PubMed

Related Articles Development of a sheathless CE-ESI-MS interface. Electrophoresis. 2018 Mar 01;: Authors: Hirayama A, Abe H, Yamaguchi N, Tabata S, Tomita M, Soga T Abstract A sheath-flow interface is the most common ionization technique in CE-ESI-MS. However, this interface dilutes the analytes with the sheath liquid and decreases the sensitivity. In this study, we developed a sheathless CE-MS interface to improve sensitivity. The interface was fabricated by making small crack approximately 2 cm from the end of a capillary column fixed on a plastic plate, and then covering the crack with a dialysis membrane to prevent metabolite loss during separation. A voltage for CE separation was applied between the capillary inlet and the buffer reservoir. Under optimum conditions, 52 cationic metabolite standards were separated and selectively detected using MS. With a pressure injection of 5 kPa for 15 s (ca. 1.4 nL), the detection limits for the tested compounds were between 0.06 and 1.7 μmol/L (S/N = 3). The method was applied to analysis of cationic metabolites extracted from a small number (12,000) of cancer cells, and the number of peaks detected was about 2.5 times higher than when using conventional sheath-flow CE-MS. Because the interface is easy to construct, it is cost-effective and can be adapted to any commercially available capillaries. This method is a powerful new tool for highly sensitive CE-MS-based metabolomic analysis. This article is protected by copyright. All rights reserved. PMID: 29493797 [PubMed - as supplied by publisher]

Related Articles [Identification of biomarkers in urine of rats with spleen Qi deficiency and biological significance]. Zhongguo Zhong Yao Za Zhi. 2017 Dec;42(24):4855-4863 Authors: Liu WP, Li CY, Huang J, Liao JZ, Ma WJ, Chen HY, Rui W Abstract To identify biomarkers for spleen Qi deficiency by analyzing small molecule metabolites in urine, in order to expound the relationship between biomarkers and metabolic pathways. The spleen Qi deficiency model was established through dietary restriction and overstrain. All of the rats received D-xylose absorption experiment and blood routine test. Urine samples were collected in the next day. The urine samples were analyzed using UPLC-Q-TOF-MS to obtain the dataset of urine metabolic group. Principal component analysis (PCA), orthogonal partialleast squares-discriminant analysis (OPLS-DA) and other multivariate statistical methods were employed to evaluate the quality of the dataset and screen out potential biomarkers of spleen Qi deficiency. The results of D-xylose absorption and blood routine demonstrated that the spleen Qi deficiency model was successfully established. In positive ion mode and negative ion mode, PCA and OPLS-DA score plots could clearly distinguish model group and blank group. According to S-plot of OPLS-DA, VIP value, t-test and area under receiver operating characteristic curve (ROC), 24 biomarkers, including phenylalanine, succinic acid, aconitic acid, isocitrate acid, betaine, kynurenine, indole, creatine, creatinine, orotic acid, xanthine, and xanthurenic acid, were identified as associated with the spleen Qi deficiency, mainly involving energy metabolism, amino acid metabolism, tryptophan metabolism, purine metabolism and pyrimidine metabolism. Urine metabolomics method combined with online software package for data processing and analysis metabolic pathway can provide new methods and ideas for studies for spleen Qi deficiency and other traditional Chinese medicine symptoms. PMID: 29493158 [PubMed - in process]

