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1.
Metformin Treatment or PRODH/POX-Knock out Similarly Induces Apoptosis by Reprograming of Amino Acid Metabolism, TCA, Urea Cycle and Pentose Phosphate Pathway in MCF-7 Breast Cancer Cells.
Huynh, TYL, Oscilowska, I, Sáiz, J, Nizioł, M, Baszanowska, W, Barbas, C, Palka, J
Biomolecules. 2021;(12)
Abstract
It has been considered that proline dehydrogenase/proline oxidase (PRODH/POX) is involved in antineoplastic activity of metformin (MET). The aim of this study is identification of key metabolites of glycolysis, pentose phosphate pathway (PPP), tricarboxylic acids (TCA), urea cycles (UC) and some amino acids in MET-treated MCF-7 cells and PRODH/POX-knocked out MCF-7 (MCF-7crPOX) cells. MCF-7crPOX cells were generated by using CRISPR-Cas9. Targeted metabolomics was performed by LC-MS/MS/QqQ. Expression of pro-apoptotic proteins was evaluated by Western blot. In the absence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to similar inhibition of glycolysis (drastic increase in intracellular glucose and pyruvate) and increase in the utilization of phospho-enol-pyruvic acid, glucose-6-phosphate and some metabolites of TCA and UC, contributing to apoptosis. However, in the presence of glutamine, MET treatment or PRODH/POX-knock out of MCF-7 cells contributed to utilization of some studied metabolites (except glucose), facilitating pro-survival phenotype of MCF-7 cells in these conditions. It suggests that MET treatment or PRODH/POX-knock out induce similar metabolic effects (glucose starvation) and glycolysis is tightly linked to glutamine metabolism in MCF-7 breast cancer cells. The data provide insight into mechanism of anticancer activity of MET as an approach to further studies on experimental breast cancer therapy.
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Urinary metabolomic profiling reveals difference between two traditional Chinese medicine subtypes of coronary heart disease.
Guo, N, Chen, Y, Yang, X, Yan, H, Fan, B, Quan, J, Wang, M, Yang, H
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2021;:122808
Abstract
The World Health Organization has shown that coronary heart disease (CHD) is a more common cause of death than cancer. In traditional Chinese medicine (TCM), CHD is classified as a form of thoracic obstruction that can be divided in different subtypes including Qi stagnation with blood stasis (QS) and Qi deficiency with blood stasis (QD). Different treatment strategies are used based on this subtyping. Owing to the lack of scientific markers in the diagnosis of these subtypes, subjective judgments made by clinicians have limited the objective manner for utility of TCM in the treatment of CHD. Untargeted (UHPLC-QTOF-MS) and targeted (UHPLC-MS/MS) metabolomics approaches were employed to search significantly different metabolites related to the QS or QD subtypes of CHD with angina pectoris in this study. A total of 42 metabolites were obtained in the untargeted metabolomics analysis and 34 amino acids were detected in the targeted metabolomics analysis. In total, 16 metabolites were found significantly different among different groups. The results showed distinct metabolic profiles of urine samples not only between CHD patients and healthy controls, but also between the two subtypes of CHD. Pathway analysis of the significantly varied metabolites revealed that there were subtype-related differences in the activity of pathways. Therefore, urinary metabolomics can reveal the pathological changes of CHD in different subtypes, make the diagnosis of CHD in different subtypes in an objective manner and comprehensive and contribute to personalized treatment by providing scientific evidence.
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Untargeted metabolomics reveals plasma metabolites predictive of ectopic fat in pancreas and liver as assessed by magnetic resonance imaging: the TOFI_Asia study.
