominant human skin eukaryotic microbe, they take part in complex microbe–host interactions. Other phylogenetically related fungi (including within Ustilagomycotina) communicate with their plant host through bioactive oxygenated polyunsaturated fatty acids, generally known as oxylipins, by regulating the plant immune system to increase their virulence. Oxylipins are similar in structure and function to human eicosanoids, which modulate the human immune system. This study reports the development of a highly sensitive mass-spectrometry-based method to capture and quantify bioactive oxygenated polyunsaturated fatty acids from the human skin surface and in vitro Malassezia cultures. It confirms that Malassezia are capable of synthesizing eicosanoid-like lipid mediators in vitro in a species dependent manner, many of which are found on human skin. This method enables sensitive identification and quantification of bioactive lipid mediators from human skin that may be derived from metabolic pathways shared between skin and its microbial residents. This enables better cross-disciplinary and detailed studies to dissect the interaction between Malassezia and human skin, and to identify potential intervention points to promote or abrogate inflammation and to improve human skin health. Full article

SARS-CoV-2 is causing the coronavirus disease 2019 (COVID-19) pandemic, for which effective pharmacological therapies are needed. SARS-CoV-2 induces a shift of the host cell metabolism towards glycolysis, and the glycolysis inhibitor 2-deoxy-d-glucose (2DG), which interferes with SARS-CoV-2 infection, is under development for the treatment of COVID-19 patients. The glycolytic pathway generates intermediates that supply the non-oxidative branch of the pentose phosphate pathway (PPP). In this study, the analysis of proteomics data indicated increased transketolase (TKT) levels in SARS-CoV-2-infected cells, suggesting that a role is played by the non-oxidative PPP. In agreement, the TKT inhibitor benfooxythiamine (BOT) inhibited SARS-CoV-2 replication and increased the anti-SARS-CoV-2 activity of 2DG. In conclusion, SARS-CoV-2 infection is associated with changes in the regulation of the PPP. The TKT inhibitor BOT inhibited SARS-CoV-2 replication and increased the activity of the glycolysis inhibitor 2DG. Notably, metabolic drugs like BOT and 2DG may also interfere with COVID-19-associated immunopathology by modifying the metabolism of immune cells in addition to inhibiting SARS-CoV-2 replication. Hence, they may improve COVID-19 therapy outcomes by exerting antiviral and immunomodulatory effects. Full article

Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprising since in previous loss-of-function studies targeting leukotriene biosynthesis (Alox5^−/− mice, inhibitor studies), more severe inflammatory symptoms were observed in the EAE model but the degree of inflammation in DSS colitis was attenuated. Taken together, our data indicate that these mutant Alox5-KI mice respond differently in two models of experimental inflammation than Alox5^−/− animals tested previously in similar experimental setups. Full article

Prematurity is a risk factor for the development of chronic adult diseases. Metabolomics can correlate the biochemical changes to a determined phenotype, obtaining real information about the state of health of a subject at that precise moment. Significative differences in the metabolomic profile of preterm newborns compared to those born at term have been already identified at birth. An observational case–control study was performed at the University Hospital of Siena. The aim was to evaluate and compare the metabolomic profiles of young adults born preterm to those born at term. Urinary samples were collected from 67 young adults (18–23 years old) born preterm (mean gestational age of 30 weeks, n = 49), and at term of pregnancy (mean gestational age of 38 weeks, n = 18). The urinary spectra of young adults born preterm was different from those born at term and resembled what was previously described at birth. The Random Forest algorithm gave the best classification (accuracy 82%) and indicated the following metabolites as responsible for the classification: citrate, CH2 creatinine, fumarate and hippurate. Urine spectra are promising tools for the early identification of neonates at risk of disease in adulthood and may provide insight into the pathogenesis and effects of fetal programming and infants’ outcomes. Full article

