Differential expression of metabolic genes in tumor and stromal components of primary and metastatic loci in pancreatic adenocarcinoma.

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Nina V Chaika

Full Text Available Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States with a five-year survival rate of 6%. It is characterized by extremely aggressive tumor growth rate and high incidence of metastasis. One of the most common and profound biochemical phenotypes of animal and human cancer cells is their ability to metabolize glucose at high rates, even under aerobic conditions. However, the contribution of metabolic interrelationships between tumor cells and cells of the surrounding microenvironment to the progression of cancer is not well understood. We evaluated differential expression of metabolic genes and, hence, metabolic pathways in primary tumor and metastases of patients with pancreatic adenocarcinoma.We analyzed the metabolic gene (those involved in glycolysis, tri-carboxylic acid pathway, pentose-phosphate pathway and fatty acid metabolism expression profiles of primary and metastatic lesions from pancreatic cancer patients by gene expression arrays. We observed two principal results: genes that were upregulated in primary and most of the metastatic lesions; and genes that were upregulated only in specific metastatic lesions in a site-specific manner. Immunohistochemical (IHC analyses of several metabolic gene products confirmed the gene expression patterns at the protein level. The IHC analyses also revealed differential tumor and stromal expression patterns of metabolic enzymes that were correlated with the metastasis sites.Here, we present the first comprehensive studies that establish differential metabolic status of tumor and stromal components and elevation of aerobic glycolysis gene expression in pancreatic cancer.

The Life Cycle of L. pneumophila: Cellular Differentiation Is Linked to Virulence and Metabolism

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Giulia Oliva

2018-01-01

Full Text Available Legionella pneumophila is a gram-negative bacterium that inhabits freshwater ecosystems, where it is present in biofilm or as planktonic form. L. pneumophila is mainly found associated with protozoa, which serve as protection from hostile environments and as replication niche. If inhaled within aerosols, L. pneumophila is also able to infect and replicate in human alveolar macrophages, eventually causing the Legionnaires' disease. The transition between intracellular and extracellular environments triggers a differentiation program in which metabolic as well as morphogenetic changes occur. We here describe the current knowledge on how the different developmental states of this bacterium are regulated, with a particular emphasis on the stringent response activated during the transition from the replicative phase to the infectious phase and the metabolic features going in hand. We propose that the cellular differentiation of this intracellular pathogen is closely associated to key metabolic changes in the bacterium and the host cell, which together have a crucial role in the regulation of L. pneumophila virulence.

Differential phenotyping of Brucella species using a newly developed semi-automated metabolic system

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Appel Bernd

2010-10-01

Full Text Available Abstract Background A commercial biotyping system (Taxa Profile™, Merlin Diagnostika testing the metabolization of various substrates by bacteria was used to determine if a set of phenotypic features will allow the identification of members of the genus Brucella and their differentiation into species and biovars. Results A total of 191 different amines, amides, amino acids, other organic acids and heterocyclic and aromatic substrates (Taxa Profile™ A, 191 different mono-, di-, tri- and polysaccharides and sugar derivates (Taxa Profile™ C and 95 amino peptidase- and protease-reactions, 76 glycosidase-, phosphatase- and other esterase-reactions, and 17 classic reactions (Taxa Profile™ E were tested with the 23 reference strains representing the currently known species and biovars of Brucella and a collection of 60 field isolates. Based on specific and stable reactions a 96-well "Brucella identification and typing" plate (Micronaut™ was designed and re-tested in 113 Brucella isolates and a couple of closely related bacteria. Brucella species and biovars revealed characteristic metabolic profiles and each strain showed an individual pattern. Due to their typical metabolic profiles a differentiation of Brucella isolates to the species level could be achieved. The separation of B. canis from B. suis bv 3, however, failed. At the biovar level, B. abortus bv 4, 5, 7 and B. suis bv 1-5 could be discriminated with a specificity of 100%. B. melitensis isolates clustered in a very homogenous group and could not be resolved according to their assigned biovars. Conclusions The comprehensive testing of metabolic activity allows cluster analysis within the genus Brucella. The biotyping system developed for the identification of Brucella and differentiation of its species and biovars may replace or at least complement time-consuming tube testing especially in case of atypical strains. An easy to handle identification software facilitates the

Differential metabolism of Mycoplasma species as revealed by their genomes

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Fabricio B.M. Arraes

2007-01-01

Full Text Available The annotation and comparative analyses of the genomes of Mycoplasma synoviae and Mycoplasma hyopneumonie, as well as of other Mollicutes (a group of bacteria devoid of a rigid cell wall, has set the grounds for a global understanding of their metabolism and infection mechanisms. According to the annotation data, M. synoviae and M. hyopneumoniae are able to perform glycolytic metabolism, but do not possess the enzymatic machinery for citrate and glyoxylate cycles, gluconeogenesis and the pentose phosphate pathway. Both can synthesize ATP by lactic fermentation, but only M. synoviae can convert acetaldehyde to acetate. Also, our genome analysis revealed that M. synoviae and M. hyopneumoniae are not expected to synthesize polysaccharides, but they can take up a variety of carbohydrates via the phosphoenolpyruvate-dependent phosphotransferase system (PEP-PTS. Our data showed that these two organisms are unable to synthesize purine and pyrimidine de novo, since they only possess the sequences which encode salvage pathway enzymes. Comparative analyses of M. synoviae and M. hyopneumoniae with other Mollicutes have revealed differential genes in the former two genomes coding for enzymes that participate in carbohydrate, amino acid and nucleotide metabolism and host-pathogen interaction. The identification of these metabolic pathways will provide a better understanding of the biology and pathogenicity of these organisms.

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

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Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Renée; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle; Beauséjour, Christian; Stroncek, David; Le Deist, Françoise; Haddad, Elie

2016-01-01

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to-DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation. PMID:27070086

Study on the regulatory mechanism of the lipid metabolism pathways during chicken male germ cell differentiation based on RNA-seq.

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Zuo, Qisheng; Li, Dong; Zhang, Lei; Elsayed, Ahmed Kamel; Lian, Chao; Shi, Qingqing; Zhang, Zhentao; Zhu, Rui; Wang, Yinjie; Jin, Kai; Zhang, Yani; Li, Bichun

2015-01-01

Here, we explore the regulatory mechanism of lipid metabolic signaling pathways and related genes during differentiation of male germ cells in chickens, with the hope that better understanding of these pathways may improve in vitro induction. Fluorescence-activated cell sorting was used to obtain highly purified cultures of embryonic stem cells (ESCs), primitive germ cells (PGCs), and spermatogonial stem cells (SSCs). The total RNA was then extracted from each type of cell. High-throughput analysis methods (RNA-seq) were used to sequence the transcriptome of these cells. Gene Ontology (GO) analysis and the KEGG database were used to identify lipid metabolism pathways and related genes. Retinoic acid (RA), the end-product of the retinol metabolism pathway, induced in vitro differentiation of ESC into male germ cells. Quantitative real-time PCR (qRT-PCR) was used to detect changes in the expression of the genes involved in the retinol metabolic pathways. From the results of RNA-seq and the database analyses, we concluded that there are 328 genes in 27 lipid metabolic pathways continuously involved in lipid metabolism during the differentiation of ESC into SSC in vivo, including retinol metabolism. Alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) are involved in RA synthesis in the cell. ADH5 was specifically expressed in PGC in our experiments and aldehyde dehydrogenase 1 family member A1 (ALDH1A1) persistently increased throughout development. CYP26b1, a member of the cytochrome P450 superfamily, is involved in the degradation of RA. Expression of CYP26b1, in contrast, decreased throughout development. Exogenous RA in the culture medium induced differentiation of ESC to SSC-like cells. The expression patterns of ADH5, ALDH1A1, and CYP26b1 were consistent with RNA-seq results. We conclude that the retinol metabolism pathway plays an important role in the process of chicken male germ cell differentiation.

Quantitative proteome and phosphoproteome analyses of Streptomyces coelicolor reveal proteins and phosphoproteins modulating differentiation and secondary metabolism

DEFF Research Database (Denmark)

Rioseras, Beatriz; Sliaha, Pavel V; Gorshkov, Vladimir

2018-01-01

identified and quantified 3461 proteins corresponding to 44.3% of the S. coelicolor proteome across three developmental stages: vegetative hypha (MI); secondary metabolite producing hyphae (MII); and sporulating hyphae. A total of 1350 proteins exhibited more than 2-fold expression changes during....../Thr/Tyr kinases, making this genus an outstanding model for the study of bacterial protein phosphorylation events. We used mass spectrometry based quantitative proteomics and phosphoproteomics to characterize bacterial differentiation and activation of secondary metabolism of Streptomyces coelicolor. We...... the bacterial differentiation process. These proteins include 136 regulators (transcriptional regulators, transducers, Ser/Thr/Tyr kinases, signalling proteins), as well as 542 putative proteins with no clear homology to known proteins which are likely to play a role in differentiation and secondary metabolism...

FDG-PET/CT assessment of differential chemotherapy effects upon skeletal muscle metabolism in patients with melanoma

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Goncalves, M.D.; Alavi, A.; Torigian, D.A.

2014-01-01

To quantify the differential effects of chemotherapy on the metabolic activity of skeletal muscle in vivo using molecular imaging with [18F]-fluorodeoxy-glucose (FDG)-positron emission tomography/computed tomography (PET/CT). In this retrospective study, 21 subjects with stage IV melanoma who underwent pre- and post-chemotherapy whole-body FDG-PET/CT imaging were included. The mean standardized uptake value (SUV mean ) of 8 different skeletal muscles was measured per subject. Pre- and post-treatment measurements were then averaged across all subjects for each muscle and compared for statistically significant differences between the muscles and following different chemotherapy regimens including dacarbazine (DTIC) and temozolomide (TMZ). Analysis of FDG-PET/CT images reliably detected changes in skeletal muscle metabolic activity based on muscle location. The percent change in metabolic activity of each skeletal muscle in each subject following chemotherapy was observed to be related to the type of chemotherapy received. Subjects receiving DTIC generally had a decrease in metabolic activity of all muscle groups, whereas subjects receiving TMZ generally had an increase in muscle activity of all muscle groups. FDG-PET/CT can reveal baseline metabolic differences between different muscles of the body. Different chemotherapies are associated with differential changes in the metabolic activity of skeletal muscle, which can be detected and quantified with FDG-PET/CT. (author)

Differential network analysis reveals evolutionary complexity in secondary metabolism of Rauvolfia serpentina over Catharanthus roseus

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Shivalika Pathania

2016-08-01

Full Text Available Comparative co-expression analysis of multiple species using high-throughput data is an integrative approach to determine the uniformity as well as diversification in biological processes. Rauvolfia serpentina and Catharanthus roseus, both members of Apocyanacae family, are reported to have remedial properties against multiple diseases. Despite of sharing upstream of terpenoid indole alkaloid pathway, there is significant diversity in tissue-specific synthesis and accumulation of specialized metabolites in these plants. This led us to implement comparative co-expression network analysis to investigate the modules and genes responsible for differential tissue-specific expression as well as species-specific synthesis of metabolites. Towards these goals differential network analysis was implemented to identify candidate genes responsible for diversification of metabolites profile. Three genes were identified with significant difference in connectivity leading to differential regulatory behavior between these plants. These mechanisms may be responsible for diversification of secondary metabolism, and thereby for species-specific metabolite synthesis. The network robustness of R. serpentina, determined based on topological properties, was also complemented by comparison of gene-metabolite networks of both plants, and may have evolved to have complex metabolic mechanisms as compared to C. roseus under the influence of various stimuli. This study reveals evolution of complexity in secondary metabolism of Rauvolfia serpentina, and key genes that contribute towards diversification of specific metabolites.

Differential Network Analysis Reveals Evolutionary Complexity in Secondary Metabolism of Rauvolfia serpentina over Catharanthus roseus.

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Pathania, Shivalika; Bagler, Ganesh; Ahuja, Paramvir S

2016-01-01

Comparative co-expression analysis of multiple species using high-throughput data is an integrative approach to determine the uniformity as well as diversification in biological processes. Rauvolfia serpentina and Catharanthus roseus, both members of Apocyanacae family, are reported to have remedial properties against multiple diseases. Despite of sharing upstream of terpenoid indole alkaloid pathway, there is significant diversity in tissue-specific synthesis and accumulation of specialized metabolites in these plants. This led us to implement comparative co-expression network analysis to investigate the modules and genes responsible for differential tissue-specific expression as well as species-specific synthesis of metabolites. Toward these goals differential network analysis was implemented to identify candidate genes responsible for diversification of metabolites profile. Three genes were identified with significant difference in connectivity leading to differential regulatory behavior between these plants. These genes may be responsible for diversification of secondary metabolism, and thereby for species-specific metabolite synthesis. The network robustness of R. serpentina, determined based on topological properties, was also complemented by comparison of gene-metabolite networks of both plants, and may have evolved to have complex metabolic mechanisms as compared to C. roseus under the influence of various stimuli. This study reveals evolution of complexity in secondary metabolism of R. serpentina, and key genes that contribute toward diversification of specific metabolites.

Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.

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de Medina, Philippe; Paillasse, Michael R; Segala, Gregory; Voisin, Maud; Mhamdi, Loubna; Dalenc, Florence; Lacroix-Triki, Magali; Filleron, Thomas; Pont, Frederic; Saati, Talal Al; Morisseau, Christophe; Hammock, Bruce D; Silvente-Poirot, Sandrine; Poirot, Marc

2013-01-01

We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.

The increase of NADH fluorescence lifetime is associated with the metabolic change during osteogenic differentiation of human mesenchymal stem cells (hMSCs)

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Guo, Han Wen; Yu, Jia Sin; Hsu, Shu Han; Wei, Yau Huei; Lee, Oscar K.; Wang, Hsing Wen

2011-03-01

Fluorescence lifetime of NADH had been used as an optical marker for monitoring cellular metabolism. In our pervious studies, we have demonstrated that NADH lifetime of hMSCs increase gradually with time of osteogenic differentiation. In this study, we measured NADH lifetime of hMSCs from a different donor as well as the corresponding metabolic indices such as ATP level, oxygen consumption and lactate release. We also measure the quantity of Complex I, III, IV and V. The results show that during differentiation more oxygen consumed, higher ATP level expressed and less lactate released, and the increase of NADH lifetime was associated with ATP level. Higher expression of the total Complex protein was observed at 3 and 4 weeks after differentiation than controls. However, Complex I expression did not show significant correlation with the increase of NADH fluorescence lifetime. In summary, we demonstrated that the change of NADH lifetime was associated with the metabolic change during osteogenic differentiation of hMSCs. The increase of NADH lifetime was in part due to the increased Complex protein interaction in mitochondria after differentiation.

Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo

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Blomberg Jensen, Martin; Jørgensen, Anne; Nielsen, John Erik

2012-01-01

and express pluripotency factors (NANOG/OCT4). Vitamin D (VD) is metabolized in the testes, and here, we examined VD metabolism in TGCT differentiation and pluripotency regulation. We established that the VD receptor (VDR) and VD-metabolizing enzymes are expressed in human fetal germ cells, CIS, and invasive......) treatment in vivo. These novel findings show that VD metabolism is involved in the mesodermal transition during differentiation of cancer cells with embryonic stem cell characteristics, which points to a function for VD during early embryonic development and possibly in the pathogenesis of TGCTs.......Testicular germ cell tumors (TGCTs) are classified as either seminomas or nonseminomas. Both tumors originate from carcinoma in situ (CIS) cells, which are derived from transformed fetal gonocytes. CIS, seminoma, and the undifferentiated embryonal carcinoma (EC) retain an embryonic phenotype...

A gradual update method for simulating the steady-state solution of stiff differential equations in metabolic circuits.

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Shiraishi, Emi; Maeda, Kazuhiro; Kurata, Hiroyuki

2009-02-01

Numerical simulation of differential equation systems plays a major role in the understanding of how metabolic network models generate particular cellular functions. On the other hand, the classical and technical problems for stiff differential equations still remain to be solved, while many elegant algorithms have been presented. To relax the stiffness problem, we propose new practical methods: the gradual update of differential-algebraic equations based on gradual application of the steady-state approximation to stiff differential equations, and the gradual update of the initial values in differential-algebraic equations. These empirical methods show a high efficiency for simulating the steady-state solutions for the stiff differential equations that existing solvers alone cannot solve. They are effective in extending the applicability of dynamic simulation to biochemical network models.

Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1.

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Endo, Yusuke; Asou, Hikari K; Matsugae, Nao; Hirahara, Kiyoshi; Shinoda, Kenta; Tumes, Damon J; Tokuyama, Hirotake; Yokote, Koutaro; Nakayama, Toshinori

2015-08-11

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Differential metabolic responses in three life stages of mussels Mytilus galloprovincialis exposed to cadmium.

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Wu, Huifeng; Xu, Lanlan; Yu, Deliang; Ji, Chenglong

2017-01-01

Cadmium (Cd) is one of the most important metal contaminants in the Bohai Sea. In this work, NMR-based metabolomics was used to investigate the toxicological effects of Cd at an environmentally relevant concentration (50 µg L -1 ) in three different life stages (D-shape larval, juvenile and adult) of mussels Mytilus galloprovincialis. Results indicated that the D-shape larval mussel was the most sensitive life stage to Cd. The significantly different metabolic profiles meant that Cd induced differential toxicological effects in three life stages of mussels. Basically, Cd caused osmotic stress in all the three life stages via different metabolic pathways. Cd exposure reduced the anaerobiosis in D-shape larval mussels and disturbed lipid metabolism in juvenile mussels, respectively. Compared with the D-shape larval and juvenile mussels, the adult mussels reduced energy consumption to deal with Cd stress.

Metabolism plays the key roles in Th cells differentiation

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A. Hosseinzadeh

2016-12-01

Full Text Available The increasing rate of autoimmunity in recent decades cannot be related to only genetic instabilities and disorders. Diet can directly influence our health. Studies have shown that there is a relationship between nutritional elements and alteration in the immune system. Among immune cells, the function of T lymphocyte is important in directing immune response. T CD4+ cells lead other immune cells to respond to pathogens by secreting cytokines. HIV+ patients, who have largely lost their T CD4+ cells, are susceptible to opportunistic infections, which do not normally affect healthy people. It seems that the metabolism of T cells is critical for their differentiation and their consequent functions. After activation, T cells need to undergo clonal expansion, which is a high energy- consuming process. Studies have shown that specific metabolites deprivation or their excess supply affects T CD4+cells subsets differentiation. Abnormal induction of subsets of T CD4+ cells causes some autoimmunity reactions and hyper-sensitivity as well, which may result from imbalance of diet uptake. In this mini-review, we describe the findings about fatty acids, glucose, amino acids, and vitamins, which are effective in determining the fates of T CD4+ cells. These findings may help us uncover the role of diet in autoimmune diseases.

Differential Role of Self-Congruity in the Consideration and Choice of a Store

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André Carlos Martins Menck

2014-03-01

Full Text Available The variable measuring the matching/mismatching between a shopper's self-image and the image he/she has of the personality of a store—self-congruity—has deserved attention in the literature, but limited to single-phased decision models. This research extends the investigation to a two-phased decision model, and finds support for the idea that self-congruity has an explanatory role on store consideration probability. Also, no statistical evidence was found that it helps explaining choice probability among stores in the consideration set. The results were obtained by binary and multinomial logit models, permitting the assessment of the relative explanatory importance of the variable, in relation to other variables whose importance in explaining behavior have long been established. A discussion on the differential effects of the shopping situation on the role played by the explanatory variables on considering and choice probabilities was also done and empirical support was found for shopping situation-dependency.

Different gene-expression profiles for the poorly differentiated carcinoma and the highly differentiated papillary adenocarcinoma in mammary glands support distinct metabolic pathways

International Nuclear Information System (INIS)

Eilon, Tali; Barash, Itamar

2008-01-01

Deregulation of Stat5 in the mammary gland of transgenic mice causes tumorigenesis. Poorly differentiated carcinoma and highly differentiated papillary adenocarcinoma tumors evolve. To distinguish the genes and elucidate the cellular processes and metabolic pathways utilized to preserve these phenotypes, gene-expression profiles were analyzed. Mammary tumors were excised from transgenic mice carrying a constitutively active variant of Stat5, or a Stat5 variant lacking s transactivation domain. These tumors displayed either the carcinoma or the papillary adenocarcinoma phenotypes. cRNAs, prepared from each tumor were hybridized to an Affymetrix GeneChip ® Mouse Genome 430A 2.0 array. Gene-ontology analysis, hierarchical clustering and biological-pathway analysis were performed to distinct the two types of tumors. Histopathology and immunofluorescence staining complemented the comparison between the tumor phenotypes. The nucleus-cytoskeleton-plasma membrane axis is a major target for differential gene expression between phenotypes. In the carcinoma, stronger expression of genes coding for specific integrins, cytoskeletal proteins and calcium-binding proteins highlight cell-adhesion and motility features of the tumor cells. This is supported by the higher expression of genes involved in O-glycan synthesis, TGF-β, activin, their receptors and Smad3, as well as the Notch ligands and members of the γ-secretase complex that enable Notch nuclear localization. The Wnt pathway was also a target for differential gene expression. Higher expression of genes encoding the degradation complex of the canonical pathway and limited TCF expression in the papillary adenocarcinoma result in membranal accumulation of β-catenin, in contrast to its nuclear translocation in the carcinoma. Genes involved in cell-cycle arrest at G1 and response to DNA damage were more highly expressed in the papillary adenocarcinomas, as opposed to favored G2/M regulation in the carcinoma tumors. At least

Metabolism of designer drugs of abuse.

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Staack, Roland F; Maurer, Hans H

2005-06-01

Abuse of designer drugs is widespread among young people, especially in the so-called "dance club scene" or "rave scene", worldwide. Severe and even fatal poisonings have been attributed to the consumption of such drugs of abuse. However, in contrast to new medicaments, which are extensively studied in controlled clinical studies concerning metabolism, including cytochrome P450 isoenzyme differentiation, and further pharmacokinetics, designer drugs are consumed without any safety testing. This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years. Para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA) and 4-methylthioamphetamine (4-MTA), were taken into consideration as new "classical" amphetamine-derived designer drugs. Furthermore, N-benzylpiperazine (BZP), 1-(3, 4-methylenedioxybenzyl)piperazine (MDBP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(3-chlorophenyl)piperazine (mCPP) and 1-(4-methoxyphenyl)piperazine (MeOPP) were taken into consideration as derivatives of the class of piperazine-derived designer drugs, as well as alpha-pyr-rolidinopropiophenone (PPP), 4'-methoxy-alpha-pyrrolidinopropiophenone (MOPPP), 3', 4'-methylenedioxy-alpha-pyrrolidino-propiophenone (MDPPP), 4'-methyl-alpha-pyrrolidinopropiophenone (MPPP), and 4'-methyl-alpha-pyrrolidinoexanophenone (MPHP) as derivatives of the class of alpha-pyrrolidinophenone-derived designer drugs. Papers describing identification of in vivo or in vitro human or animal metabolites and cytochrome P450 isoenzyme dependent metabolism have been considered and summarized.

Metabolic aspects of Neuronal – Oligodendrocytic - Astrocytic (NOA interactions

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Ana I Amaral

2013-05-01

Full Text Available Whereas astrocytes have been in the limelight on the metabolic glucose interaction scene for a while, oligodendrocytes are still waiting for a place. We would like to call oligodendrocyte interaction with astrocytes and neurons: NOA (neuron – oligodendrocyte – astrocyte interactions. One of the reasons to find out more about oligodendrocyte interaction with neurons and astrocytes is to detect markers of healthy oligodendrocyte metabolism, to be used in diagnosis and treatment assessment in diseases such as Perinatal hypoxic-ischemic encephalopathy and multiple sclerosis in which oligodendrocyte function is impaired, possibly due to glutamate toxicity. Glutamate receptors are expressed in oligodendrocytes and also vesicular glutamate release in the white matter has received considerable attention. It is also important to establish if the glial precursor cells recruited to damaged areas are developing oligodendrocyte characteristics or those of astrocytes. Thus, it is important to study astrocytes and oligodendrocytes separately to be able to differentiate between them. This is of particular importance in the white matter where the number of oligodendrocytes is considerable. The present review summarizes the not very extensive information published on glucose metabolism in oligodendrocytes in an attempt to stimulate research into this important field.

[{sup 18}F]FETO: metabolic considerations

Energy Technology Data Exchange (ETDEWEB)

Ettlinger, Dagmar E.; Machek, Michael; Rendl, Gundula; Karanikas, Georgios; Kletter, Kurt [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Wadsak, Wolfgang; Dudczak, Robert [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Ludwig-Boltzmann-Institute for Nuclear Medicine, Vienna (Austria); Mien, Leonhard-Key [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutic Technology and Biopharmaceutics, Vienna (Austria); Medical University of Vienna, Department of Psychiatry, Vienna (Austria); Wabnegger, Leila [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); Medical University of Vienna, Department of Psychiatry, Vienna (Austria); Viernstein, Helmut [University of Vienna, Department of Pharmaceutic Technology and Biopharmaceutics, Vienna (Austria); Mitterhauser, Markus [Medical University of Vienna, Department of Nuclear Medicine, Vienna (Austria); University of Vienna, Department of Pharmaceutic Technology and Biopharmaceutics, Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna, Vienna (Austria)

2006-08-15

11{beta}-Hydroxylase is a key enzyme in the biosynthesis of adrenocortical steroid hormones and is a suitable target for the imaging of the adrenal cortex. [{sup 11}C]Metomidate (MTO), [{sup 11}C]etomidate (ETO) and desethyl-[{sup 18}F]fluoroethyl-etomidate (FETO) are potent inhibitors of this enzyme and are used for PET imaging of adrenocortical pathologies. The aims of this study were (1) to evaluate and compare the metabolic stability of MTO, ETO and FETO against esterases and (2) to investigate the metabolic pattern of FETO in vivo. In vitro assays were performed using different concentrations of MTO, ETO and FETO with constant concentrations of carboxylesterase. Human in vivo studies were performed with human blood samples drawn from the cubital vein. After sample clean-up, the serum was analysed by HPLC methods. In vitro assays showed Michaelis-Menten constants of 115.1 {mu}mol for FETO, 162.0 {mu}mol for MTO and 168.6 {mu}mol for ETO. Limiting velocities were 1.54 {mu}mol/min (FETO), 1.47 {mu}mol/min (MTO) and 1.35 {mu}mol/min (ETO). This implies insignificantly decreased esterase stability of FETO compared with MTO and ETO. In vivo investigations showed a rapid metabolisation of FETO within the first 10 min (2 min: 91.41%{+-}6.44%, n=6; 10 min: 23.78%{+-}5.54%, n=4) followed by a smooth decrease in FETO from 20 to 90 min (20 min: 11.23%{+-}3.79% n=4; 90 min: 3.68%{+-}3.65%, n=4). Recovery rate was 61.43%{+-}3.19% (n=12). In vitro experiments demonstrated that FETO stability against esterases is comparable to that of ETO and MTO. The metabolic profile showed that FETO kinetics in humans are fast. (orig.)

Metabolic response to optic centers to visual stimuli in the albino rat: anatomical and physiological considerations

International Nuclear Information System (INIS)

Toga, A.W.; Collins, R.C.

1981-01-01

The functional organization of the visual system was studied in the albino rat. Metabolic differences were measured using the 14 C-2-deoxyglucose (DG) autoradiographic technique during visual stimulation of one entire retina in unrestrained animals. All optic centers responded to changes in light intensity but to different degrees. The greatest change occurred in the superior colliculus, less in the lateral geniculate, and considerably less in second-order sites such as layer IV of visual cortex. These optic centers responded in particular to on/off stimuli, but showed no incremental change during pattern reversal or movement of orientation stimuli. Both the superior colliculus and lateral geniculate increased their metabolic rate as the frequency of stimulation increased, but the magnitude was twice as great in the colliculus. The histological pattern of metabolic change in the visual system was not homogenous. In the superior colliculus glucose utilization increased only in stratum griseum superficiale and was greatest in visuotopic regions representing the peripheral portions of the visual field. Similarly, in the lateral geniculate, only the dorsal nucleus showed an increased response to greater stimulus frequencies. Second-order regions of the visual system showed changes in metabolism in response to visual stimulation, but no incremental response specific for type or frequency of stimuli. To label proteins of axoplasmic transport to study the terminal fields of retinal projections 14 C-amino acids were used. This was done to study how the differences in the magnitude of the metabolic response among optic centers were related to the relative quantity of retinofugal projections to these centers

The relationship between fat depot-specific preadipocyte differentiation and metabolic syndrome in obese women

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N V Mazurina

2013-03-01

Full Text Available Реферат по материалам статьи The relationship between fat depot-specific preadipocyte differentiation and metabolic syndrome in obese women. Park HТ, Lee ES, Cheon EP, Lee DR, Yang K-S, Kim YT, Hur JY, Kim SH, Lee KW, Kim T. Clinical Endocrinology 2012; 76, 59-66.

Clonal characterization of rat muscle satellite cells: proliferation, metabolism and differentiation define an intrinsic heterogeneity.

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Carlo A Rossi

2010-01-01

Full Text Available Satellite cells (SCs represent a distinct lineage of myogenic progenitors responsible for the postnatal growth, repair and maintenance of skeletal muscle. Distinguished on the basis of their unique position in mature skeletal muscle, SCs were considered unipotent stem cells with the ability of generating a unique specialized phenotype. Subsequently, it was demonstrated in mice that opposite differentiation towards osteogenic and adipogenic pathways was also possible. Even though the pool of SCs is accepted as the major, and possibly the only, source of myonuclei in postnatal muscle, it is likely that SCs are not all multipotent stem cells and evidences for diversities within the myogenic compartment have been described both in vitro and in vivo. Here, by isolating single fibers from rat flexor digitorum brevis (FDB muscle we were able to identify and clonally characterize two main subpopulations of SCs: the low proliferative clones (LPC present in major proportion (approximately 75% and the high proliferative clones (HPC, present instead in minor amount (approximately 25%. LPC spontaneously generate myotubes whilst HPC differentiate into adipocytes even though they may skip the adipogenic program if co-cultured with LPC. LPC and HPC differ also for mitochondrial membrane potential (DeltaPsi(m, ATP balance and Reactive Oxygen Species (ROS generation underlying diversities in metabolism that precede differentiation. Notably, SCs heterogeneity is retained in vivo. SCs may therefore be comprised of two distinct, though not irreversibly committed, populations of cells distinguishable for prominent differences in basal biological features such as proliferation, metabolism and differentiation. By these means, novel insights on SCs heterogeneity are provided and evidences for biological readouts potentially relevant for diagnostic purposes described.