Related Articles Explaining combinatorial effects of mycotoxins Deoxynivalenol and Zearalenone in mice with urinary metabolomic profiling. Sci Rep. 2018 Feb 28;8(1):3762 Authors: Ji J, Zhu P, Blaženović I, Cui F, Gholami M, Sun J, Habimana J, Zhang Y, Sun X Abstract Urine metabolic profiling of mice was conducted utilizing gas chromatography-mass spectrometry (GC-MS) to investigate the combinatory effect of mycotoxins deoxynivalenol (DON) and zearalenone (ZEN) on the metabolism of the mice. Experiments were conducted by means of five-week-old mice which were individually exposed to 2 mg/kg DON, 20 mg/kg ZEN and the mixture of DON and ZEN (2 mg/kg and 20 mg/kg, respectively). The intragastric administration was applied for three weeks and urine samples were collected for metabolic analysis. Univariate and multivariate analysis were applied to data matrix processing along with respective pathway analysis by MetaMapp and CytoScape. The results showed that the combined DON and ZEN administration resulted in lower significant changes, compared to the individual mycotoxin treated groups verified by heatmap. Metabolic pathways network mapping indicated that the combined mycotoxins treated groups showed a little effect on the metabolites in most pathways, especially in glucose metabolism and its downstream amino acid metabolism. In glucose metabolism, the content of galactose, mannitol, galactonic acid, myo-inositol, tagatose was drastically down-regulated. Furthermore, the organic acids, pyruvate, and amino acids metabolism displayed the same phenomenon. In conclusion, the combined DON/ZEN administration might lead to an "antagonistic effect" in mice metabolism. PMID: 29491435 [PubMed - in process]

Related Articles Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma. Cancer Res. 2018 Feb 28;: Authors: Makinoshima H, Umemura S, Suzuki A, Nakanishi H, Maruyama A, Udagawa H, Mimaki S, Matsumoto S, Niho S, Ishii G, Tsuboi M, Ochiai A, Esumi H, Sasaki T, Goto K, Tsuchihara K Abstract Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product: PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1 (HPRT1), a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment. PMID: 29490947 [PubMed - as supplied by publisher]

Aspirin Recapitulates Features of Caloric Restriction. Cell Rep. 2018 Feb 27;22(9):2395-2407 Authors: Pietrocola F, Castoldi F, Markaki M, Lachkar S, Chen G, Enot DP, Durand S, Bossut N, Tong M, Malik SA, Loos F, Dupont N, Mariño G, Abdelkader N, Madeo F, Maiuri MC, Kroemer R, Codogno P, Sadoshima J, Tavernarakis N, Kroemer G Abstract The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM. PMID: 29490275 [PubMed - in process]

Metabolomic Markers of Essential Fatty Acids, Carnitine, and Cholesterol Metabolism in Adults and Adolescents with Phenylketonuria. J Nutr. 2018 Feb 01;148(2):194-201 Authors: Stroup BM, Nair N, Murali SG, Broniowska K, Rohr F, Levy HL, Ney DM Abstract Background: Individuals with phenylketonuria (PKU) have a risk of cognitive impairment and inflammation. Many follow a low-phenylalanine (low-Phe) diet devoid of animal protein in combination with medical foods (MFs). Objective: To assess lipid metabolism in participants with PKU consuming amino acid MFs (AA-MFs) or glycomacropeptide MFs (GMP-MFs), we conducted fatty acid and metabolomics analyses. Methods: We used subsets of fasting plasma and urine samples from our randomized crossover trial in which participants with early-treated classical and variant (milder) PKU consumed a low-Phe diet combined with AA-MFs or GMP-MFs for 3 wk each. Fatty acid profiles of red blood cell (RBC) membranes were determined for 25 adults (aged 18-49 y) with PKU and 143 control participants. Metabolomics analyses of plasma and urine samples were conducted by Metabolon for 9-10 adolescent and adult participants with PKU and for 15 control participants. Results: RBC fatty acid profiles were not significantly different with AA-MFs or GMP-MFs. PKU participants showed higher total n-6:n-3 (ω-6:ω-3) fatty acids (mean ± SD percentages of total fatty acids: AA-MF = 5.45% ± 1.07%; controls = 4.33%; P < 0.001) and lower docosahexaenoic acid (DHA; AA-MF = 3.21% ± 0.98%; controls = 3.70% ± 1.01%; P = 0.02) and eicosapentaenoic acid (AA-MF = 0.33% ± 0.12%; controls = 0.60% ± 0.43%; P < 0.001) in RBCs than did control participants. Despite higher carnitine intake from AA-MFs than GMP-MFs (mean ± SE intake: AA-MFs = 58.6 ± 5.3 mg/d; GMP-MFs = 0.3 ± 0.01 mg/d; P < 0.001), plasma concentrations of carnitine were similar and not different from those in the control group (AA-MF compared with GMP-MF, P = 0.73). AA-MFs resulted in higher urinary excretion of trimethylamine N-oxide (TMAO), which is synthesized by bacteria from carnitine, compared with GMP-MFs (mean ± SE scaled intensity-TMAO: AA-MFs = 1.2 ± 0.1, GMP-MFs = 0.9 ± 0.1; P = 0.005). Plasma deoxycarnitine was lower in PKU participants than in control participants, suggesting reduced carnitine biosynthesis in PKU (AA-MF = 0.9 ± 0.1; GMP-MF = 1.0 ± 0.1; controls = 1.3 ± 0.1; AA-MF compared with controls, P = 0.01; GMP-MF compared with controls, P = 0.04). Conclusions: Supplementation with DHA is needed in PKU. Carnitine supplementation of AA-MFs shows reduced bioavailability due, in part, to bacterial degradation to TMAO, whereas the bioavailability of carnitine is greater with prebiotic GMP-MFs. This trial was registered at www.clinicaltrials.gov as NCT01428258. PMID: 29490096 [PubMed - in process]

Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements. J Nutr. 2018 Feb 01;148(2):285-297 Authors: Pinart M, Nimptsch K, Bouwman J, Dragsted LO, Yang C, De Cock N, Lachat C, Perozzi G, Canali R, Lombardo R, D'Archivio M, Guillaume M, Donneau AF, Jeran S, Linseisen J, Kleiser C, Nöthlings U, Barbaresko J, Boeing H, Stelmach-Mardas M, Heuer T, Laird E, Walton J, Gasparini P, Robino A, Castaño L, Rojo-Martínez G, Merino J, Masana L, Standl M, Schulz H, Biagi E, Nurk E, Matthys C, Gobbetti M, de Angelis M, Windler E, Zyriax BC, Tafforeau J, Pischon T Abstract Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease. Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis. Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information. Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration. Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition. PMID: 29490094 [PubMed - in process]

Development of a Reverse Phase HPLC Retention Index Model for Non-Targeted Metabolomics Using Synthetic Compounds. J Chem Inf Model. 2018 Feb 28;: Authors: Hall LM, Hill DW, Bugden K, Cawley SM, Hall L, Chen MH, Grant DF Abstract The MolFind application has been developed as a non-targeted metabolomics chemometric tool to facilitate structure identification when HPLC biofluids analysis reveals a feature of interest. Here synthetic compounds are selected and measured to form the basis of a new, more accurate, HPLC retention index model for use with MolFind. We show that relatively inexpensive synthetic screening compounds with simple structures can be used to develop an artificial neural network model that is successful in making quality predictions for human metabolites. A total of 1955 compounds were obtained and measured for the model. A separate set of 202 human metabolites was used for independent validation. The new ANN model showed improved accuracy over previous models. The model, based on relatively simple compounds, was able to make quality predictions for complex compounds not similar to training data. Independent validation metabolites with feature combinations found in three or more training compounds were predicted with 97% sensitivity while metabolites with feature combinations found in less than three training compounds were predicted with >90% sensitivity. The study describes the method used to select synthetic compounds and new descriptors developed to encode the relationship between lipophilic molecular subgraphs and HPLC retention. Finally, we introduce the QRI (qualitative range of interest) modification of neural network back-propagation learning to generate models simultaneously based on quantitative and qualitative data. PMID: 29489351 [PubMed - as supplied by publisher]