The rs7041 and rs4588 polymorphisms found in the GC gene, encoding vitamin D-binding protein (DBP), have distinct biochemical phenotypes. The aim of this study was to investigate vitamin D parameters with these polymorphisms, in individuals with possible vitamin D deficiency. The most common (49% of the cohort) genotype in rs7041 was GT, especially among individuals with high levels of free 25(OH)D calculated but with low levels of bioavailable 25(OH)D, and in rs4588 it was AC in particular among the individuals with low levels of bioavailable 25(OH)D. The most common phenotypes were Gc1s/2 (35.3%) and Gc1s/1s (31.4%), and Gc1f/1f was rare (5.9%). The variations in free and bioavailable 25(OH)D levels among healthy Turkish individuals may be attributed to the variations in total 25(OH)D as well as GC gene polymorphisms. The Turkish population shares a similarity for allele frequencies of rs7041 with the European population and similarity for allele frequencies of rs4588 with Gujarati Indians, and this may also be important in relation to certain ethnic populations showing associations between vitamin D and COVID-19. Full article

Metabolic flexibility is the ability of an organism to adapt its energy source based on nutrient availability and energy requirements. In humans, this ability has been linked to cardio-metabolic health and healthy aging. Genome-scale metabolic models have been employed to simulate metabolic flexibility by computing the Respiratory Quotient (RQ), which is defined as the ratio of carbon dioxide produced to oxygen consumed, and varies between values of 0.7 for pure fat metabolism and 1.0 for pure carbohydrate metabolism. While the nutritional determinants of metabolic flexibility are known, the role of low energy expenditure and sedentary behavior in the development of metabolic inflexibility is less studied. In this study, we present a new description of metabolic flexibility in genome-scale metabolic models which accounts for energy expenditure, and we study the interactions between physical activity and nutrition in a set of patient-derived models of skeletal muscle metabolism in older adults. The simulations show that fuel choice is sensitive to ATP consumption rate in all models tested. The ability to adapt fuel utilization to energy demands is an intrinsic property of the metabolic network. Full article

Several differential panels of metabolites have been associated with the presence of metabolic syndrome and its related conditions, namely non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study aimed to perform a systematic review to summarize the most recent finding in terms of circulating biomarkers following NAFLD/NASH syndromes. Hence, the research was focused on NAFLD/NASH studies analysed by metabolomics approaches. Following Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, a systematic search was conducted on the PubMed database. The inclusion criteria were (i) publication date between 2010 and 2021, (ii) presence of the combination of terms: metabolomics and NAFLD/NASH, and (iii) published in a scholarly peer-reviewed journal. Studies were excluded from the review if they were (i) single-case studies, (ii) unpublished thesis and dissertation studies, and (iii) not published in a peer-reviewed journal. Following these procedures, 10 eligible studies among 93 were taken into consideration. The metabolisms of amino acids, fatty acid, and vitamins were significantly different in patients affected by NAFLD and NASH compared to healthy controls. These findings suggest that low weight metabolites are an important indicator for NAFLD/NASH syndrome and there is a strong overlap between NAFLD/NASH and the metabolic syndrome. These findings may lead to new perspectives in early diagnosis, identification of novel biomarkers, and providing novel targets for pharmacological interventions. Full article

Microbial natural products are a major source of bioactive compounds for drug discovery. Among these molecules, nonribosomal peptides (NRPs) represent a diverse class of natural products that include antibiotics, immunosuppressants, and anticancer agents. Recent breakthroughs in natural product discovery have revealed the chemical structure of several thousand NRPs. However, biosynthetic gene clusters (BGCs) encoding them are known only for a few hundred compounds. Here, we developed Nerpa, a computational method for the high-throughput discovery of novel BGCs responsible for producing known NRPs. After searching 13,399 representative bacterial genomes from the RefSeq repository against 8368 known NRPs, Nerpa linked 117 BGCs to their products. We further experimentally validated the predicted BGC of ngercheumicin from Photobacterium galatheae via mass spectrometry. Nerpa supports searching new genomes against thousands of known NRP structures, and novel molecular structures against tens of thousands of bacterial genomes. The availability of these tools can enhance our understanding of NRP synthesis and the function of their biosynthetic enzymes. Full article