Skeletal muscle substrate metabolism during exercise: methodological considerations

DEFF Research Database (Denmark)

Van Hall, Gerrit; González-Alonso, J; Sacchetti, M

1999-01-01

and the respiratory exchange ratio. However, if the aim is to quantify limb or muscle metabolism, invasive measurements have to be carried out, such as the determination of blood flow, arterio-venous (a-v) difference measurements for O2 and relevant substrates, and biopsies of the active muscle. As many substrates...... substrates. There are several methodological concerns to be aware of when studying the metabolic response to exercise in human subjects. These concerns include: (1) the muscle mass involved in the exercise is largely unknown (bicycle or treadmill). Moreover, whether the muscle sample obtained from a limb......; (3) the use of net limb glycerol release to estimate lipolysis is probably not valid (triacylglycerol utilization by muscle), since glycerol can be metabolized in skeletal muscle; (4) the precision of blood-borne substrate concentrations during exercise measured by a-v difference is hampered since...

Differential effects of fasting vs food restriction on liver thyroid hormone metabolism in male rats.

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de Vries, E M; van Beeren, H C; Ackermans, M T; Kalsbeek, A; Fliers, E; Boelen, A

2015-01-01

A variety of illnesses that leads to profound changes in the hypothalamus-pituitary-thyroid (HPT) are axis collectively known as the nonthyroidal illness syndrome (NTIS). NTIS is characterized by decreased tri-iodothyronine (T3) and thyroxine (T4) and inappropriately low TSH serum concentrations, as well as altered hepatic thyroid hormone (TH) metabolism. Spontaneous caloric restriction often occurs during illness and may contribute to NTIS, but it is currently unknown to what extent. The role of diminished food intake is often studied using experimental fasting models, but partial food restriction might be a more physiologically relevant model. In this comparative study, we characterized hepatic TH metabolism in two models for caloric restriction: 36 h of complete fasting and 21 days of 50% food restriction. Both fasting and food restriction decreased serum T4 concentration, while after 36-h fasting serum T3 also decreased. Fasting decreased hepatic T3 but not T4 concentrations, while food restriction decreased both hepatic T3 and T4 concentrations. Fasting and food restriction both induced an upregulation of liver D3 expression and activity, D1 was not affected. A differential effect was seen in Mct10 mRNA expression, which was upregulated in the fasted rats but not in food-restricted rats. Other metabolic pathways of TH, such as sulfation and UDP-glucuronidation, were also differentially affected. The changes in hepatic TH concentrations were reflected by the expression of T3-responsive genes Fas and Spot14 only in the 36-h fasted rats. In conclusion, limited food intake induced marked changes in hepatic TH metabolism, which are likely to contribute to the changes observed during NTIS. © 2015 Society for Endocrinology.

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

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Dall’Olio Giovanni

2012-06-01

Full Text Available Abstract Background Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Results Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. Conclusions These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

OpenAIRE

Selleri, Silvia; Bifsha, Panojot; Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Ren?e; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle

2016-01-01

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-...

Differential metabolic responses of Beauveria bassiana cultured in pupae extracts, root exudates and its interactions with insect and plant.

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Luo, Feifei; Wang, Qian; Yin, Chunlin; Ge, Yinglu; Hu, Fenglin; Huang, Bo; Zhou, Hong; Bao, Guanhu; Wang, Bin; Lu, Ruili; Li, Zengzhi

2015-09-01

Beauveria bassiana is a kind of world-wide entomopathogenic fungus and can also colonize plant rhizosphere. Previous researches showed differential expression of genes when entomopathogenic fungi are cultured in insect or plant materials. However, so far there is no report on metabolic alterations of B. bassiana in the environments of insect or plant. The purpose of this paper is to address this problem. Herein, we first provide the metabolomic analysis of B. bassiana cultured in insect pupae extracts (derived from Euproctis pseudoconspersa and Bombyx mori, EPP and BMP), plant root exudates (derived from asparagus and carrot, ARE and CRE), distilled water and minimal media (MM), respectively. Principal components analysis (PCA) shows that mycelia cultured in pupae extracts and root exudates are evidently separated and individually separated from MM, which indicates that fungus accommodates to insect and plant environments by different metabolic regulation mechanisms. Subsequently, orthogonal projection on latent structure-discriminant analysis (OPLS-DA) identifies differential metabolites in fungus under three environments relative to MM. Hierarchical clustering analysis (HCA) is performed to cluster compounds based on biochemical relationships, showing that sphingolipids are increased in BMP but are decreased in EPP. This observation further implies that sphingolipid metabolism may be involved in the adaptation of fungus to different hosts. In the meantime, sphingolipids are significantly decreased in root exudates but they are not decreased in distilled water, suggesting that some components of the root exudates can suppress sphingolipid to down-regulate sphingolipid metabolism. Pathway analysis finds that fatty acid metabolism is maintained at high level but non-ribosomal peptides (NRP) synthesis is unaffected in mycelia cultured in pupae extracts. In contrast, fatty acid metabolism is not changed but NRP synthesis is high in mycelia cultured in root exudates

Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells

International Nuclear Information System (INIS)

Prawitt, Janne; Niemeier, Andreas; Kassem, Moustapha; Beisiegel, Ulrike; Heeren, Joerg

2008-01-01

There is a great demand for cell models to study human adipocyte function. Here we describe the adipogenic differentiation of a telomerase-immortalized human mesenchymal stem cell line (hMSC-Tert) that maintains numerous features of terminally differentiated adipocytes even after prolonged withdrawal of the peroxisome proliferator activated receptor γ (PPARγ) agonist rosiglitazone. Differentiated hMSC-Tert developed the characteristic monolocular phenotype of mature adipocytes. The expression of adipocyte specific markers was highly increased during differentiation. Most importantly, the presence of the PPARγ agonist rosiglitazone was not required for the stable expression of lipoprotein lipase, adipocyte fatty acid binding protein and perilipin on mRNA and protein levels. Adiponectin expression was post-transcriptionally down-regulated in the absence of rosiglitazone. Insulin sensitivity as measured by insulin-induced phosphorylation of Akt and S6 ribosomal protein was also independent of rosiglitazone. In addition to commonly used adipogenic markers, we investigated further PPARγ-stimulated proteins with a role in lipid metabolism. We observed an increase of lipoprotein receptor (VLDLR, LRP1) and apolipoprotein E expression during differentiation. Despite this increased expression, the receptor-mediated endocytosis of lipoproteins was decreased in differentiated adipocytes, suggesting that these proteins may have an additional function in adipose tissue beyond lipoprotein uptake

Differential Metabolism of a Two-Carbon Substrate by Members of the Paracoccidioides Genus

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Lilian C. Baeza

2017-11-01

Full Text Available The genus Paracoccidioides comprises known fungal pathogens of humans and can be isolated from different infection sites. Metabolic peculiarities in different members of the Paracoccidioides led us to perform proteomic studies in the presence of the two-carbon molecule acetate, which predominates in the nutrient-poor environment of the phagosome. To investigate the expression rates of proteins of different members of Paracoccidioides, including one isolate of P. lutzii (Pb01 and three isolates of P. brasiliensis (Pb03, Pb339, and PbEPM83, using sodium acetate as a carbon source, proteins were quantified using label-free and data-independent liquid chromatography-mass spectrometry. Protein profiles of the isolates were statistically analyzed, revealing proteins that were differentially expressed when the fungus was cultivated in a non-preferential carbon source rather than glucose. A total of 1,160, 1,211, 1,280, and 1,462 proteins were reproducibly identified and relatively quantified in P. lutzii and the P. brasiliensis isolates Pb03, Pb339, and PbEPM83, respectively. Notably, 526, 435, 744, and 747 proteins were differentially expressed among P. lutzii and the P. brasiliensis isolates Pb03, Pb339, and PbEPM83, respectively, with a fold-change equal to or higher than 1.5. This analysis revealed that reorganization of metabolism occurred through the induction of proteins related to gluconeogenesis, glyoxylic/glyoxylate cycle, response to stress, and degradation of amino acids in the four isolates. The following differences were observed among the isolates: higher increases in the expression levels of proteins belonging to the TCA and respiratory chain in PbEPM83 and Pb01; increase in ethanol production in Pb01; utilization of cell wall components for gluconeogenesis in Pb03 and PbEPM83; and increased β-oxidation and methylcitrate cycle proteins in Pb01and PbEPM83. Proteomic profiles indicated that the four isolates reorganized their metabolism

Monitoring Bone Tissue Engineered (BTE) Constructs Based on the Shifting Metabolism of Differentiating Stem Cells.

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Simmons, Aaron D; Sikavitsas, Vassilios I

2018-01-01

Ever-increasing demand for bone grafts necessitates the realization of clinical implementation of bone tissue engineered constructs. The predominant hurdle to implementation remains to be securing FDA approval, based on the lack of viable methods for the rigorous monitoring of said constructs. The study presented herein details a method for such monitoring based on the shifting metabolism of mesenchymal stem cells (MSCs) as they differentiate into osteoblasts. To that end, rat MSCs seeded on 85% porous spunbonded poly(L-lactic acid) scaffolds were cultured in flow perfusion bioreactors with baseline or osteoinductive media, and levels of key physio-metabolic markers (oxygen, glucose, osteoprotegerin, and osteocalcin) were monitored throughout culture. Comparison of these non-destructively obtained values and current standard destructive analyses demonstrated key trends useful for the concurrent real-time monitoring of construct cellularity and maturation. Principle among these is the elucidation of the ratio of the rates of oxygen uptake to glucose consumption as a powerful quality marker. This ratio, supported on a physiological basis, has been shown herein to be reliable in the determination of both construct maturation (defined as osteoblastic differentiation and accompanying mineralization) and construct cellularity. Supplementary monitoring of OPG and OCN are shown to provide further validation of such metrics.

Ordinary differential equations and Boolean networks in application to modelling of 6-mercaptopurine metabolism.

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Lavrova, Anastasia I; Postnikov, Eugene B; Zyubin, Andrey Yu; Babak, Svetlana V

2017-04-01

We consider two approaches to modelling the cell metabolism of 6-mercaptopurine, one of the important chemotherapy drugs used for treating acute lymphocytic leukaemia: kinetic ordinary differential equations, and Boolean networks supplied with one controlling node, which takes continual values. We analyse their interplay with respect to taking into account ATP concentration as a key parameter of switching between different pathways. It is shown that the Boolean networks, which allow avoiding the complexity of general kinetic modelling, preserve the possibility of reproducing the principal switching mechanism.

Aryl hydrocarbon receptor–ligand axis mediates pulmonary fibroblast migration and differentiation through increased arachidonic acid metabolism

International Nuclear Information System (INIS)

Su, Hsiang-Han; Lin, Hsin-Ting; Suen, Jau-Ling; Sheu, Chau Chyun; Yokoyama, Kazunari K.; Huang, Shau-Ku; Cheng, Chih Mei

2016-01-01

Pulmonary fibroblast migration and differentiation are critical events in fibrogenesis; meanwhile, fibrosis characterizes the pathology of many respiratory diseases. The role of aryl hydrocarbon receptor (AhR), a unique cellular chemical sensor, has been suggested in tissue fibrosis, but the mechanisms through which the AhR-ligand axis influences the fibrotic process remain undefined. In this study, the potential impact of the AhR-ligand axis on pulmonary fibroblast migration and differentiation was analyzed using human primary lung fibroblasts HFL-1 and CCL-202 cells. Boyden chamber-based cell migration assay showed that activated AhR in HFL-1cells significantly enhanced cell migration in response to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), and a known AhR antagonist, CH223191, inhibited its migratory activity. Furthermore, the calcium mobilization and subsequent upregulated expression of arachidonic acid metabolizing enzymes, including cyclooxygenase2 (COX-2) and 5-lipoxygenase (5-LOX), were observed in TCDD-treated HFL-1 cells, concomitant with elevated levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion. Also, significantly increased expression of α-smooth muscle actin α-SMA), a fibroblast differentiation marker, was also noted in TCDD-treated HFL-1 cells (p < 0.05), resulting in a dynamic change in cytoskeleton protein levels and an increase in the nuclear translocation of the myocardin-related transcription factor. Moreover, the enhanced levels of α-SMA expression and fibroblast migration induced by TCDD, PGE2 and LTB4 were abrogated by selective inhibitors for COX-2 and 5-LOX. Knockdown of AhR by siRNA Completely diminished intracellular calcium uptake and reduced α-SMA protein verified by promoter-reporter assays and chromatin immunoprecipitation. Taken together, our results suggested the importance of the AhR-ligand axis in fibroblast migration and differentiation through its capacity in enhancing arachidonic acid metabolism.

Changes in ceramide metabolism are essential in Madin-Darby canine kidney cell differentiation.

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Pescio, Lucila Gisele; Santacreu, Bruno Jaime; Lopez, Vanina Gisela; Paván, Carlos Humberto; Romero, Daniela Judith; Favale, Nicolás Octavio; Sterin-Speziale, Norma Beatriz

2017-07-01

Ceramides (Cers) and complex sphingolipids with defined acyl chain lengths play important roles in numerous cell processes. Six Cer synthase (CerS) isoenzymes (CerS1-6) are the key enzymes responsible for the production of the diversity of molecular species. In this study, we investigated the changes in sphingolipid metabolism during the differentiation of Madin-Darby canine kidney (MDCK) cells. By MALDI TOF TOF MS, we analyzed the molecular species of Cer, glucosylceramide (GlcCer), lactosylceramide (LacCer), and SM in nondifferentiated and differentiated cells (cultured under hypertonicity). The molecular species detected were the same, but cells subjected to hypertonicity presented higher levels of C24:1 Cer, C24:1 GlcCer, C24:1 SM, and C16:0 LacCer. Consistently with the molecular species, MDCK cells expressed CerS2, CerS4, and CerS6, but with no differences during cell differentiation. We next evaluated the different synthesis pathways with sphingolipid inhibitors and found that cells subjected to hypertonicity in the presence of amitriptyline, an inhibitor of acid sphingomyelinase, showed decreased radiolabeled incorporation in LacCer and cells did not develop a mature apical membrane. These results suggest that hypertonicity induces the endolysosomal degradation of SM, generating the Cer used as substrate for the synthesis of specific molecular species of glycosphingolipids that are essential for MDCK cell differentiation. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Metabolic differentiation of early Lyme disease from southern tick-associated rash illness (STARI).