Metabolomics analysis reveals an effect of homocysteine on arachidonic acid and linoleic acid metabolism pathway. Mol Med Rep. 2018 Feb 27;: Authors: Li B, Gao G, Zhang W, Li B, Yang C, Jiang X, Tian Y, Liang H Abstract An increase in serum homocysteine level has been associated with an increased risk of vascular disease; however, the biochemical mechanisms that underlie these effects remain largely unknown. The present study aimed to use high-performance liquid chromatography-mass spectrometry (HPLC‑MS) to demonstrate the effects of serum homocysteine on human blood metabolites. A total of 75 fasting serum samples were investigated in the present study. Using a threshold of 15 µmol/l serum homocysteine level, samples were divided into high‑ and low‑homocysteine groups, and the serum extracts were analyzed with an HPLC‑MS‑based method. A total of 269 features exhibited significant differences and correlation with serum homocysteine levels in the electrospray ionization‑positive [ESI(+)] mode, and 69 features were identified in the ESI(‑) mode between the two groups. The principal component analysis plot revealed a separation between the high‑ and the low‑homocysteine groups. Metabolite set enrichment analysis identified arachidonic acid metabolism and linoleic acid metabolism as the two pathways with significantly enriched differences. These results revealed that arachidonic acid and linoleic acid metabolism may be associated with serum homocysteine levels and may be involved in homocysteine-induced vascular disease. PMID: 29488618 [PubMed - as supplied by publisher]

A metabolomic study on early detection of steroid-induced avascular necrosis of the femoral head. Oncotarget. 2018 Jan 30;9(8):7984-7995 Authors: Ren X, Fan W, Shao Z, Chen K, Yu X, Liang Q Abstract The early and accurate diagnosis of steroid-induced avascular necrosis of the femoral head (SANFH) is appealing considering its irreversible progression and serious consequence for the patients. The purpose of this study was to investigate the metabolic change of SANFH for its early detection. Two stages were designed in this study, namely discovery and verification. Except the biochemical index anomaly and the accidental death, 30 adult healthy adult Japanese white rabbits were used for screening out the potential metabolites in discovery experiment and 13 rabbits were used in verification experiment. The femoral heads were assessed with magnetic resonance imaging and transmission electron microscopy. The metabolomic profiling of serum samples were analysis by UHPLC-MS/MS. Metabolomic cluster analysis enable us to differentiate the rabbits without and with injection of the glucocorticoid in 1 week even when there is no obvious abnormal symptom in behaviors or imaging diagnosis. The majority of differential metabolites were identified as phospholipids which were observed significant change after injection of glucocorticoid in 1, 2, 3 weeks. And the results obtained in verification experiment of 6 weeks showed that these differential metabolites exhibited consistent trends in late progression with that in early-stage. At the end of 6 weeks the damage of SANFH could be verified by pathological imaging. Therefore the finding of serum metabolite profile links to the progression of SANFH and provides the potential of early detection of SANFH. PMID: 29487708 [PubMed]

A metabolomics study of Qiliqiangxin in a rat model of heart failure: a reverse pharmacology approach. Sci Rep. 2018 Feb 27;8(1):3688 Authors: Fu J, Chang L, Harms AC, Jia Z, Wang H, Wei C, Qiao L, Tian S, Hankemeier T, Wu Y, Wang M Abstract The Chinese medicine Qiliqiangxin (QL) has been shown to have a protective role in heart failure. Here, we explore the underlying working mechanism of the key therapeutic component in QL using a rat model of heart failure. Heart failure after myocardial infarction was induced surgically and confirmed using echocardiography; a separate group of rats underwent sham surgery. The rats with heart failure were randomly assigned to receive QL, the angiotensin-converting enzyme inhibitor benazepril, or placebo groups. Blood samples were collected from the rats at four time points for up to 8 weeks and used for biochemical analysis and mass spectrometry‒based metabolomics profiling. In total, we measured nine well-known biochemical parameters of heart failure and 147 metabolites. In the rats with heart failure, QL significantly improved these biochemical parameters and metabolomics profiles, significantly increasing the cardioprotective parameter angiopoietin-like 4 and significantly lowering inflammation-related oxylipins and lysophosphatidic acids compared to benazepril. Mechanistically, QL may improve outcome in heart failure by controlling inflammatory process and cardiac hypertrophy. Clinical studies should be designed in order to investigate these putative mechanisms in patients. PMID: 29487344 [PubMed - in process]