Given the high biological impact of classical and emerging toxicants, a sensitive and comprehensive assessment of the hazards and risks of these substances to organisms is urgently needed. In this sense, toxicometabolomics emerged as a new and growing field in life sciences, which use metabolomics to provide new sets of susceptibility, exposure, and/or effects biomarkers; and to characterize in detail the metabolic responses and altered biological pathways that various stressful stimuli cause in many organisms. The present review focuses on the analytical platforms and the typical workflow employed in toxicometabolomic studies, and gives an overview of recent exploratory research that applied metabolomics in various areas of toxicology. Full article

The prevalence and the incidence of type 2 diabetes (T2D), representing >90% of all cases of diabetes, are increasing rapidly worldwide. Identification of individuals at high risk of developing diabetes is of great importance, as early interventions might delay or even prevent full-blown disease. T2D is a complex disease caused by multiple genetic variants in interaction with lifestyle and environmental factors. Cardiovascular disease (CVD) is the major cause of morbidity and mortality. Detailed understanding of molecular mechanisms underlying in CVD events is still largely missing. Several risk factors are shared between T2D and CVD, including obesity, insulin resistance, dyslipidemia, and hyperglycemia. CVD can precede the development of T2D, and T2D is a major risk factor for CVD, suggesting that both conditions have common genetic and environmental antecedents and that they share “common soil”. We analyzed the relationship between the risk factors for T2D and CVD based on genetics and population-based studies with emphasis on Mendelian randomization studies. Full article

Apolipoprotein (apo) B, the critical structural protein of the atherogenic lipoproteins, has two major isoforms: apoB48 and apoB100. ApoB48 is found in chylomicrons and chylomicron remnants with one apoB48 molecule per chylomicron particle. Similarly, a single apoB100 molecule is contained per particle of very-low-density lipoprotein (VLDL), intermediate density lipoprotein, LDL and lipoprotein(a). This unique one apoB per particle ratio makes plasma apoB concentration a direct measure of the number of circulating atherogenic lipoproteins. ApoB levels indicate the atherogenic particle concentration independent of the particle cholesterol content, which is variable. While LDL, the major cholesterol-carrying serum lipoprotein, is the primary therapeutic target for management and prevention of atherosclerotic cardiovascular disease, there is strong evidence that apoB is a more accurate indicator of cardiovascular risk than either total cholesterol or LDL cholesterol. This review examines multiple aspects of apoB structure and function, with a focus on the controversy over use of apoB as a therapeutic target in clinical practice. Ongoing coronary artery disease residual risk, despite lipid-lowering treatment, has left patients and clinicians with unsatisfactory options for monitoring cardiovascular health. At the present time, the substitution of apoB for LDL-C in cardiovascular disease prevention guidelines has been deemed unjustified, but discussions continue. Full article

Zinc plays a pivotal role in the function of cells and can induce apoptosis in various cancer cells, including Raji B lymphoma. However, the metabolic mechanism of Zn-induced apoptosis in Raji cells has not been explored. In this study, we performed global metabolic profiling using UPLC−Orbitrap−MS to assess the apoptosis of Raji cells induced by Zn ions released from ZnO nanorods. Multivariate analysis and database searches identified altered metabolites. Furthermore, the differences in the phosphorylation of 1380 proteins were also evaluated by Full Moon kinase array to discover the protein associated Zn−induced apoptosis. From the results, a prominent increase in glycerophosphocholine and fatty acids was observed after Zn ion treatment, but only arachidonic acid was shown to induce apoptosis. The kinase array revealed that the phosphorylation of p53, GTPase activation protein, CaMK2a, PPAR−γ, and PLA−2 was changed. From the pathway analysis, metabolic changes showed earlier onset than protein signaling, which were related to choline metabolism. LC−MS analysis was used to quantify the intracellular choline concentration, which decreased after Zn treatment, which may be related to the choline consumption required to produce choline-containing metabolites. Overall, we found that choline metabolism plays an important role in Zn-induced Raji cell apoptosis. Full article