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Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Andre, Barbara G; Hess, Ann M; Delorey, Mark J; Pilgard, Mark A; Johnson, Barbara J; Webb, Kristofor; Islam, M Nurul; Pegalajar-Jurado, Adoracion; Molla, Irida; Jewett, Mollie W; Belisle, John T

2017-08-16

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N -acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. Development of classification models with the 261-MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to inform patient management by objectively distinguishing early Lyme disease from an illness with nearly identical symptoms. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Cell organisation, sulphur metabolism and ion transport-related genes are differentially expressed in Paracoccidioides brasiliensis mycelium and yeast cells

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Passos Geraldo AS

2006-08-01

Full Text Available Abstract Background Mycelium-to-yeast transition in the human host is essential for pathogenicity by the fungus Paracoccidioides brasiliensis and both cell types are therefore critical to the establishment of paracoccidioidomycosis (PCM, a systemic mycosis endemic to Latin America. The infected population is of about 10 million individuals, 2% of whom will eventually develop the disease. Previously, transcriptome analysis of mycelium and yeast cells resulted in the assembly of 6,022 sequence groups. Gene expression analysis, using both in silico EST subtraction and cDNA microarray, revealed genes that were differential to yeast or mycelium, and we discussed those involved in sugar metabolism. To advance our understanding of molecular mechanisms of dimorphic transition, we performed an extended analysis of gene expression profiles using the methods mentioned above. Results In this work, continuous data mining revealed 66 new differentially expressed sequences that were MIPS(Munich Information Center for Protein Sequences-categorised according to the cellular process in which they are presumably involved. Two well represented classes were chosen for further analysis: (i control of cell organisation – cell wall, membrane and cytoskeleton, whose representatives were hex (encoding for a hexagonal peroxisome protein, bgl (encoding for a 1,3-β-glucosidase in mycelium cells; and ags (an α-1,3-glucan synthase, cda (a chitin deacetylase and vrp (a verprolin in yeast cells; (ii ion metabolism and transport – two genes putatively implicated in ion transport were confirmed to be highly expressed in mycelium cells – isc and ktp, respectively an iron-sulphur cluster-like protein and a cation transporter; and a putative P-type cation pump (pct in yeast. Also, several enzymes from the cysteine de novo biosynthesis pathway were shown to be up regulated in the yeast form, including ATP sulphurylase, APS kinase and also PAPS reductase. Conclusion Taken

Independent AMP and NAD signaling regulates C2C12 differentiation and metabolic adaptation.

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Hsu, Chia George; Burkholder, Thomas J

2016-12-01

The balance of ATP production and consumption is reflected in adenosine monophosphate (AMP) and nicotinamide adenine dinucleotide (NAD) content and has been associated with phenotypic plasticity in striated muscle. Some studies have suggested that AMPK-dependent plasticity may be an indirect consequence of increased NAD synthesis and SIRT1 activity. The primary goal of this study was to assess the interaction of AMP- and NAD-dependent signaling in adaptation of C2C12 myotubes. Changes in myotube developmental and metabolic gene expression were compared following incubation with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and nicotinamide mononucleotide (NMN) to activate AMPK- and NAD-related signaling. AICAR showed no effect on NAD pool or nampt expression but significantly reduced histone H3 acetylation and GLUT1, cytochrome C oxidase subunit 2 (COX2), and MYH3 expression. In contrast, NMN supplementation for 24 h increased NAD pool by 45 % but did not reduce histone H3 acetylation nor promote mitochondrial gene expression. The combination of AMP and NAD signaling did not induce further metabolic adaptation, but NMN ameliorated AICAR-induced myotube reduction. We interpret these results as indication that AMP and NAD contribute to C2C12 differentiation and metabolic adaptation independently.

Metabolic regulation of inflammation.

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Gaber, Timo; Strehl, Cindy; Buttgereit, Frank

2017-05-01

Immune cells constantly patrol the body via the bloodstream and migrate into multiple tissues where they face variable and sometimes demanding environmental conditions. Nutrient and oxygen availability can vary during homeostasis, and especially during the course of an immune response, creating a demand for immune cells that are highly metabolically dynamic. As an evolutionary response, immune cells have developed different metabolic programmes to supply them with cellular energy and biomolecules, enabling them to cope with changing and challenging metabolic conditions. In the past 5 years, it has become clear that cellular metabolism affects immune cell function and differentiation, and that disease-specific metabolic configurations might provide an explanation for the dysfunctional immune responses seen in rheumatic diseases. This Review outlines the metabolic challenges faced by immune cells in states of homeostasis and inflammation, as well as the variety of metabolic configurations utilized by immune cells during differentiation and activation. Changes in cellular metabolism that contribute towards the dysfunctional immune responses seen in rheumatic diseases are also briefly discussed.

Connecting Mitochondria, Metabolism, and Stem Cell Fate

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Wanet, Anaïs; Arnould, Thierry; Najimi, Mustapha

2015-01-01

As sites of cellular respiration and energy production, mitochondria play a central role in cell metabolism. Cell differentiation is associated with an increase in mitochondrial content and activity and with a metabolic shift toward increased oxidative phosphorylation activity. The opposite occurs during reprogramming of somatic cells into induced pluripotent stem cells. Studies have provided evidence of mitochondrial and metabolic changes during the differentiation of both embryonic and somatic (or adult) stem cells (SSCs), such as hematopoietic stem cells, mesenchymal stem cells, and tissue-specific progenitor cells. We thus propose to consider those mitochondrial and metabolic changes as hallmarks of differentiation processes. We review how mitochondrial biogenesis, dynamics, and function are directly involved in embryonic and SSC differentiation and how metabolic and sensing pathways connect mitochondria and metabolism with cell fate and pluripotency. Understanding the basis of the crosstalk between mitochondria and cell fate is of critical importance, given the promising application of stem cells in regenerative medicine. In addition to the development of novel strategies to improve the in vitro lineage-directed differentiation of stem cells, understanding the molecular basis of this interplay could lead to the identification of novel targets to improve the treatment of degenerative diseases. PMID:26134242

Deciphering the Differential Effective and Toxic Responses of Bupleuri Radix following the Induction of Chronic Unpredictable Mild Stress and in Healthy Rats Based on Serum Metabolic Profiles

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Xiaoxia Gao

2018-01-01

Full Text Available The petroleum ether fraction of Bupleuri Radix which is contained in the traditional Chinese medicine prescription of Xiaoyaosan (XYS may have a therapeutic effect in depressed subjects based on the results of our previous study. It has been reported that Bupleuri Radix can cause liver toxicity following overdosing or long-term use. Therefore, this study aimed to decipher the differential effective and toxic responses of Bupleuri Radix in chronic unpredictable mild stress (CUMS (with depression and healthy rats based on serum metabolic profiles. Serum metabolic profiles were obtained using the UHPLC- Q Exactive Orbitrap-MS technique. Our results demonstrated that the petroleum ether fraction of Bupleuri Radix (PBR produces an antidepressant effect through regulating glycometabolism, amino acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and fatty acid metabolism. It also induces more severe toxic reactions in the liver or kidney in healthy rats than in CUMS rats, which exhibited a comparatively mild drug-induced toxic reaction. The altered lysine degradation, sphingolipid metabolism, glycerophospholipid metabolism, fatty acid metabolism, and bile acid metabolism could be at least partly responsible for the PBR toxic responses in healthy rats. The differential effective and toxic response of PBR in CUMS rats and healthy rats provide a new standard for the more rational and safer application of clinical drugs in the future.

Mesenchymal stem cells from different murine tissues have differential capacity to metabolize extracellular nucleotides.

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Iser, Isabele C; Bracco, Paula A; Gonçalves, Carlos E I; Zanin, Rafael F; Nardi, Nance B; Lenz, Guido; Battastini, Ana Maria O; Wink, Márcia R

2014-10-01

Mesenchymal stem cells (MSCs) have shown a great potential for cell-based therapy and many different therapeutic purposes. Despite the recent advances in the knowledge of MSCs biology, their biochemical and molecular properties are still poorly defined. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) and ecto-5'-nucleotidase (eNT/CD73) are widely expressed enzymes that hydrolyze extracellular nucleotides, generating an important cellular signaling cascade. Currently, studies have evidenced the relationship between the purinergic system and the development, maintenance, and differentiation of stem cells. The objective of this study is to identify the NTPDases and eNT/CD73 and compare the levels of nucleotide hydrolysis on MSCs isolated from different murine tissues (bone marrow, lung, vena cava, kidney, pancreas, spleen, skin, and adipose tissue). MSCs from all tissues investigated expressed the ectoenzymes at different levels. In MSCs from pancreas and adipose tissue, the hydrolysis of triphosphonucleosides was significantly higher when compared to the other cells. The diphosphonucleosides were hydrolyzed at a higher rate by MSC from pancreas when compared to MSC from other tissues. The differential nucleotide hydrolysis activity and enzyme expression in these cells suggests that MSCs play different roles in regulating the purinergic system in these tissues. Overall MSCs are an attractive adult-derived cell population for therapies, however, the fact that ecto-nucleotide metabolism can affect the microenvironment, modulating important events, such as immune response, makes the assessment of this metabolism an important part of the characterization of MSCs to be applied therapeutically. © 2014 Wiley Periodicals, Inc.

Preventing Allograft Rejection by Targeting Immune Metabolism

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Chen-Fang Lee

2015-10-01

Full Text Available Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG, the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON. Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Differential retention of metabolic genes following whole-genome duplication.

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Gout, Jean-François; Duret, Laurent; Kahn, Daniel

2009-05-01

Classical studies in Metabolic Control Theory have shown that metabolic fluxes usually exhibit little sensitivity to changes in individual enzyme activity, yet remain sensitive to global changes of all enzymes in a pathway. Therefore, little selective pressure is expected on the dosage or expression of individual metabolic genes, yet entire pathways should still be constrained. However, a direct estimate of this selective pressure had not been evaluated. Whole-genome duplications (WGDs) offer a good opportunity to address this question by analyzing the fates of metabolic genes during the massive gene losses that follow. Here, we take advantage of the successive rounds of WGD that occurred in the Paramecium lineage. We show that metabolic genes exhibit different gene retention patterns than nonmetabolic genes. Contrary to what was expected for individual genes, metabolic genes appeared more retained than other genes after the recent WGD, which was best explained by selection for gene expression operating on entire pathways. Metabolic genes also tend to be less retained when present at high copy number before WGD, contrary to other genes that show a positive correlation between gene retention and preduplication copy number. This is rationalized on the basis of the classical concave relationship relating metabolic fluxes with enzyme expression.

Differential effects of lipopolysaccharide on energy metabolism in murine microglial N9 and cholinergic SN56 neuronal cells.

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Klimaszewska-Łata, Joanna; Gul-Hinc, Sylwia; Bielarczyk, Hanna; Ronowska, Anna; Zyśk, Marlena; Grużewska, Katarzyna; Pawełczyk, Tadeusz; Szutowicz, Andrzej

2015-04-01

There are significant differences between acetyl-CoA and ATP levels, enzymes of acetyl-CoA metabolism, and toll-like receptor 4 contents in non-activated microglial N9 and non-differentiated cholinergic SN56 neuroblastoma cells. Exposition of N9 cells to lipopolysaccharide caused concentration-dependent several-fold increases of nitrogen oxide synthesis, accompanied by inhibition of pyruvate dehydrogenase complex, aconitase, and α-ketoglutarate dehydrogenase complex activities, and by nearly proportional depletion of acetyl-CoA, but by relatively smaller losses in ATP content and cell viability (about 5%). On the contrary, SN56 cells appeared to be insensitive to direct exposition to high concentration of lipopolysaccharide. However, exogenous nitric oxide resulted in marked inhibition pyruvate dehydrogenase and aconitase activities, depletion of acetyl-CoA, along with respective loss of SN56 cells viability. These data indicate that these two common neurodegenerative signals may differentially affect energy-acetyl-CoA metabolism in microglial and cholinergic neuronal cell compartments in the brain. Moreover, microglial cells appeared to be more resistant than neuronal cells to acetyl-CoA and ATP depletion evoked by these neurodegenerative conditions. Together, these data indicate that differential susceptibility of microglia and cholinergic neuronal cells to neurotoxic signals may result from differences in densities of toll-like receptors and degree of disequilibrium between acetyl-CoA provision in mitochondria and its utilization for energy production and acetylation reactions in each particular group of cells. There are significant differences between acetyl-CoA and ATP levels and enzymes of acetyl-CoA metabolism in non-activated microglial N9 and non-differentiated cholinergic SN56 neuroblastoma cells. Pathological stimulation of microglial toll-like receptors (TLRs) triggered excessive synthesis of microglia-derived nitric oxide (NO)/NOO radicals that

A role for differential glycoconjugation in the emission of phenylpropanoid volatiles from tomato fruit discovered using a metabolic data fusion approach.

NARCIS (Netherlands)

Tikunov, Y.M.; Vos, de C.H.; Gonzalez Paramas, A.M.; Hall, R.D.; Bovy, A.G.

2010-01-01

A role for differential glycoconjugation in the emission of phenylpropanoid volatiles from ripening tomato fruit (Solanum lycopersicum) upon fruit tissue disruption has been discovered in this study. Application of a multiinstrumental analytical platform for metabolic profiling of fruits from a

Robust Regression Analysis of GCMS Data Reveals Differential Rewiring of Metabolic Networks in Hepatitis B and C Patients

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Cedric Simillion

2017-10-01

Full Text Available About one in 15 of the world’s population is chronically infected with either hepatitis virus B (HBV or C (HCV, with enormous public health consequences. The metabolic alterations caused by these infections have never been directly compared and contrasted. We investigated groups of HBV-positive, HCV-positive, and uninfected healthy controls using gas chromatography-mass spectrometry analyses of their plasma and urine. A robust regression analysis of the metabolite data was conducted to reveal correlations between metabolite pairs. Ten metabolite correlations appeared for HBV plasma and urine, with 18 for HCV plasma and urine, none of which were present in the controls. Metabolic perturbation networks were constructed, which permitted a differential view of the HBV- and HCV-infected liver. HBV hepatitis was consistent with enhanced glucose uptake, glycolysis, and pentose phosphate pathway metabolism, the latter using xylitol and producing threonic acid, which may also be imported by glucose transporters. HCV hepatitis was consistent with impaired glucose uptake, glycolysis, and pentose phosphate pathway metabolism, with the tricarboxylic acid pathway fueled by branched-chain amino acids feeding gluconeogenesis and the hepatocellular loss of glucose, which most probably contributed to hyperglycemia. It is concluded that robust regression analyses can uncover metabolic rewiring in disease states.