Wu, ZE, Fraser, K, Kruger, MC, Sequeira, IR, Yip, W, Lu, LW, Plank, LD, Murphy, R, Cooper, GJS, Martin, JC, et al
International journal of obesity (2005). 2021;(8):1844-1854
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Abstract
BACKGROUND Excess visceral obesity and ectopic organ fat is associated with increased risk of cardiometabolic disease. However, circulating markers for early detection of ectopic fat, particularly pancreas and liver, are lacking. METHODS Lipid storage in pancreas, liver, abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 68 healthy or pre-diabetic Caucasian and Chinese women enroled in the TOFI_Asia study was assessed by magnetic resonance imaging/spectroscopy (MRI/S). Plasma metabolites were measured with untargeted liquid chromatography-mass spectroscopy (LC-MS). Multivariate partial least squares (PLS) regression identified metabolites predictive of VAT/SAT and ectopic fat; univariate linear regression adjusting for potential covariates identified individual metabolites associated with VAT/SAT and ectopic fat; linear regression adjusted for ethnicity identified clinical and anthropometric correlates for each fat depot. RESULTS PLS identified 56, 64 and 31 metabolites which jointly predicted pancreatic fat (R2Y = 0.81, Q2 = 0.69), liver fat (RY2 = 0.8, Q2 = 0.66) and VAT/SAT ((R2Y = 0.7, Q2 = 0.62)) respectively. Among the PLS-identified metabolites, none of them remained significantly associated with pancreatic fat after adjusting for all covariates. Dihydrosphingomyelin (dhSM(d36:0)), 3 phosphatidylethanolamines, 5 diacylglycerols (DG) and 40 triacylglycerols (TG) were associated with liver fat independent of covariates. Three DGs and 12 TGs were associated with VAT/SAT independent of covariates. Notably, comparison with clinical correlates showed better predictivity of ectopic fat by these PLS-identified plasma metabolite markers. CONCLUSIONS Untargeted metabolomics identified candidate markers of visceral and ectopic fat that improved fat level prediction over clinical markers. Several plasma metabolites were associated with level of liver fat and VAT/SAT ratio independent of age, total and visceral adiposity, whereas pancreatic fat deposition was only associated with increased sulfolithocholic acid independent of adiposity-related parameters, but not age.
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Effects of Sodium Selenite Injection on Serum Metabolic Profiles in Women Diagnosed with Breast Cancer-Related Lymphedema-Secondary Analysis of a Randomized Placebo-Controlled Trial Using Global Metabolomics.
Lee, H, Lee, B, Kim, Y, Min, S, Yang, E, Lee, S
Nutrients. 2021;(9)
Abstract
In our previous study, intravenous (IV) injection of selenium alleviated breast cancer-related lymphedema (BCRL). This secondary analysis aimed to explore the metabolic effects of selenium on patients with BCRL. Serum samples of the selenium-treated (SE, n = 15) or the placebo-controlled (CTRL, n = 14) groups were analyzed by ultra-high-performance liquid chromatography with Q-Exactive Orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). The SE group showed a lower ratio of extracellular water to segmental water (ECW/SW) in the affected arm to ECW/SW in the unaffected arm (arm ECW/SW ratio) than the CTRL group. Metabolomics analysis showed a valid classification at 2-weeks and 107 differential metabolites were identified. Among them, the levels of corticosterone, LTB4-DMA, and PGE3-which are known anti-inflammatory compounds-were elevated in the SE group. Pathway analysis demonstrated that lipid metabolism (glycerophospholipid metabolism, steroid hormone biosynthesis, or arachidonic acid metabolism), nucleotide metabolism (pyrimidine or purine metabolism), and vitamin metabolism (pantothenate and CoA biosynthesis, vitamin B6 metabolism, ascorbate and aldarate metabolism) were altered in the SE group compared to the CTRL group. In addition, xanthurenic acid levels were negatively associated with whole blood selenium level (WBSe) and positively associated with the arm ECW/SW. In conclusion, selenium IV injection improved the arm ECW/SW ratio and altered the serum metabolic profiles in patients with BCRL, and improved the anti-inflammatory process in lipid, nucleotide and vitamin pathways, which might alleviate the symptoms of BCRL.
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Metabolomics: small molecules that matter more.
Muthubharathi, BC, Gowripriya, T, Balamurugan, K
Molecular omics. 2021;(2):210-229
Abstract
Metabolomics, an analytical study with high-throughput profiling, helps to understand interactions within a biological system. Small molecules, called metabolites or metabolomes with the size of <1500 Da, depict the status of a biological system in a different manner. Currently, we are in need to globally analyze the metabolome and the pathways involved in healthy, as well as diseased conditions, for possible therapeutic applications. Metabolome analysis has revealed high-abundance molecules during different conditions such as diet, environmental stress, microbiota, and disease and treatment states. As a result, it is hard to understand the complete and stable network of metabolites of a biological system. This review helps readers know the available techniques to study metabolomics in addition to other major omics such as genomics, transcriptomics, and proteomics. This review also discusses the metabolomics in various pathological conditions and the importance of metabolomics in therapeutic applications.