Tailed giant Tupanvirus possesses the most complete translational apparatus of the known virosphere. Nat Commun. 2018 Feb 27;9(1):749 Authors: Abrahão J, Silva L, Silva LS, Khalil JYB, Rodrigues R, Arantes T, Assis F, Boratto P, Andrade M, Kroon EG, Ribeiro B, Bergier I, Seligmann H, Ghigo E, Colson P, Levasseur A, Kroemer G, Raoult D, La Scola B Abstract Here we report the discovery of two Tupanvirus strains, the longest tailed Mimiviridae members isolated in amoebae. Their genomes are 1.44-1.51 Mb linear double-strand DNA coding for 1276-1425 predicted proteins. Tupanviruses share the same ancestors with mimivirus lineages and these giant viruses present the largest translational apparatus within the known virosphere, with up to 70 tRNA, 20 aaRS, 11 factors for all translation steps, and factors related to tRNA/mRNA maturation and ribosome protein modification. Moreover, two sequences with significant similarity to intronic regions of 18 S rRNA genes are encoded by the tupanviruses and highly expressed. In this translation-associated gene set, only the ribosome is lacking. At high multiplicity of infections, tupanvirus is also cytotoxic and causes a severe shutdown of ribosomal RNA and a progressive degradation of the nucleus in host and non-host cells. The analysis of tupanviruses constitutes a new step toward understanding the evolution of giant viruses. PMID: 29487281 [PubMed - in process]

Metabolic characterization of human aqueous humor in the cataract progression after pars plana vitrectomy. BMC Ophthalmol. 2018 Feb 27;18(1):63 Authors: Ji Y, Rong X, Lu Y Abstract BACKGROUND: While pars plana vitrectomy (PPV) has become the third most commonly performed surgery in the world, it can also induce multiple post complications easily. Among them, cataract progression is the most frequent one that can lead to blindness eventually. METHODS: To understand the underlying mechanisms of post PPV cataract progression, we performed comprehensive metabolic characterization of aqueous humor (AH) samples from 20 cataract patients (10 post PPV complication and 10 none PPV cataract) by a non-targeted metabolomic analysis using gas chromatography combined with time-of-flight mass spectrometer (GC/TOF MS). RESULTS: A total of 263 metabolites were identified and eight of them are determined to be significantly different (VIP ≥ 1 and p ≤ 0.05) between post PPV group and none PPV control group. The significantly changed metabolites included glutaric acid and pelargonic acid that play key roles in the regulation of oxidative stress and inflammatory responses. Furthermore, we constructed a metabolic regulatory network in each group based on metabolite-metabolite correlations, which reveals key metabolic pathways and regulatory elements including amino acids and lipids metabolisms that are related to cataract progression. CONCLUSIONS: Altogether, this work discovered some potential metabolite biomarkers for post PPV cataract diagnostics, as well as casted some novel insights into the underlying mechanisms of cataract progression after PPV. PMID: 29486760 [PubMed - in process]

Related Articles MALDI-MS Imaging in the Study of Glomerulonephritis. Methods Mol Biol. 2017;1618:85-94 Authors: Smith A, Galli M, L'Imperio V, Pagni F, Magni F Abstract Glomerulonephritis (GNs) are one of the most frequent causes of chronic kidney disease (CKD), a renal condition that often leads to end-stage renal failure, and a careful assessment of these diseases is essential for prognostic and therapeutic purposes. The application of MALDI-MSI directly on bioptic renal tissue represents a new stimulating perspective and facilitates the detection of specific proteomic indicators that are directly correlated with the pathological alterations that occur within the glomeruli during the development of glomerulonephritis. Here, we describe the standard workflow for the MALDI-MSI analysis of clinical fresh-frozen and FFPE renal biopsies and highlight how the obtained molecular information, when combined with histology, can be used to detect specific protein markers of GNs. PMID: 28523502 [PubMed - indexed for MEDLINE]