Plant cell cultures derived from Taxus are used to produce valuable metabolites like paclitaxel, a chemotherapeutic drug. Methyl jasmonate elicitation enhances paclitaxel accumulation, but also inhibits culture growth and increases phenylpropanoid biosynthesis, two side effects that detract from taxane accumulation. To understand the connection between all of these processes, a systems approach is applied to investigate cell-wide metabolism in Taxus. Non-paclitaxel and paclitaxel accumulating cultures were elicited over single and multi-generational periods, and subsequent changes in conserved and specialized metabolism were quantified. Methyl jasmonate typically resulted in decreased growth and increased metabolite content in paclitaxel accumulating cultures. Conversely, elicitation typically resulted in either no change or decrease in accumulation of metabolites in the non-paclitaxel accumulating cultures. In both sets of cultures, variability was seen in the response to methyl jasmonate across generations of cell growth. Consolidation of these data determined that paclitaxel accumulation and basal levels of phenolic and flavonoid compounds are indirectly correlated with aggregate size. These approaches assess alternative metabolic pathways that are linked to paclitaxel biosynthesis and provide a comprehensive strategy to both understand the relationship between conserved and specialized metabolism in plants and in the design of strategies to increase natural product yields in plant cell culture. Full article

Early detection of pathogenesis through biomarkers holds the key to controlling hypertension and preventing cardiovascular complications. Metabolomics profiling acts as a potent and high throughput tool offering new insights on disease pathogenesis and potential in the early diagnosis of clinical hypertension with a tremendous translational promise. This review summarizes the latest progress of metabolomics and metabolites fingerprints and mainly discusses the current trends in the application in clinical hypertension. We also discussed the associated mechanisms and pathways involved in hypertension’s pathogenesis and explored related research challenges and future perspectives. The information will improve our understanding of the development of hypertension and inspire the clinical application of metabolomics in hypertension and its associated cardiovascular complications. Full article

After ingestion, consumed drugs and their metabolites are incorporated into hair, which has a long detection window, ranging up to months. Therefore, in addition to conventional blood and urine analyses, hair analysis can provide useful information on long-term drug exposure. Meta-bolite-to-drug (MD) ratios are helpful in interpreting hair results, as they provide useful information on drug metabolism and can be used to distinguish drug use from external contamination, which is otherwise a limitation in hair analysis. Despite this, the MD ratios of a wide range of pharmaceuticals have scarcely been explored. This review aims to provide an overview of MD ratios in hair in a range of pharmaceuticals of interest to forensic toxicology, such as antipsychotic drugs, antidepressant drugs, benzodiazepines, common opiates/opioids, etc. The factors influencing the ratio were evaluated. MD ratios of 41 pharmaceuticals were reported from almost 100 studies. MD ratios below 1 were frequently reported, indicating higher concentrations of the parent pharmaceutical than of its metabolite in hair, but wide-ranging MD ratios of the majority of pharmaceuticals were found. Intra- and interindividual differences and compound properties were variables possibly contributing to this. This overview presents guidance for future comparison and evaluation of MD ratios of pharmaceuticals. Full article

As an emerging platform technology, metabolomics offers new insights into the pathomechanisms associated with complex disease conditions, including cardiovascular diseases. It also facilitates assessing the risk of developing the disease before its clinical manifestation. For this reason, metabolomics is of growing interest for understanding the pathogenesis of acute coronary syndromes (ACS), finding new biomarkers of ACS, and its associated risk management. Metabolomics-based studies in ACS have already demonstrated immense potential for biomarker discovery and mechanistic insights by identifying metabolomic signatures (e.g., branched-chain amino acids, acylcarnitines, lysophosphatidylcholines) associated with disease progression. Herein, we discuss the various metabolomics approaches and the challenges involved in metabolic profiling, focusing on ACS. Special attention has been paid to the clinical studies of metabolomics and lipidomics in ACS, with an emphasis on ischemia/reperfusion injury. Full article