Potential Role of Metabolic Intervention in the Management of Advanced Differentiated Thyroid Cancer

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Sri Harsha Tella

2017-07-01

Full Text Available Well-differentiated thyroid carcinoma (DTC is the most common endocrine malignancy that has an excellent prognosis with a 5-year survival rate of about 98%. However, approximately 50% of the patients with DTC who present with distant metastases (advanced DTC die from the disease within 5 years of initial diagnosis even after getting the appropriate therapy. Apart from recent advancements in chemotherapy agents, the potential role of metabolic interventions, including the use of metformin, ketogenic diet, and high-dose vitamin C in the management of advanced cancers have been investigated as a less toxic co-adjuvant therapies. The role of vitamin C has been of interest again after a preclinical mice study showed that high-dose vitamin C is selectively lethal to KRAS and BRAF mutant colorectal cancer cells by targeting the glutathione pathway. This raises the possibility of utilizing high-doses of vitamin C in the treatment of aDTC where KRAS and BRAF mutations are common. Similarly, alteration of cellular metabolism by low-carbohydrate ketogenic diets can be an important therapeutic strategy to selectively kill cancer cells that mainly survive on glycolysis. Among the potential adjuvant therapies proposed in this paper, metformin is the only agent that has shown benefit in human model of aDTC, the others have shown benefit but in preclinical/animal studies only and need to be further evaluated in large clinical trials. In conclusion, in addition to concurrent chemotherapy options, these metabolic interventions may have a great potential as co-adjuvant therapy in the management of aDTC.

Differential fipronil susceptibility and metabolism in two rice stem borers from China.

Science.gov (United States)

Fang, Qi; Huang, Cheng-Hua; Ye, Gong-Yin; Yao, Hong-Wei; Cheng, Jia-An; Akhtar, Zunnu-Raen

2008-08-01

The susceptibilities of larvae of two rice stem borers, namely, Chilo suppressalis (Walker) (Lepidoptera: Crambidae) and Sesamia inferens (Walker) (Lepidoptera: Nocutidae) to fipronil and its metabolites were investigated, and then the activities of microsomal O-demethylase, and glutathione transferase (GST) in two species were measured. The metabolism of fipronil in both stem borers was determined in vivo and in vitro. The LD50 value of fipronil to S. inferens was 118.5-fold higher than that of C. suppressalis. The bioassay results offipronil metabolites showed that the toxicities of sulfone and sulfide were higher than fipronil for both species, and the differential toxicity between sulfone and fipronil was remarkable. Alternatively, the activities of microsomal O-demethylase and GST of C. suppressalis were 1.35- and 2.06-fold higher than S. inferens, respectively. The in vivo and in vitro studies on metabolism of fipronil showed that all of fipronil, sulfone, and sulfide were detected and the content of sulfone was higher than sulfide in both stem borers. The residue of sulfone in C. suppressalis was significantly higher than that in S. inferens. These results suggest that the higher activity of mixed function oxidases may cause the higher capacity of C. suppressalis to produce fipronil-sulfone, which is more toxic than fipronil leading to the higher susceptibility of this species.

Respiratory and metabolic acidosis differentially affect the respiratory neuronal network in the ventral medulla of neonatal rats.

Science.gov (United States)

Okada, Yasumasa; Masumiya, Haruko; Tamura, Yoshiyasu; Oku, Yoshitaka

2007-11-01

Two respiratory-related areas, the para-facial respiratory group/retrotrapezoid nucleus (pFRG/RTN) and the pre-Bötzinger complex/ventral respiratory group (preBötC/VRG), are thought to play key roles in respiratory rhythm. Because respiratory output patterns in response to respiratory and metabolic acidosis differ, we hypothesized that the responses of the medullary respiratory neuronal network to respiratory and metabolic acidosis are different. To test these hypotheses, we analysed respiratory-related activity in the pFRG/RTN and preBötC/VRG of the neonatal rat brainstem-spinal cord in vitro by optical imaging using a voltage-sensitive dye, and compared the effects of respiratory and metabolic acidosis on these two populations. We found that the spatiotemporal responses of respiratory-related regional activities to respiratory and metabolic acidosis are fundamentally different, although both acidosis similarly augmented respiratory output by increasing respiratory frequency. PreBötC/VRG activity, which is mainly inspiratory, was augmented by respiratory acidosis. Respiratory-modulated pixels increased in the preBötC/VRG area in response to respiratory acidosis. Metabolic acidosis shifted the respiratory phase in the pFRG/RTN; the pre-inspiratory dominant pattern shifted to inspiratory dominant. The responses of the pFRG/RTN activity to respiratory and metabolic acidosis are complex, and involve either augmentation or reduction in the size of respiratory-related areas. Furthermore, the activation pattern in the pFRG/RTN switched bi-directionally between pre-inspiratory/inspiratory and post-inspiratory. Electrophysiological study supported the results of our optical imaging study. We conclude that respiratory and metabolic acidosis differentially affect activities of the pFRG/RTN and preBötC/VRG, inducing switching and shifts of the respiratory phase. We suggest that they differently influence the coupling states between the pFRG/RTN and preBötC/VRG.

Gentamicin differentially alters cellular metabolism of cochlear hair cells as revealed by NAD(P)H fluorescence lifetime imaging

Science.gov (United States)

Zholudeva, Lyandysha V.; Ward, Kristina G.; Nichols, Michael G.; Smith, Heather Jensen

2015-05-01

Aminoglycoside antibiotics are implicated as culprits of hearing loss in more than 120,000 individuals annually. Research has shown that the sensory cells, but not supporting cells, of the cochlea are readily damaged and/or lost after use of such antibiotics. High-frequency outer hair cells (OHCs) show a greater sensitivity to antibiotics than high- and low-frequency inner hair cells (IHCs). We hypothesize that variations in mitochondrial metabolism account for differences in susceptibility. Fluorescence lifetime microscopy was used to quantify changes in NAD(P)H in sensory and supporting cells from explanted murine cochleae exposed to mitochondrial uncouplers, inhibitors, and an ototoxic antibiotic, gentamicin (GM). Changes in metabolic state resulted in a redistribution of NAD(P)H between subcellular fluorescence lifetime pools. Supporting cells had a significantly longer lifetime than sensory cells. Pretreatment with GM increased NAD(P)H intensity in high-frequency sensory cells, as well as the NAD(P)H lifetime within IHCs. GM specifically increased NAD(P)H concentration in high-frequency OHCs, but not in IHCs or pillar cells. Variations in NAD(P)H intensity in response to mitochondrial toxins and GM were greatest in high-frequency OHCs. These results demonstrate that GM rapidly alters mitochondrial metabolism, differentially modulates cell metabolism, and provides evidence that GM-induced changes in metabolism are significant and greatest in high-frequency OHCs.

Altered metabolism in cancer

Directory of Open Access Journals (Sweden)

Locasale Jason W

2010-06-01

Full Text Available Abstract Cancer cells have different metabolic requirements from their normal counterparts. Understanding the consequences of this differential metabolism requires a detailed understanding of glucose metabolism and its relation to energy production in cancer cells. A recent study in BMC Systems Biology by Vasquez et al. developed a mathematical model to assess some features of this altered metabolism. Here, we take a broader look at the regulation of energy metabolism in cancer cells, considering their anabolic as well as catabolic needs. See research article: http://www.biomedcentral.com/1752-0509/4/58/

Constraint Differentiation

DEFF Research Database (Denmark)

Mödersheim, Sebastian Alexander; Basin, David; Viganò, Luca

2010-01-01

We introduce constraint differentiation, a powerful technique for reducing search when model-checking security protocols using constraint-based methods. Constraint differentiation works by eliminating certain kinds of redundancies that arise in the search space when using constraints to represent...... results show that constraint differentiation substantially reduces search and considerably improves the performance of OFMC, enabling its application to a wider class of problems....

Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling

Energy Technology Data Exchange (ETDEWEB)

Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada); Faure, Robert [Département de Pédiatrie, Université Laval and Centre de recherche du CHUQ (Centre Mère-Enfant), Québec, Qc, Canada G1V 4G2 (Canada); Marceau, Normand, E-mail: normand.marceau@crhdq.ulaval.ca [Centre de recherche en cancérologie de l' Université Laval and Centre de recherche du CHUQ (L' Hôtel-Dieu de Québec), 9 McMahon, Québec, Qc, Canada G1R 2J6 (Canada)

2013-02-15

As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

[Mortality in Mexico. Some considerations on rural-urban differentials].

Science.gov (United States)

Camposortega Cruz, S

1989-01-01

"In this essay, certain aspects related to rural-urban mortality differentials in Mexico are analyzed....[These include] the availability, advantages, and limitations of different sources of information and the disparity of levels and tendencies according to particular indicators of acceptable reliability, especially those deriving from recent demographic surveys conducted in Mexico. The findings confirm an inverse ratio between size of settlement and mortality, and reveal a widening of the differentials over time." (SUMMARY IN ENG) excerpt

Differentiation of U937 cells induced by 5,8,11,14-eicosatetraynoic acid, a competitive inhibitor of arachidonic acid metabolism

International Nuclear Information System (INIS)

Ondrey, F.; Anderson, K.; Hoeltgen, D.; Harris, J.

1988-01-01

5,8,11,14-Eicosatetraynoic acid, a competitive inhibitor of arachidonic acid metabolism, rapidly and reversibly inhibited DNA synthesis in U937 cells. This inhibition was not due to cytotoxicity, as judged by studies with trypan blue, release of 51 Cr-labeled proteins, and its reversibility. When cells were cultured in the presence of ETYA for several days, morphologic, enzymatic, and functional changes consistent with differentiation occurred. The cells enlarged, the ratio of cytoplasm to nuclei increased, secretory granules and vacuoles developed, the apparent activity of nonspecific esterase rose, and ingestion of latex particles increased. A morphology consistent with that of an immature monocyte was evident by electron microscopy. When cells differentiated by ETYA were cultured in media free of the inhibitor, DNA synthesis reinitiated and the cell number increased; differentiation was phenotypic and not genotypic. To examine whether ETYA-induced differentiation was obligatorily related to its suppression of DNA synthesis, cells were incubated in 50 μM hydroxyurea and DNA synthesis was inhibited for 24 to 36 h without morphologic evidence of cellular differentiation. However, addition of ETYA to cells prevented from dividing by hydroxyurea and subsequent culture for 72 h induced morphologic evidence of differentiation. The effects of ETYA on cell division and cell differentiation are closely related but can be dissociated

Metabolic Flux Analysis in Isotope Labeling Experiments Using the Adjoint Approach.

Science.gov (United States)

Mottelet, Stephane; Gaullier, Gil; Sadaka, Georges

2017-01-01

Comprehension of metabolic pathways is considerably enhanced by metabolic flux analysis (MFA-ILE) in isotope labeling experiments. The balance equations are given by hundreds of algebraic (stationary MFA) or ordinary differential equations (nonstationary MFA), and reducing the number of operations is therefore a crucial part of reducing the computation cost. The main bottleneck for deterministic algorithms is the computation of derivatives, particularly for nonstationary MFA. In this article, we explain how the overall identification process may be speeded up by using the adjoint approach to compute the gradient of the residual sum of squares. The proposed approach shows significant improvements in terms of complexity and computation time when it is compared with the usual (direct) approach. Numerical results are obtained for the central metabolic pathways of Escherichia coli and are validated against reference software in the stationary case. The methods and algorithms described in this paper are included in the sysmetab software package distributed under an Open Source license at http://forge.scilab.org/index.php/p/sysmetab/.

N-13 labeled amino acids: biodistribution, metabolism and dosimetric considerations

International Nuclear Information System (INIS)

Rosenspire, K.C.; Gelbard, A.S.

1986-01-01

With the growing interest in metabolic imaging and with the increasing number of cyclotron/PET facilities, more studies are being performed in animal and humans using short-lived positron-emitting radionuclides. Amino acids labeled either with N-13 or C-11 are one group of compounds being used to study in vivo regional organ (i.e., brain and heart) or tumor metabolism. Of the studies previously reported using C-11 or N-13 labeled amino acids (methionine, alanine, valine, glutamate, glutamine and tryptophan), imaging was restricted mainly to the organ or tissue of interest with little information obtained about the whole-bode distribution of the label. Such data are important for studying interorgan transport of amino acids and for determining accurate dosimetric measurements after intravenous injection of labeled amino acids. The goals of the authors study were to compare the distribution of several N-13 L-amino acids and N-13 ammonia in tumor-bearing mice and to determine the metabolic fate of the label in vivo. The following amino acids were enzymatically labeled using N-13 ammonia: glutamine, glutamate, methionine, α-aminobutyric acid, valine and leucine. 30 references, 2 figures, 14 tables

Shoot differentiation from protocorm callus cultures of Vanilla planifolia (Orchidaceae: proteomic and metabolic responses at early stage

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Payet Bertrand

2010-05-01

subculture of embryogenic/organogenic calli onto shoot differentiation medium triggers the stimulation of cell metabolism principally at three levels namely (i initiation of photosynthesis, glycolysis and phenolic compounds synthesis; (ii amino acid - protein synthesis, and protein stabilization; (iii sugar degradation. These biochemical mechanisms associated with the initiation of shoot formation during protocorm - like body (PLB organogenesis could be coordinated by the removal of TDZ in callus maintenance medium. These results might contribute to elucidate the complex mechanism that leads to vanilla callus differentiation and subsequent shoot formation into PLB organogenesis. Moreover, our results highlight an early intermediate metabolic event in vanillin biosynthetic pathway with respect to secondary metabolism. Indeed, for the first time in vanilla tissue culture, phenolic compounds such as glucoside A and glucoside B were identified. The degradation of these compounds in specialized tissue (i.e. young green beans probably contributes to the biosynthesis of glucovanillin, the parent compound of vanillin.

Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice.

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Marije Boesjes

Full Text Available The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.

Carbon monoxide improves neuronal differentiation and yield by increasing the functioning and number of mitochondria.

Science.gov (United States)

Almeida, Ana S; Sonnewald, Ursula; Alves, Paula M; Vieira, Helena L A

2016-08-01

The process of cell differentiation goes hand-in-hand with metabolic adaptations, which are needed to provide energy and new metabolites. Carbon monoxide (CO) is an endogenous cytoprotective molecule able to inhibit cell death and improve mitochondrial metabolism. Neuronal differentiation processes were studied using the NT2 cell line, which is derived from human testicular embryonic teratocarcinoma and differentiates into post-mitotic neurons upon retinoic acid treatment. CO-releasing molecule A1 (CORM-A1) was used do deliver CO into cell culture. CO treatment improved NT2 neuronal differentiation and yield, since there were more neurons and the total cell number increased following the differentiation process. CO supplementation enhanced the mitochondrial population in post-mitotic neurons derived from NT2 cells, as indicated by an increase in mitochondrial DNA. CO treatment during neuronal differentiation increased the extent of the classical metabolic change that occurs during neuronal differentiation, from glycolytic to more oxidative metabolism, by decreasing the ratio of lactate production and glucose consumption. The expression of pyruvate and lactate dehydrogenases was higher, indicating an augmented oxidative metabolism. Moreover, these findings were corroborated by an increased percentage of (13) C incorporation from [U-(13) C]glucose into the tricarboxylic acid cycle metabolites malate and citrate, and also glutamate and aspartate in CO-treated cells. Finally, under low levels of oxygen (5%), which enhances glycolytic metabolism, some of the enhancing effects of CO on mitochondria were not observed. In conclusion, our data show that CO improves neuronal and mitochondrial yield by stimulation of tricarboxylic acid cycle activity, and thus oxidative metabolism of NT2 cells during the process of neuronal differentiation. The process of cell differentiation is coupled with metabolic adaptations. Carbon monoxide (CO) is an endogenous cytoprotective

Brain metabolism and memory in age differentiated healthy adults

International Nuclear Information System (INIS)

Riege, W.H.; Metter, E.J.; Kuhl, D.E.; Phelps, M.E.