Related Articles MALDI-MSI Analysis of Cytological Smears: The Study of Thyroid Cancer. Methods Mol Biol. 2017;1618:37-47 Authors: Mosele N, Smith A, Galli M, Pagni F, Magni F Abstract Fine needle aspiration (FNA) biopsies are the current gold-standard for the preoperative evaluation of thyroid nodules. However, a significant number of them (15-30%) are unable to be affirmatively diagnosed and are given an "indeterminate for malignancy" final report, meaning that the malignant nature of the thyroid nodule remains unknown and the recommended therapeutic approach is total thyroidectomy. Furthermore, cytomorphological evaluation of biopsies taken post-surgery indicates that approximately 80% of nodules within this group of patients are in fact benign, and the total thyroidectomy unwarranted. Therefore, the identification of new possible diagnostic targets that can assist in the preoperative diagnosis of thyroid tumors and reduce the number of unnecessary thyroidectomies is imperative.Matrix-Assisted Laser Desorption/Ionization (MALDI)-Mass Spectrometry Imaging (MSI) has the ability to provide very precise and localized information regarding protein expression in cytological specimens. This enables the detection of cell subpopulations based on their different protein profiles, even within regions that are indistinguishable at the microscopic level, and the feasibility of this approach to investigate FNA specimens has already been highlighted in a number of studies. Here, an overview about the sample preparation procedure for the MALDI-MSI analysis of ex vivo FNA biopsies is provided, highlighting how molecular imaging can be combined with traditional histology to generate protein signatures of the different thyroid lesions, and, ultimately, build classification models that can be potentially used to classify benign and malignant thyroid nodules from a molecular standpoint. PMID: 28523498 [PubMed - indexed for MEDLINE]

Related Articles Metabolic profiling-multitude of technologies with great research potential, but (when) will translation emerge? Int J Epidemiol. 2016 10;45(5):1311-1318 Authors: Ala-Korpela M, Davey Smith G PMID: 27789667 [PubMed - indexed for MEDLINE]

Novel fused oxazepino-indoles (FOIs) attenuate liver carcinogenesis through IL-6/JAK2/STAT3 signaling blockade with strong metabolic regulations. Life Sci. 2018 Feb 24;: Authors: Singh AK, Kumar U, Raj V, Maurya V, Kumar D, Maity B, Prakash A, De A, Samanta A, Saha S Abstract AIMS: In quest for alternative drugs to the well known paullones, recently we synthesized novel paullone-like scaffold, 5H-benzo [2,3][1,4]oxazepino[5,6-b]indoles, where compounds 13a (Ta) and 14a (Tb) attenuated liver cancer specific Hep-G2 cells in vitro and formed stable binding complex with IL-6. Henceforth, we hypothesized that this action is probably due to the blockade of IL-6 mediated JAK2/STAT3 signaling cascade. Other objective was to explore the ability of FOIs to regulate metabolic perturbations during hepatocellular carcinoma (HCC). MAIN METHODS: A preclinical study was conducted using NDEA-induced HCC rat model by oral administration of FOIs at 10 mg/kg dose for 15 days. The molecular insights were confirmed through ELISA, qRT-PCR and western blot analyses. Further, 1H NMR based metabolomics study was performed to unveil metabolite discriminations among various studied groups. KEY FINDINGS: FOIs exerted notable antitumor effects as evidenced through restoration of body weight, oxidative stress parameters, liver marker enzymes, histological architecture and decrease in cancerous nodules. We identified that FOIs down-regulated the level of IL-6 that was over-expressed during NDEA-induced HCC. It was further confirmed that FOIs obliterated IL-6 over-expression, with concomitant blockade of JAK2-STAT3 signals. Besides, FOIs showed their potential ability in restoring perturbed metabolites linked to HCC and provided evidence of their cellular functioning. In particular, the anticancer efficacy of Ta was comparable or somewhat better than marketed chemotherapeutics, 5-flurouracil. SIGNIFICANCE: These findings altogether opened up possibilities of developing fused oxazepino-indoles (FOIs) as new candidate molecule for plausible alternative of paullones to treat liver cancer. PMID: 29486150 [PubMed - as supplied by publisher]