Two species of oak are dominant in French forests: pedunculate oak (Quercus robur L.) and sessile oak (Quercus petraea Liebl.). Their differentiation is not straightforward but is essential to better understand their respective molecular content in order to better valorize them. Thus, to improve oak species identification, an untargeted UHPLC-HRMS/MS method associated with a two-step data treatment was developed to analyze a wide range of specialized metabolites enabling the comparison of both species of oak extracts. Pooled extracts from sessile and pedunculate oaks, composed of extracts from several trees of pure species from various origins, were compared using first the Venn diagram, as a quick way to get an initial idea of how close the extracts are, and then using a molecular network to visualize, on the one hand, the ions shared between the two species and, on the other hand, the compounds specific to one species. The molecular network showed that the two species shared common clusters mainly representative of tannins derivatives and that each species has specific molecules with similar fragmentation patterns, associated in specific clusters. This methodology was then applied to compare these two pooled extracts to unknown individuals in order to determine the species. The Venn diagram allowed for the quick presumption of the species of the individual and then the species could be assigned more precisely with the molecular network, at the level of specific clusters. This method, developed for the first time, has several interests. First, it makes it possible to discriminate the species and to correctly assign the species of unknown samples. Moreover, it gave an overview of the metabolite composition of each sample to better target oak tree utilization and valorization. Full article

Fungi represent a huge reservoir of structurally diverse bio-metabolites. Although there has been a marked increase in the number of isolated fungal metabolites over the past years, many hidden metabolites still need to be discovered. Depsides are a group of polyketides consisting of two or more ester-linked hydroxybenzoic acid moieties. They possess valuable bioactive properties, such as anticancer, antidiabetic, antibacterial, antiviral, anti-inflammatory, antifungal, antifouling, and antioxidant qualities, as well as various human enzyme-inhibitory activities. This review provides an overview of the reported data on fungal depsides, including their sources, biosynthesis, physical and spectral data, and bioactivities in the period from 1975 to 2020. Overall, 110 metabolites and more than 122 references are confirmed. This is the first review of these multi-faceted metabolites from fungi. Full article

Since obese patients form cholesterol gallstones very rapidly after bariatric surgery, in patients who did not form gallstones during preceding years, we hypothesized that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. We therefore analyzed the lipid composition of gallbladder bile derived from 18 bariatric gallstone patients and 17 nonbariatric gallstone patients (median (IQR) age, 46.0 (28.0–54.0) years; 33 (94%) female) during laparoscopic cholecystectomy using an enzymatic and lipidomics approach. We observed a higher concentration of total lipids (9.9 vs. 5.8 g/dL), bile acids (157.7 vs. 81.5 mM), cholesterol (10.6 vs. 5.4 mM), and phospholipids (30.4 vs. 21.8 mM) in bariatric gallstone patients compared to nonbariatric gallstone patients. The cholesterol saturation index did not significantly differ between the two groups. Lipidomics analysis revealed an interesting pattern. Enhanced amounts of a number of lipid species were found in the gallbladder bile of nonbariatric gallstone patients. Most striking was a fivefold higher amount of triglyceride. A concomitant ninefold increase of apolipoprotein B was found, suggesting secretion of triglyceride-rich lipoproteins (TRLs) at the canalicular pole of the hepatocyte in livers from nonbariatric gallstone patients. These findings suggest that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. Impaired gallbladder emptying might explain the rapid gallstone formation after bariatric surgery, while biliary TRL secretion might contribute to gallstone formation in nonbariatric patients. Full article