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Metabolic phenotyping and cardiovascular disease: an overview of evidence from epidemiological settings.
Iliou, A, Mikros, E, Karaman, I, Elliott, F, Griffin, JL, Tzoulaki, I, Elliott, P
Heart (British Cardiac Society). 2021;(14):1123-1129
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Abstract
Metabolomics, the comprehensive measurement of low-molecular-weight molecules in biological fluids used for metabolic phenotyping, has emerged as a promising tool to better understand pathways underlying cardiovascular disease (CVD) and to improve cardiovascular risk stratification. Here, we present the main methodologies for metabolic phenotyping, the methodological steps to analyse these data in epidemiological settings and the associated challenges. We discuss evidence from epidemiological studies linking metabolites to coronary heart disease and stroke. These studies indicate the systemic nature of CVD and identify associated metabolic pathways such as gut microbial cometabolism, branched-chain amino acids, glycerophospholipid and cholesterol metabolism, as well as activation of inflammatory processes. Integration of metabolomic with genomic data can provide new evidence for involved biochemical pathways and potential for causality using Mendelian randomisation. The clinical utility of metabolic biomarkers for cardiovascular risk stratification in healthy individuals has not yet been established. As sample sizes with high-dimensional molecular data increase in epidemiological settings, integration of metabolomic data across studies and platforms with other molecular data will lead to new understanding of the metabolic processes underlying CVD and contribute to identification of potentially novel preventive and pharmacological targets. Metabolic phenotyping offers a powerful tool in the characterisation of the molecular signatures of CVD, paving the way to new mechanistic understanding and therapies, as well as improving risk prediction of CVD patients. However, there are still challenges to face in order to contribute to clinically important improvements in CVD.
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New plant breeding techniques and their regulatory implications: An opportunity to advance metabolomics approaches.
Enfissi, EMA, Drapal, M, Perez-Fons, L, Nogueira, M, Berry, HM, Almeida, J, Fraser, PD
Journal of plant physiology. 2021;:153378
Abstract
Over the previous decades, biotechnological innovations have led to improved agricultural productivity, more nutritious foods and lower chemical usage. Both in western societies and Low Medium Income Countries (LMICs). However, the projected increases in the global population, means the production of nutritious food stuffs must increase dramatically. Building on existing genetic modification technologies a series of New Plant Breeding Technologies (NPBT) has recently emerged. These approaches include, Agro-infiltration, grafting, cis and intragenesis and gene editing technologies. How these new techniques should be regulated has fostered considerable debate. Concerns have also been raised, to ensure over-regulation does not arise, creating administrative and economic burden. In this article the existing landscape of genetically modified crops is reviewed and the potential of several New Plant Breeding Techniques (NPBT) described. Metabolomics is an omic technology that has developed in a concurrent manner with biotechnological advances in plant breeding. There is potentially further opportunities to advance our metabolomic technologies to characterise the outputs of New Plant Breeding Technologies, in a manner that is beneficial both from an academic, biosafety and industrial perspective.
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Evaluation of change in metabolome caused by comprehensive diabetes treatment: A prospective observational study of diabetes inpatients with gas chromatography/mass spectrometry-based non-target metabolomic analysis.