1984-01-01

The [F-18]-fluorodeoxyglucose (FDG) scan method with positron emission tomography was used to determine age differences in factors underlying both the performances on 18 multivariate memory tests and the rates of cerebral glucose utilization in 9 left and 9 right hemispheric regions of 23 healthy adults in the age range of 27-78 years. Young persons below age 42 had higher scores than middle-aged (age 48-65 yrs) or old (age 66-78 yrs) persons on two of seven factors, reflecting memory for sequences of words or events together with metabolic indices of Broca's (and its mirror region) and Thalamic areas. Reliable correlations (critical r = 0.48, p<0.02) indicated that persons with high Superior Frontal and low Caudate-Thalamic metabolic measures were the same who performed well in tests of memory for sentences, story, designs, and complex patterns; while metabolic indices of Occipital and Posterior Temporal regions were correlated with the decision criteria adopted in testing. The mean metabolic ratio (b = -0.033, F = 5.47, p<0.03) and those of bilateral Broca's regions (b = -0.002, F = 13.65, p<0.001) significantly declined with age. The functional interrelation of frontal-subcortical metabolic ratios with memory processing was more prominent in younger persons under study and implicates decreasing thalamo-frontal interaction with age

Mitochondrial activity in the regulation of stem cell self-renewal and differentiation.

Science.gov (United States)

Khacho, Mireille; Slack, Ruth S

2017-12-01

Mitochondria are classically known as the essential energy producers in cells. As such, the activation of mitochondrial metabolism upon cellular differentiation was deemed a necessity to fuel the high metabolic needs of differentiated cells. However, recent studies have revealed a direct role for mitochondrial activity in the regulation of stem cell fate and differentiation. Several components of mitochondrial metabolism and respiration have now been shown to regulate different aspects of stem cell differentiation through signaling, transcriptional, proteomic and epigenetic modulations. In light of these findings mitochondrial metabolism is no longer considered a consequence of cellular differentiation, but rather a key regulatory mechanism of this process. This review will focus on recent progress that defines mitochondria as the epicenters for the regulation of stem cell fate decisions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.

Science.gov (United States)

Mauro, Claudio; Smith, Joanne; Cucchi, Danilo; Coe, David; Fu, Hongmei; Bonacina, Fabrizia; Baragetti, Andrea; Cermenati, Gaia; Caruso, Donatella; Mitro, Nico; Catapano, Alberico L; Ammirati, Enrico; Longhi, Maria P; Okkenhaug, Klaus; Norata, Giuseppe D; Marelli-Berg, Federica M

2017-03-07

Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4 + T cells. Memory CD4 + T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4 + T cell differentiation into CD44 hi -CCR7 lo -CD62L lo -CXCR3 + -LFA1 + effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4 + T cells and dendritic cells and was mediated via direct exposure of CD4 + T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Investing in the use of a checklist during differential diagnoses consideration: what's the trade-off?

Science.gov (United States)

Chew, Keng Sheng; van Merrienboer, Jeroen J G; Durning, Steven J

2017-11-29

A key challenge clinicians face when considering differential diagnoses is whether the patient data have been adequately collected. Insufficient data may inadvertently lead to premature closure of the diagnostic process. This study aimed to test the hypothesis that the application of a mnemonic checklist helps to stimulate more patient data collection, thus leading to better diagnostic consideration. A total of 88 final year medical students were assigned to either an educational intervention group or a control group in a non-equivalent group post-test only design. Participants in the intervention group received a tutorial on the use of a mnemonic checklist aimed to minimize cognitive errors in clinical decision-making. Two weeks later, the participants in both groups were given a script concordance test consisting of 10 cases, with 3 items per case, to assess their clinical decisions when additional data are given in the case scenarios. The Mann-Whitney U-test performed on the total scores from both groups showed no statistical significance (U = 792, z = -1.408, p = 0.159). When comparisons were made for the first half and the second half of the SCT, it was found that participants in the intervention group performed significantly better than participants in the control group in the first half of the test, with median scores of 9.15 (IQR 8.00-10.28) vs. 8.18 (IQR 7.16-9.24) respectively, U = 642.5, z = -2.661, p = 0.008. No significant difference was found in the second half of the test, with the median score of 9.58 (IQR 8.90-10.56) vs. 9.81 (IQR 8.83-11.12) for the intervention group and control group respectively (U = 897.5, z = -0.524, p = 0.60). Checklist use in differential diagnoses consideration did show some benefit. However, this benefit seems to have been traded off by the time and effort in using it. More research is needed to determine whether this benefit could be translated into clinical practice after repetitive

Differential games

CERN Document Server

Friedman, Avner

2006-01-01

This volume lays the mathematical foundations for the theory of differential games, developing a rigorous mathematical framework with existence theorems. It begins with a precise definition of a differential game and advances to considerations of games of fixed duration, games of pursuit and evasion, the computation of saddle points, games of survival, and games with restricted phase coordinates. Final chapters cover selected topics (including capturability and games with delayed information) and N-person games.Geared toward graduate students, Differential Games will be of particular interest

[Menopause and metabolic syndrome].

Science.gov (United States)

Meirelles, Ricardo M R

2014-03-01

The incidence of cardiovascular disease increases considerably after the menopause. One reason for the increased cardiovascular risk seems to be determined by metabolic syndrome, in which all components (visceral obesity, dyslipidemia, hypertension, and glucose metabolism disorder) are associated with higher incidence of coronary artery disease. After menopause, metabolic syndrome is more prevalent than in premenopausal women, and may plays an important role in the occurrence of myocardial infarction and other atherosclerotic and cardiovascular morbidities. Obesity, an essential component of the metabolic syndrome, is also associated with increased incidence of breast, endometrial, bowel, esophagus, and kidney cancer. The treatment of metabolic syndrome is based on the change in lifestyle and, when necessary, the use of medication directed to its components. In the presence of symptoms of the climacteric syndrome, hormonal therapy, when indicated, will also contribute to the improvement of the metabolic syndrome.

Proton NMR metabolic profiling of CSF reveals distinct differentiation of meningitis from negative controls.

Science.gov (United States)

Chatterji, Tanushri; Singh, Suruchi; Sen, Manodeep; Singh, Ajai Kumar; Agarwal, Gaurav Raj; Singh, Deepak Kumar; Srivastava, Janmejai Kumar; Singh, Alka; Srivastava, Rajeshwar Nath; Roy, Raja

2017-06-01

Cerebrospinal fluid (CSF) is an essential bio-fluid of the central nervous system (CNS), playing a vital role in the protection of CNS and performing neuronal function regulation. The chemical composition of CSF varies during onset of meningitis, neurodegenerative disorders (positive controls) and in traumatic cases (negative controls). The study design was broadly categorized into meningitis cases, negative controls and positive controls. Further differentiation among the three groups was carried out using Principal Component Analysis (PCA) followed by supervised Partial Least Square Discriminant Analysis (PLS-DA). The statistical analysis of meningitis vs. negative controls using PLS-DA model resulted in R 2 of 0.97 and Q 2 of 0.85. There was elevation in the levels of ketone bodies, total free amino acids, glutamine, creatine, citrate and choline containing compounds (choline and GPC) in meningitis cases. Similarly, meningitis vs. positive controls resulted in R 2 of 0.80 and Q 2 of 0.60 and showed elevation in the levels of total free amino acids, glutamine, creatine/creatinine and citrate in the meningitis group. Four cases of HIV were identified by PLS-DA model as well as by clinical investigations. On the basis of metabolic profile it was found that negative control CSF samples are more appropriate for differentiation of meningitis than positive control CSF samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism.

Directory of Open Access Journals (Sweden)

Eleanor C Saunders

2014-01-01

Full Text Available Leishmania parasites alternate between extracellular promastigote stages in the insect vector and an obligate intracellular amastigote stage that proliferates within the phagolysosomal compartment of macrophages in the mammalian host. Most enzymes involved in Leishmania central carbon metabolism are constitutively expressed and stage-specific changes in energy metabolism remain poorly defined. Using (13C-stable isotope resolved metabolomics and (2H2O labelling, we show that amastigote differentiation is associated with reduction in growth rate and induction of a distinct stringent metabolic state. This state is characterized by a global decrease in the uptake and utilization of glucose and amino acids, a reduced secretion of organic acids and increased fatty acid β-oxidation. Isotopomer analysis showed that catabolism of hexose and fatty acids provide C4 dicarboxylic acids (succinate/malate and acetyl-CoA for the synthesis of glutamate via a compartmentalized mitochondrial tricarboxylic acid (TCA cycle. In vitro cultivated and intracellular amastigotes are acutely sensitive to inhibitors of mitochondrial aconitase and glutamine synthetase, indicating that these anabolic pathways are essential for intracellular growth and virulence. Lesion-derived amastigotes exhibit a similar metabolism to in vitro differentiated amastigotes, indicating that this stringent response is coupled to differentiation signals rather than exogenous nutrient levels. Induction of a stringent metabolic response may facilitate amastigote survival in a nutrient-poor intracellular niche and underlie the increased dependence of this stage on hexose and mitochondrial metabolism.

[Metabolic acidosis].

Science.gov (United States)

Regolisti, Giuseppe; Fani, Filippo; Antoniotti, Riccardo; Castellano, Giuseppe; Cremaschi, Elena; Greco, Paolo; Parenti, Elisabetta; Morabito, Santo; Sabatino, Alice; Fiaccadori, Enrico

2016-01-01

Metabolic acidosis is frequently observed in clinical practice, especially among critically ill patients and/or in the course of renal failure. Complex mechanisms are involved, in most cases identifiable by medical history, pathophysiology-based diagnostic reasoning and measure of some key acid-base parameters that are easily available or calculable. On this basis the bedside differential diagnosis of metabolic acidosis should be started from the identification of the two main subtypes of metabolic acidosis: the high anion gap metabolic acidosis and the normal anion gap (or hyperchloremic) metabolic acidosis. Metabolic acidosis, especially in its acute forms with elevated anion gap such as is the case of lactic acidosis, diabetic and acute intoxications, may significantly affect metabolic body homeostasis and patients hemodynamic status, setting the stage for true medical emergencies. The therapeutic approach should be first aimed at early correction of concurrent clinical problems (e.g. fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, hemodialysis for acute intoxications etc.), in parallel to the formulation of a diagnosis. In case of severe acidosis, the administration of alkalizing agents should be carefully evaluated, taking into account the risk of side effects, as well as the potential need of renal replacement therapy.

Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling

Energy Technology Data Exchange (ETDEWEB)

Zhdanov, Alexander V., E-mail: a.zhdanov@ucc.ie [School of Biochemistry and Cell Biology, University College Cork, Cavanagh Pharmacy Building, College Road, Cork (Ireland); Waters, Alicia H.C. [School of Biochemistry and Cell Biology, University College Cork, Cavanagh Pharmacy Building, College Road, Cork (Ireland); Golubeva, Anna V. [Alimentary Pharmabiotic Centre, University College Cork, Bioscience Institute, Western Road, Cork (Ireland); Papkovsky, Dmitri B. [School of Biochemistry and Cell Biology, University College Cork, Cavanagh Pharmacy Building, College Road, Cork (Ireland)

2015-01-01

Changes in availability and utilisation of O{sub 2} and metabolic substrates are common in ischemia and cancer. We examined effects of substrate deprivation on HIF signalling in PC12 cells exposed to different atmospheric O{sub 2}. Upon 2–4 h moderate hypoxia, HIF-α protein levels were dictated by the availability of glutamine and glucose, essential for deep cell deoxygenation and glycolytic ATP flux. Nuclear accumulation of HIF-1α dramatically decreased upon inhibition of glutaminolysis or glutamine deprivation. Elevation of HIF-2α levels was transcription-independent and associated with the activation of Akt and Erk1/2. Upon 2 h anoxia, HIF-2α levels strongly correlated with cellular ATP, produced exclusively via glycolysis. Without glucose, HIF signalling was suppressed, giving way to other regulators of cell adaptation to energy crisis, e.g. AMPK. Consequently, viability of cells deprived of O{sub 2} and glucose decreased upon inhibition of AMPK with dorsomorphin. The capacity of cells to accumulate HIF-2α decreased after 24 h glucose deprivation. This effect, associated with increased AMPKα phosphorylation, was sensitive to dorsomorphin. In chronically hypoxic cells, glutamine played no major role in HIF-2α accumulation, which became mainly glucose-dependent. Overall, the availability of O{sub 2} and metabolic substrates intricately regulates HIF signalling by affecting cell oxygenation, ATP levels and pathways involved in production of HIF-α. - Highlights: • Gln and Glc regulate HIF levels in hypoxic cells by maintaining low O{sub 2} and high ATP. • HIF-α levels under anoxia correlate with cellular ATP and critically depend on Glc. • Gln and Glc modulate activity of Akt, Erk and AMPK, regulating HIF production. • HIF signalling is differentially inhibited by prolonged Glc and Gln deprivation. • Unlike Glc, Gln plays no major role in HIF signalling in chronically hypoxic cells.

Differential contribution of key metabolic substrates and cellular oxygen in HIF signalling

International Nuclear Information System (INIS)

Zhdanov, Alexander V.; Waters, Alicia H.C.; Golubeva, Anna V.; Papkovsky, Dmitri B.