Silencing barley cystatins HvCPI-2 and HvCPI-4 specifically modifies leaf responses to drought stress. Plant Cell Environ. 2018 Feb 27;: Authors: Velasco-Arroyo B, Diaz-Mendoza M, Gomez-Sanchez A, Moreno-Garcia B, Santamaria ME, Torija-Bonilla M, Hensel G, Kumlehn J, Martinez M, Diaz I Abstract Protein breakdown and mobilization are some of the major metabolic features associated with abiotic stresses, essential for nutrient recycling and plant survival. Genetic manipulation of protease and/or protease inhibitors may contribute to modulate proteolytic processes and plant responses. The expression analysis of the whole cystatin family, inhibitors of C1A cysteine proteases, after water deprivation in barley leaves highlighted the involvement of Icy2 and Icy4 cystatin genes. Artificial microRNA lines independently silencing the two drought-induced cystatins were generated to assess their function in planta. Phenotype alterations at the final stages of the plant life cycle are represented by the stay-green phenotype of silenced cystatin 2 lines. Besides, the enhanced tolerance to drought and differential responses to water deprivation at the initial growing stages are observed. The mutual compensating expression of Icy2 and Icy4 genes in the silencing lines pointed to their cooperative role. Proteolytic patterns by silencing these cystatins were concomitant with modifications in the expression of potential target proteases, in particular HvPap-1, HvPap-12 and HvPap-16 C1A proteases. Metabolomics analyses lines also revealed specific modifications in the accumulation of several metabolites. These findings support the use of plants with altered proteolytic regulation in crop improvement in the face of climate change. PMID: 29486055 [PubMed - as supplied by publisher]

Challenges and emergent solutions for LC-MS/MS based untargeted metabolomics in diseases. Mass Spectrom Rev. 2018 Feb 27;: Authors: Cui L, Lu H, Lee YH Abstract In the past decade, advances in liquid chromatography-mass spectrometry (LC-MS) have revolutionized untargeted metabolomics analyses. By mining metabolomes more deeply, researchers are now primed to uncover key metabolites and their associations with diseases. The employment of untargeted metabolomics has led to new biomarker discoveries and a better mechanistic understanding of diseases with applications in precision medicine. However, many major pertinent challenges remain. First, compound identification has been poor, and left an overwhelming number of unidentified peaks. Second, partial, incomplete metabolomes persist due to factors such as limitations in mass spectrometry data acquisition speeds, wide-range of metabolites concentrations, and cellular/tissue/temporal-specific expression changes that confound our understanding of metabolite perturbations. Third, to contextualize metabolites in pathways and biology is difficult because many metabolites partake in multiple pathways, have yet to be described species specificity, or possess unannotated or more-complex functions that are not easily characterized through metabolomics analyses. From a translational perspective, information related to novel metabolite biomarkers, metabolic pathways, and drug targets might be sparser than they should be. Thankfully, significant progress has been made and novel solutions are emerging, achieved through sustained academic and industrial community efforts in terms of hardware, computational, and experimental approaches. Given the rapidly growing utility of metabolomics, this review will offer new perspectives, increase awareness of the major challenges in LC-MS metabolomics that will significantly benefit the metabolomics community and also the broader the biomedical community metabolomics aspire to serve. PMID: 29486047 [PubMed - as supplied by publisher]

Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. FASEB J. 2018 Feb 27;:fj201701378RR Authors: Marosi K, Moehl K, Navas-Enamorado I, Mitchell SJ, Zhang Y, Lehrmann E, Aon MA, Cortassa S, Becker KG, Mattson MP Abstract Evolutionary considerations suggest that the body has been optimized to perform at a high level in the food-deprived state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because controlled food deprivation in laboratory animals and intermittent energy restriction in humans is a potent physiologic stimulus for ketosis, we designed a study to determine the impact of intermittent food deprivation during endurance training on performance and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day food deprivation (ADF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 mo. A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on ADF during training compared to mice fed ad libitum during training. Maximal O2 consumption was increased similarly by treadmill training in mice on ADF or ad libitum diets, whereas respiratory exchange ratio was reduced in ADF mice on food-deprivation days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by ADF and potentiated by exercise strongly modulates molecular pathways involved in mitochondrial biogenesis, metabolism, and cellular plasticity. Our findings demonstrate that ADF engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity.-Marosi, K., Moehl, K., Navas-Enamorado, I., Mitchell, S. J., Zhang, Y., Lehrmann, E., Aon, M. A., Cortassa, S., Becker, K. G., Mattson, M. P. Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation. PMID: 29485903 [PubMed - as supplied by publisher]