Taya, N, Katakami, N, Omori, K, Arakawa, S, Hosoe, S, Watanabe, H, Takahara, M, Miyashita, K, Nishizawa, H, Matsuoka, TA, et al
Journal of diabetes investigation. 2021;(12):2232-2241
Abstract
AIMS/INTRODUCTION Diabetes patients develop a variety of metabolic abnormalities in addition to hyperglycemia. However, details regarding change in various metabolites after comprehensive diabetes treatment remain unknown. This study aimed to identify the short-term change in metabolome in inpatients who were subject to comprehensive diabetes treatment, using gas chromatography/mass spectrometry-based non-target metabolomics techniques. MATERIALS AND METHODS Participants of the present study were randomly recruited from the patients with type 2 diabetes hospitalized due to problems with glycemic control (n = 31) and volunteers without diabetes (n = 30), both of whom were aged between 20 and 75 years. A metabolomic analysis of fasting plasma samples on the 2nd (pre-treatment) and 16th hospital (post-treatment) day with gas chromatography/mass spectrometry using a multiple reaction monitoring mode was carried out. RESULTS A principal component analysis showed that metabolome of fasting plasma was different between individuals with and without diabetes. The metabolome of fasting plasma in diabetes patients after treatment was different from that of pre-treatment, as well as individuals without diabetes. Many amino acids (proline, glycine, serine, threonine, methionine, pyroglutamic acid, glutamine and lysine) were significantly increased by >10% after administering the inpatient diabetes treatment. A hierarchical clustering analysis showed that in the case of patients with markedly decreased monosaccharide levels and increased 1,5-anhydroglucitol, the levels of amino acids increased more significantly. CONCLUSIONS After a 2-week comprehensive treatment, the plasma levels of various amino acids increased in conjunction with the reduction in monosaccharide levels in poorly controlled type 2 diabetes patients.
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Multi-omics data integration in anorexia nervosa patients before and after weight regain: A microbiome-metabolomics investigation.
Monteleone, AM, Troisi, J, Fasano, A, Dalle Grave, R, Marciello, F, Serena, G, Calugi, S, Scala, G, Corrivetti, G, Cascino, G, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(3):1137-1146
Abstract
BACKGROUND & AIMS We have recently reported specific fecal metabolomic changes in acute and short-term weight restored patients with anorexia nervosa (AN). In this study we explored the association between those metabolomic changes and patients' gut microbiome composition. METHODS The gut microbiome of AN women was sequenced in both the underweight phase (n = 21) and after short-term weight restoration (n = 16) and compared to that of 20 healthy women. According to a multi-omics approach, microbiome data were correlated with 49 relevant fecal metabolites previously characterized in our participants by an untargeted metabolomic procedure. RESULTS Compared to healthy women, AN patients showed a decreased intra-individual bacterial richness, an increased Bacteroidetes-to-Firmicutes abundance ratio and significant changes in the relative abundances of several bacteria at phylum, class, order, family and genus levels. These changes were observed in both the underweight and weight-restored condition. Moreover, the relationships among the 49 previously selected fecal metabolites and bacteria genera showed structures of different complexity among the 3 groups. In particular, a quarter of those relationships showed a divergent direction in the acutely ill patients with respect to the weight-restored ones or normal controls. Finally, in acutely ill patients 70% of those correlations showed a negative sign suggesting a prevalent metabolites consummation by gut microbiome. CONCLUSIONS These data confirm a profound perturbation in the gut microbiome composition of AN patients. Moreover, for the first time, they provide the evidence that in AN gut bacteria are connected with several fecal metabolites in a different way from normal controls and with divergent directions in the acute phase with respect to the weight-restored phase.
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A Scoping Review of the Application of Metabolomics in Nutrition Research: The Literature Survey 2000-2019.
Shibutami, E, Takebayashi, T
Nutrients. 2021;(11)
Abstract
Nutrimetabolomics is an emerging field in nutrition research, and it is expected to play a significant role in deciphering the interaction between diet and health. Through the development of omics technology over the last two decades, the definition of food and nutrition has changed from sources of energy and major/micro-nutrients to an essential exposure factor that determines health risks. Furthermore, this new approach has enabled nutrition research to identify dietary biomarkers and to deepen the understanding of metabolic dynamics and the impacts on health risks. However, so far, candidate markers identified by metabolomics have not been clinically applied and more efforts should be made to validate those. To help nutrition researchers better understand the potential of its application, this scoping review outlined the historical transition, recent focuses, and future prospects of the new realm, based on trends in the number of human research articles from the early stage of 2000 to the present of 2019 by searching the Medical Literature Analysis and Retrieval System Online (MEDLINE). Among them, objective dietary assessment, metabolic profiling, and health risk prediction were positioned as three of the principal applications. The continued growth will enable nutrimetabolomics research to contribute to personalized nutrition in the future.