2015-01-01

Changes in availability and utilisation of O 2 and metabolic substrates are common in ischemia and cancer. We examined effects of substrate deprivation on HIF signalling in PC12 cells exposed to different atmospheric O 2 . Upon 2–4 h moderate hypoxia, HIF-α protein levels were dictated by the availability of glutamine and glucose, essential for deep cell deoxygenation and glycolytic ATP flux. Nuclear accumulation of HIF-1α dramatically decreased upon inhibition of glutaminolysis or glutamine deprivation. Elevation of HIF-2α levels was transcription-independent and associated with the activation of Akt and Erk1/2. Upon 2 h anoxia, HIF-2α levels strongly correlated with cellular ATP, produced exclusively via glycolysis. Without glucose, HIF signalling was suppressed, giving way to other regulators of cell adaptation to energy crisis, e.g. AMPK. Consequently, viability of cells deprived of O 2 and glucose decreased upon inhibition of AMPK with dorsomorphin. The capacity of cells to accumulate HIF-2α decreased after 24 h glucose deprivation. This effect, associated with increased AMPKα phosphorylation, was sensitive to dorsomorphin. In chronically hypoxic cells, glutamine played no major role in HIF-2α accumulation, which became mainly glucose-dependent. Overall, the availability of O 2 and metabolic substrates intricately regulates HIF signalling by affecting cell oxygenation, ATP levels and pathways involved in production of HIF-α. - Highlights: • Gln and Glc regulate HIF levels in hypoxic cells by maintaining low O 2 and high ATP. • HIF-α levels under anoxia correlate with cellular ATP and critically depend on Glc. • Gln and Glc modulate activity of Akt, Erk and AMPK, regulating HIF production. • HIF signalling is differentially inhibited by prolonged Glc and Gln deprivation. • Unlike Glc, Gln plays no major role in HIF signalling in chronically hypoxic cells

Measuring energy metabolism in the mouse – theoretical, practical and analytical considerations

Directory of Open Access Journals (Sweden)

John Roger Speakman

2013-03-01

Full Text Available The mouse is one of the most important model organisms for understanding human genetic function and disease. This includes characterisation of the factors that influence energy expenditure and dysregulation of energy balance leading to obesity and its sequalae. Measuring energy metabolism in the mouse presents a challenge because the animals are small, and in this respect it presents similar challenges to measuring energy demands in many other species of small mammal. This paper considers some theoretical, practical and analytical considerations to be considered when measuring energy expenditure in mice. Theoretically total daily energy expenditure is comprised of several different components: basal or resting expenditure, physical activity, thermoregulation and the thermic effect of food. Energy expenditure in mice is normally measured using open flow indirect calorimetry apparatus. Two types of system are available – one of which involves a single small Spartan chamber linked to a single analyser, which is ideal for measuring the individual components of energy demand. The other type of system involves a large chamber which mimics the home cage environment and is generally configured with several chambers per analyser. These latter systems are ideal for measuring total daily energy expenditure but at present do not allow accurate decomposition of the total expenditure into its components. The greatest analytical challenge for mouse expenditure data is how to account for body size differences between individuals. This has been a matter of some discussion for at least 120 years. The statistically most appropriate approach is to use ANCOVA with individual aspects of body composition as independent predictors.

Differential proteomic analysis highlights metabolic strategies associated with balhimycin production in Amycolatopsis balhimycina chemostat cultivations

DEFF Research Database (Denmark)

Gallo, Giuseppe; Alduina, Rosa; Renzone, Giovanni

2010-01-01

Background Proteomics was recently used to reveal enzymes whose expression is associated with the production of the glycopeptide antibiotic balhimycin in Amycolatopsis balhimycina batch cultivations. Combining chemostat fermentation technology, where cells proliferate with constant parameters...... in a highly reproducible steady-state, and differential proteomics, the relationships between physiological status and metabolic pathways during antibiotic producing and non-producing conditions could be highlighted. Results Two minimal defined media, one with low Pi (0.6 mM; LP) and proficient glucose (12 g....../l) concentrations and the other one with high Pi (1.8 mM) and limiting (6 g/l; LG) glucose concentrations, were developed to promote and repress antibiotic production, respectively, in A. balhimycina chemostat cultivations. Applying the same dilution rate (0.03 h-1), both LG and LP chemostat cultivations showed...

Stem cell metabolism in tissue development and aging

Science.gov (United States)

Shyh-Chang, Ng; Daley, George Q.; Cantley, Lewis C.

2013-01-01

Recent advances in metabolomics and computational analysis have deepened our appreciation for the role of specific metabolic pathways in dictating cell fate. Once thought to be a mere consequence of the state of a cell, metabolism is now known to play a pivotal role in dictating whether a cell proliferates, differentiates or remains quiescent. Here, we review recent studies of metabolism in stem cells that have revealed a shift in the balance between glycolysis, mitochondrial oxidative phosphorylation and oxidative stress during the maturation of adult stem cells, and during the reprogramming of somatic cells to pluripotency. These insights promise to inform strategies for the directed differentiation of stem cells and to offer the potential for novel metabolic or pharmacological therapies to enhance regeneration and the treatment of degenerative disease. PMID:23715547

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

Energy Technology Data Exchange (ETDEWEB)

Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra, E-mail: sukhmahendrasingh@yahoo.com

2013-11-15

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment. �

Antitumor and chemosensitizing action of dichloroacetate implicates modulation of tumor microenvironment: A role of reorganized glucose metabolism, cell survival regulation and macrophage differentiation

International Nuclear Information System (INIS)

Kumar, Ajay; Kant, Shiva; Singh, Sukh Mahendra

2013-01-01

Targeting of tumor metabolism is emerging as a novel therapeutic strategy against cancer. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), has been shown to exert a potent tumoricidal action against a variety of tumor cells. The main mode of its antineoplastic action implicates a shift of glycolysis to oxidative metabolism of glucose, leading to generation of cytotoxic reactive oxygen intermediates. However, the effect of DCA on tumor microenvironment, which in turn regulates tumor cell survival; remains speculative to a large extent. It is also unclear if DCA can exert any modulatory effect on the process of hematopoiesis, which is in a compromised state in tumor-bearing hosts undergoing chemotherapy. In view of these lacunas, the present study was undertaken to investigate the so far unexplored aspects with respect to the molecular mechanisms of DCA-dependent tumor growth retardation and chemosensitization. BALB/c mice were transplanted with Dalton's lymphoma (DL) cells, a T cell lymphoma of spontaneous origin, followed by administration of DCA with or without cisplatin. DCA-dependent tumor regression and chemosensitization to cisplatin was found to be associated with altered repertoire of key cell survival regulatory molecules, modulated glucose metabolism, accompanying reconstituted tumor microenvironment with respect to pH homeostasis, cytokine balance and alternatively activated TAM. Moreover, DCA administration also led to an alteration in the MDR phenotype of tumor cells and myelopoietic differentiation of macrophages. The findings of this study shed a new light with respect to some of the novel mechanisms underlying the antitumor action of DCA and thus may have immense clinical applications. - Highlights: • DCA modulates tumor progression and chemoresistance. • DCA alters molecules regulating cell survival, glucose metabolism and MDR. • DCA reconstitutes biophysical and cellular composition of tumor microenvironment. �

Effects of CD44 Ligation on Signaling and Metabolic Pathways in Acute Myeloid Leukemia

KAUST Repository

Madhoun, Nour Y.

2017-04-01

Acute myeloid leukemia (AML) is characterized by a blockage in the differentiation of myeloid cells at different stages. CD44-ligation using anti-CD44 monoclonal antibodies (mAbs) has been shown to reverse the blockage of differentiation and to inhibit the proliferation of blasts in most AML-subtypes. However, the molecular mechanisms underlying this property have not been fully elucidated. Here, we sought to I) analyze the effects of anti-CD44 mAbs on downstream signaling pathways, including the ERK1/2 (extracellular signal-regulated kinase 1 and 2) and mTOR (mammalian target of rapamycin) pathways and II) use state-of-the-art Nuclear Magnetic Resonance (NMR) technology to determine the global metabolic changes during differentiation induction of AML cells using anti-CD44 mAbs and other two previously reported differentiation agents. In the first objective (Chapter 4), our studies provide evidence that CD44-ligation with specific mAbs in AML cells induced an increase in ERK1/2 phosphorylation. The use of the MEK inhibitor (U0126) significantly inhibited the CD44-induced differentiation of HL60 cells, suggesting that ERK1/2 is critical for the CD44-triggered differentiation in AML. In addition, this was accompanied by a marked decrease in the phosphorylation of the mTORC1 and mTORC2 complexes, which are strongly correlated with the inhibition of the PI3K/Akt pathway. In the second objective (Chapter 5), 1H NMR experiments demonstrated that considerable changes in the metabolic profiles of HL60 cells were induced in response to each differentiation agent. These most notable metabolites that significantly changed upon CD44 ligation were involved in the tricarboxylic acid (TCA) cycle and glycolysis such as, succinate, fumarate and lactate. Therefore, we sought to analyze the mechanisms underlying their alterations. Our results revealed that anti-CD44 mAbs treatment induced upregulation in fumarate hydratase (FH) expression and its activity which was accompanied by a

Inhibitor of Differentiation-3 and Estrogenic Endocrine Disruptors: Implications for Susceptibility to Obesity and Metabolic Disorders

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Mayur Doke

2018-01-01

Full Text Available The rising global incidence of obesity cannot be fully explained within the context of traditional risk factors such as an unhealthy diet, physical inactivity, aging, or genetics. Adipose tissue is an endocrine as well as a metabolic organ that may be susceptible to disruption by environmental estrogenic chemicals. Since some of the endocrine disruptors are lipophilic chemicals with long half-lives, they tend to bioaccumulate in the adipose tissue of exposed populations. Elevated exposure to these chemicals may predispose susceptible individuals to weight gain by increasing the number and size of fat cells. Genetic studies have demonstrated that the transcriptional regulator inhibitor of differentiation-3 (ID3 promotes high fat diet-induced obesity in vivo. We have shown previously that PCB153 and natural estrogen 17β-estradiol increase ID3 expression. Based on our findings, we postulate that ID3 is a molecular target of estrogenic endocrine disruptors (EEDs in the adipose tissue and a better understanding of this relationship may help to explain how EEDs can lead to the transcriptional programming of deviant fat cells. This review will discuss the current understanding of ID3 in excess fat accumulation and the potential for EEDs to influence susceptibility to obesity or metabolic disorders via ID3 signaling.

HPLC-MS-Based Metabonomics Reveals Disordered Lipid Metabolism in Patients with Metabolic Syndrome

Directory of Open Access Journals (Sweden)

Xinjie Zhao

2011-12-01

Full Text Available Ultra-high performance liquid chromatography/ quadrupole time of flight mass spectrometry-based metabonomics platform was employed to profile the plasma metabolites of patients with metabolic syndrome and the healthy controls. Data analysis revealed lots of differential metabolites between the two groups, and most of them were identified as lipids. Several fatty acids and lysophosphatidylcholines were of higher plasma levels in the patient group, indicating the occurrence of insulin resistance and inflammation. The identified ether phospholipids were decreased in the patient group, reflecting the oxidative stress and some metabolic disorders. These identified metabolites can also be used to aid diagnosis of patients with metabolic syndrome. These results showed that metabonomics was a promising and powerful method to study metabolic syndrome.

Differential regional metabolism of glucagon in anesthetized pigs

DEFF Research Database (Denmark)

Deacon, Carolyn F; Kelstrup, Mette; Trebbien, Ramona

2003-01-01

Glucagon metabolism under basal (endogenous) conditions and during intravenous glucagon infusion was studied in anesthetized pigs by use of midregion (M), COOH-terminal (C), and NH2-terminal (N)-RIAs. Arteriovenous concentration differences revealed a negative extraction of endogenous glucagon.......5 +/- 6.7%, M-, C-, N-RIA) and exogenous conditions (46.9 +/- 4.8, 46.4 +/- 6.0, 47.0 +/- 7.7%; M-, C-, N-RIA), indicating substantial elimination of the peptide. Hepatic glucagon extraction was undetectable under basal conditions and detected only by M-RIA (10.0 +/- 3.8%) during glucagon infusion......, indicating limited midregional cleavage of the molecule. The plasma half-life determined by C- and N-RIAs (2.7 +/- 0.2 and 2.3 +/- 0.2 min) were similar, but both were shorter than when determined by M-RIA (3.2 +/- 0.2 min, P Metabolic clearance rates were similar regardless of assay (14.4 +/- 1...

[Drug-Drug Interactions with Consideration of Pharmacogenetics].

Science.gov (United States)

Ozawa, Shogo

2018-01-01

　Elderly patients often suffer from a variety of diseases and therefore may be prescribed several kinds of drugs. Interactions between these drugs may cause problems in some patients. Guidelines for drug interactions were released on July 8, 2014 "Drug Interaction Guideline for Drug Development and Labeling Recommendations (Final Draft)". These guidelines include the theoretical basis for evaluating the mechanisms of drug interaction, the possible extent of drug interactions, and take into consideration special populations (e.g., infants, children, elderly patients, patients with hepatic or renal dysfunction, and subjects with minor deficient alleles for drug metabolizing enzymes and drug transporters). In this symposium article, I discuss this last special population: altered drug metabolism and drug interactions in subjects with minor alleles of genes encoding deficient drug metabolizing enzymes. I further discuss a drug label for eliglustat (Cerdelga) with instructions for patients with ultra-rapid, extensive, intermediate, and poor metabolizer phenotypes that arise from different CYP2D6 gene alleles.

Changes in metabolic correlates of personality traits in healthy elderly women

International Nuclear Information System (INIS)

Park, Hyun Soo; Cho, Sang Soo; Yoon, Eun Jin; Bang, Seong Ae; Kim, Yu Kyeong; Kim, Sang Eun

2007-01-01

Personality traits are generally known to be stable, although the brain changes with aging. Especially women experience striking alterations in the neuroendocrinergic system at menopause, which may cause considerable changes in personality traits and alter their underlying neural substrates. To investigate changes in the neural substrates underlying personality traits, we investigated metabolic correlates of personality traits in women before and after menopause. We obtained FDG PET images from 13 young (24.0±3.1 y) and 11 elderly females (66.8±3.3 y). Three factors of personality traits (novelty seeking (NS), harm avoidance (HA), reward dependence (RD)) were assessed using Cloninger's 240-item Temperament and Characteristic Inventory. Three ANCOVA maps were created in SPM2 (P < 0.01 uncorrected, k = 100), each constructed to assess the metabolic correlates of each temperament factor. In young females NS scores were negatively correlated with glucose metabolism in the right insula and right cingulate; in elderly females, the right cuneus. In young females HA scores were positively correlated with glucose metabolism in the right lingual gyrus; in elderly females, the left anterior cingulate and bilateral hippocampus. Only in elderly females, HA scores were negatively correlated with glucose metabolism in the right orbital gyrus and bilateral frontal gyri. In young females, RD scores were positively correlated with glucose metabolism in the bilateral frontal gyri and bilateral cingulate; in elderly females, the right middle frontal gyrus. In young females, RD scores were negatively correlated with glucose metabolism in the right precuneus; in elderly females, the left insula. We found that neural substrates underlying personality traits in females were dissociable across young and elderly women. These results may provide better understanding of differential prevalence and susceptibility to psychiatric illnesses in young and elderly females

Changes in metabolic correlates of personality traits in healthy elderly women

Energy Technology Data Exchange (ETDEWEB)

Park, Hyun Soo; Cho, Sang Soo; Yoon, Eun Jin; Bang, Seong Ae; Kim, Yu Kyeong; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

2007-07-01

Personality traits are generally known to be stable, although the brain changes with aging. Especially women experience striking alterations in the neuroendocrinergic system at menopause, which may cause considerable changes in personality traits and alter their underlying neural substrates. To investigate changes in the neural substrates underlying personality traits, we investigated metabolic correlates of personality traits in women before and after menopause. We obtained FDG PET images from 13 young (24.0{+-}3.1 y) and 11 elderly females (66.8{+-}3.3 y). Three factors of personality traits (novelty seeking (NS), harm avoidance (HA), reward dependence (RD)) were assessed using Cloninger's 240-item Temperament and Characteristic Inventory. Three ANCOVA maps were created in SPM2 (P < 0.01 uncorrected, k = 100), each constructed to assess the metabolic correlates of each temperament factor. In young females NS scores were negatively correlated with glucose metabolism in the right insula and right cingulate; in elderly females, the right cuneus. In young females HA scores were positively correlated with glucose metabolism in the right lingual gyrus; in elderly females, the left anterior cingulate and bilateral hippocampus. Only in elderly females, HA scores were negatively correlated with glucose metabolism in the right orbital gyrus and bilateral frontal gyri. In young females, RD scores were positively correlated with glucose metabolism in the bilateral frontal gyri and bilateral cingulate; in elderly females, the right middle frontal gyrus. In young females, RD scores were negatively correlated with glucose metabolism in the right precuneus; in elderly females, the left insula. We found that neural substrates underlying personality traits in females were dissociable across young and elderly women. These results may provide better understanding of differential prevalence and susceptibility to psychiatric illnesses in young and elderly females.

