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1.
Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.
Zolla, L, Ceci, M
International journal of molecular sciences. 2022;(3)
Abstract
Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while β-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.
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Entailing the Next-Generation Sequencing and Metabolome for Sustainable Agriculture by Improving Plant Tolerance.
Ashraf, MF, Hou, D, Hussain, Q, Imran, M, Pei, J, Ali, M, Shehzad, A, Anwar, M, Noman, A, Waseem, M, et al
International journal of molecular sciences. 2022;(2)
Abstract
Crop production is a serious challenge to provide food for the 10 billion individuals forecasted to live across the globe in 2050. The scientists' emphasize establishing an equilibrium among diversity and quality of crops by enhancing yield to fulfill the increasing demand for food supply sustainably. The exploitation of genetic resources using genomics and metabolomics strategies can help generate resilient plants against stressors in the future. The innovation of the next-generation sequencing (NGS) strategies laid the foundation to unveil various plants' genetic potential and help us to understand the domestication process to unmask the genetic potential among wild-type plants to utilize for crop improvement. Nowadays, NGS is generating massive genomic resources using wild-type and domesticated plants grown under normal and harsh environments to explore the stress regulatory factors and determine the key metabolites. Improved food nutritional value is also the key to eradicating malnutrition problems around the globe, which could be attained by employing the knowledge gained through NGS and metabolomics to achieve suitability in crop yield. Advanced technologies can further enhance our understanding in defining the strategy to obtain a specific phenotype of a crop. Integration among bioinformatic tools and molecular techniques, such as marker-assisted, QTLs mapping, creation of reference genome, de novo genome assembly, pan- and/or super-pan-genomes, etc., will boost breeding programs. The current article provides sequential progress in NGS technologies, a broad application of NGS, enhancement of genetic manipulation resources, and understanding the crop response to stress by producing plant metabolites. The NGS and metabolomics utilization in generating stress-tolerant plants/crops without deteriorating a natural ecosystem is considered a sustainable way to improve agriculture production. This highlighted knowledge also provides useful research that explores the suitable resources for agriculture sustainability.
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3.
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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4.
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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5.
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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7.
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.