Poorly Differentiated Thyroid Carcinoma.

Science.gov (United States)

Setia, Namrata; Barletta, Justine A

2014-12-01

Poorly differentiated thyroid carcinoma (PDTC) has been recognized for the past 30 years as an entity showing intermediate differentiation and clinical behavior between well-differentiated thyroid carcinomas (ie, papillary thyroid carcinoma and follicular thyroid carcinoma) and anaplastic thyroid carcinoma; however, there has been considerable controversy around the definition of PDTC. In this review, the evolution in the definition of PDTC, current diagnostic criteria, differential diagnoses, potentially helpful immunohistochemical studies, and molecular alterations are discussed with the aim of highlighting where the diagnosis of PDTC currently stands. Published by Elsevier Inc.

Genetic and metabolic engineering in diatoms.

Science.gov (United States)

Huang, Weichao; Daboussi, Fayza

2017-09-05

Diatoms have attracted considerable attention due to their success in diverse environmental conditions, which probably is a consequence of their complex origins. Studies of their metabolism will provide insight into their adaptation capacity and are a prerequisite for metabolic engineering. Several years of investigation have led to the development of the genome engineering tools required for such studies, and a profusion of appropriate tools is now available for exploring and exploiting the metabolism of these organisms. Diatoms are highly prized in industrial biotechnology, due to both their richness in natural lipids and carotenoids and their ability to produce recombinant proteins, of considerable value in diverse markets. This review provides an overview of recent advances in genetic engineering methods for diatoms, from the development of gene expression cassettes and gene delivery methods, to cutting-edge genome-editing technologies. It also highlights the contributions of these rapid developments to both basic and applied research: they have improved our understanding of key physiological processes; and they have made it possible to modify the natural metabolism to favour the production of specific compounds or to produce new compounds for green chemistry and pharmaceutical applications.This article is part of the themed issue 'The peculiar carbon metabolism in diatoms'. © 2017 The Author(s).

Macroautophagy and Selective Mitophagy Ameliorate Chondrogenic Differentiation Potential in Adipose Stem Cells of Equine Metabolic Syndrome: New Findings in the Field of Progenitor Cells Differentiation.

Science.gov (United States)

Marycz, Krzysztof; Kornicka, Katarzyna; Grzesiak, Jakub; Śmieszek, Agnieszka; Szłapka, Jolanta

2016-01-01

Equine metabolic syndrome (EMS) is mainly characterized by insulin resistance, obesity, and local or systemic inflammation. That unfriendly environment of adipose tissue has huge impact on stem cells population (ASC) residing within. In the present study, using molecular biology techniques and multiple imaging techniques (SEM, FIB-SEM, and confocal microscopy), we evaluated the impact of EMS on ASC viability and chondrogenic differentiation. Moreover, we visualized the mitochondrial network and dynamics in ASC CTRL and ASC EMS during control and chondrogenic conditions. In control conditions, ASC EMS were characterized by increased mitochondrial fission in comparison to ASC CTRL . We found that extensive remodeling of mitochondrial network including fusion and fission occurs during early step of differentiation. Moreover, we observed mitochondria morphology deterioration in ASC EMS . These conditions seem to cause autophagic shift in ASC EMS , as we observed increased accumulation of LAMP2 and formation of multiple autophagosomes in those cells, some of which contained dysfunctional mitochondria. "Autophagic" switch may be a rescue mechanism allowing ASC EMS to clear impaired by ROS proteins and mitochondria. Moreover it provides a precursors-to-macromolecules synthesis, especially during chondrogenesis. Our data indicates that autophagy in ASC EMS would be crucial for the quality control mechanisms and maintenance of cellular homeostasis ASC EMS allowing them to be in "stemness" status.

Macroautophagy and Selective Mitophagy Ameliorate Chondrogenic Differentiation Potential in Adipose Stem Cells of Equine Metabolic Syndrome: New Findings in the Field of Progenitor Cells Differentiation

Directory of Open Access Journals (Sweden)

Krzysztof Marycz

2016-01-01

Full Text Available Equine metabolic syndrome (EMS is mainly characterized by insulin resistance, obesity, and local or systemic inflammation. That unfriendly environment of adipose tissue has huge impact on stem cells population (ASC residing within. In the present study, using molecular biology techniques and multiple imaging techniques (SEM, FIB-SEM, and confocal microscopy, we evaluated the impact of EMS on ASC viability and chondrogenic differentiation. Moreover, we visualized the mitochondrial network and dynamics in ASCCTRL and ASCEMS during control and chondrogenic conditions. In control conditions, ASCEMS were characterized by increased mitochondrial fission in comparison to ASCCTRL. We found that extensive remodeling of mitochondrial network including fusion and fission occurs during early step of differentiation. Moreover, we observed mitochondria morphology deterioration in ASCEMS. These conditions seem to cause autophagic shift in ASCEMS, as we observed increased accumulation of LAMP2 and formation of multiple autophagosomes in those cells, some of which contained dysfunctional mitochondria. “Autophagic” switch may be a rescue mechanism allowing ASCEMS to clear impaired by ROS proteins and mitochondria. Moreover it provides a precursors-to-macromolecules synthesis, especially during chondrogenesis. Our data indicates that autophagy in ASCEMS would be crucial for the quality control mechanisms and maintenance of cellular homeostasis ASCEMS allowing them to be in “stemness” status.

An infection of human adenovirus 31 affects the differentiation of preadipocytes into fat cells, its metabolic profile and fat accumulation.

Science.gov (United States)

Bil-Lula, Iwona; Krzywonos-Zawadzka, Anna; Sawicki, Grzegorz; Woźniak, Mieczysław

2016-03-01

The primary issue undertaken in this study was to test the hypothesis that preadipocytes would have intrinsically elevated propensity to differentiate into mature adipocytes due to HAdV31 infection. To prove that, the metabolic and molecular mechanisms responsible for HAdV31-induced adipogenesis were examined. 3T3L1 cells (mouse embryonic fibroblast, adipose like cell line) were used as a surrogate model to analyze an increased proliferation, differentiation, and maturation of preadipocytes infected with human adenovirus. An expression of E4orf1, C/EBP-β, PPAR-γ, GAPDH, aP2, LEP, and fatty acid synthase genes, intracellular lipid accumulation as well as cytokine release from the fat cells were assessed. Data showed that HAdV31 increased an expression of C/EBP-β and PPAR-γ genes leading to an enhanced differentiation of preadipocytes into fat cells. Besides, overexpression of GAPDH and fatty acid synthase, and decreased expression of leptin caused an increased accumulation of intracellular lipids. Secretion of TNF-α and IL-6 from HAdV31-infected cells was strongly decreased, leading to unlimited virus replication. The results obtained from this study provided the evidences that HAdV31, likewise previously documented HAdV36, is a subsequent human adenovirus affecting the differentiation and lipid accumulation of 3T3L1 cells. © 2015 Wiley Periodicals, Inc.

Choline and methionine differentially alter methyl carbon metabolism in bovine neonatal hepatocytes.

Science.gov (United States)

Chandler, Tawny L; White, Heather M

2017-01-01

Intersections in hepatic methyl group metabolism pathways highlights potential competition or compensation of methyl donors. The objective of this experiment was to examine the expression of genes related to methyl group transfer and lipid metabolism in response to increasing concentrations of choline chloride (CC) and DL-methionine (DLM) in primary neonatal hepatocytes that were or were not exposed to fatty acids (FA). Primary hepatocytes isolated from 4 neonatal Holstein calves were maintained as monolayer cultures for 24 h before treatment with CC (61, 128, 2028, and 4528 μmol/L) and DLM (16, 30, 100, 300 μmol/L), with or without a 1 mmol/L FA cocktail in a factorial arrangement. After 24 h of treatment, media was collected for quantification of reactive oxygen species (ROS) and very low-density lipoprotein (VLDL), and cell lysates were collected for quantification of gene expression. No interactions were detected between CC, DLM, or FA. Both CC and DLM decreased the expression of methionine adenosyltransferase 1A (MAT1A). Increasing CC did not alter betaine-homocysteine S-methyltranferase (BHMT) but did increase 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylenetetrahydrofolate reductase (MTHFR) expression. Increasing DLM decreased expression of BHMT and MTR, but did not affect MTHFR. Expression of both phosphatidylethanolamine N-methyltransferase (PEMT) and microsomal triglyceride transfer protein (MTTP) were decreased by increasing CC and DLM, while carnitine palmitoyltransferase 1A (CPT1A) was unaffected by either. Treatment with FA decreased the expression of MAT1A, MTR, MTHFR and tended to decrease PEMT but did not affect BHMT and MTTP. Treatment with FA increased CPT1A expression. Increasing CC increased secretion of VLDL and decreased the accumulation of ROS in media. Within neonatal bovine hepatocytes, choline and methionine differentially regulate methyl carbon pathways and suggest that choline may play a critical role in

Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action

Energy Technology Data Exchange (ETDEWEB)

McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda A. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Alaee, Mehran [Environment Canada, 867 Lakeshore Rd., P.O. Box 5050, Burlington, ON L7R 4A6 (Canada); Simpson, Andre J. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Simpson, Myrna J., E-mail: myrna.simpson@utoronto.ca [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada)

2011-12-15

Nuclear magnetic resonance (NMR) - based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms. - Highlights: > NMR-based earthworm metabolomic analysis of the toxic mode of action of various environmental contaminants. > Organic chemicals with different toxic modes of action resulted in varied metabolomic responses for E. fetida. > NMR-based metabolomics differentiates between the different modes of action associated with sub-lethal toxicity. - {sup 1}H NMR metabolomics was used to identify potential biomarkers of organic contaminant exposure in Eisenia fetida earthworms.

Differential metabolic responses of perennial grass Cynodon transvaalensis×Cynodon dactylon (C₄) and Poa Pratensis (C₃) to heat stress.

Science.gov (United States)

Du, Hongmei; Wang, Zhaolong; Yu, Wenjuan; Liu, Yimin; Huang, Bingru

2011-03-01

Differential metabolic responses to heat stress may be associated with variations in heat tolerance between cool-season (C₃) and warm-season (C₄) perennial grass species. The main objective of this study was to identify metabolites associated with differential heat tolerance between C₄ bermudagrass and C₃ Kentucky bluegrass by performing metabolite profile analysis using gas chromatography-mass spectrometry. Plants of Kentucky bluegrass (Poa Pratensis'Midnight') and hybrid bermudagrass (Cynodon transvaalensis x Cynodon dactylon'Tifdwarf') were grown under optimum temperature conditions (20/15 °C for Kentucky bluegrass and 30/25 °C for bermudagrass) or heat stress (35/30 °C for Kentucky bluegrass and 45/40 °C for bermudagrass). Physiological responses to heat stress were evaluated by visual rating of grass quality, measuring photochemical efficiency (variable fluorescence to maximal fluorescence) and electrolyte leakage. All of these parameters indicated that bermudagrass exhibited better heat tolerance than Kentucky bluegrass. The metabolite analysis of leaf polar extracts revealed 36 heat-responsive metabolites identified in both grass species, mainly consisting of organic acids, amino acids, sugars and sugar alcohols. Most metabolites showed higher accumulation in bermudagrass compared with Kentucky bluegrass, especially following long-term (18 days) heat stress. The differentially accumulated metabolites included seven sugars (sucrose, fructose, galactose, floridoside, melibiose, maltose and xylose), a sugar alcohol (inositol), six organic acids (malic acid, citric acid, threonic acid, galacturonic acid, isocitric acid and methyl malonic acid) and nine amino acids (Asn, Ala, Val, Thr, γ-aminobutyric acid, IIe, Gly, Lys and Met). The differential accumulation of those metabolites could be associated with the differential heat tolerance between C₃ Kentucky bluegrass and C₄ bermudagrass. Copyright © Physiologia Plantarum 2010.

Clinical utility of metabolic syndrome severity scores: considerations for practitioners

Directory of Open Access Journals (Sweden)

DeBoer MD

2017-02-01

Full Text Available Mark D DeBoer,1,2 Matthew J Gurka2 11Division of Pediatric Endocrinology, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, 2Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA Abstract: The metabolic syndrome (MetS is marked by abnormalities in central obesity, high blood pressure, high triglycerides, low high-density lipoprotein-cholesterol, and high fasting glucose and appears to be produced by underlying processes of inflammation, oxidative stress, and adipocyte dysfunction. MetS has traditionally been classified based on dichotomous criteria that deny that MetS-related risk likely exists as a spectrum. Continuous MetS scores provide a way to track MetS-related risk over time. We generated MetS severity scores that are sex- and race/ethnicity-specific, acknowledging that the way MetS is manifested may be different by sex and racial/ethnic subgroup. These scores are correlated with long-term risk for type 2 diabetes mellitus and cardiovascular disease. Clinical use of scores like these provide a potential opportunity to identify patients at highest risk, motivate patients toward lifestyle change, and follow treatment progress over time. Keywords: metabolic syndrome, insulin resistance, cardiovascular disease, type 2 diabetes, risk prediction

Differential induction of enzymes and genes involved in lipid metabolism in liver and visceral adipose tissue of juvenile yellow catfish Pelteobagrus fulvidraco exposed to copper

International Nuclear Information System (INIS)

Chen, Qi-Liang; Luo, Zhi; Pan, Ya-Xiong; Zheng, Jia-Lang; Zhu, Qing-Ling; Sun, Lin-Dan; Zhuo, Mei-Qin; Hu, Wei

2013-01-01

Highlights: •Cu downregulates lipogenesis and reduces lipid deposition in liver and adipose tissue. •Mechanism of Cu affecting lipid metabolism is determined at the enzymatic and molecular levels. •Cu exposure differentially influences lipid metabolism between liver and adipose tissue. -- Abstract: The present study was conducted to determine the mechanism of waterborne Cu exposure influencing lipid metabolism in liver and visceral adipose tissue (VAT) of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to four waterborne copper (Cu) concentrations (2 (control), 24 (low), 71 (medium), 198 (high) μg Cu/l, respectively) for 6 weeks. Waterborne Cu exposure had a negative effect on growth and several condition indices (condition factor, viscerosomatic index, hepatosomatic index and visceral adipose index). In liver, lipid content, activities of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and fatty acid synthase (FAS)) as well as mRNA levels of 6PGD, G6PD, FAS and sterol-regulator element-binding protein-1 (SREBP-1) genes decreased with increasing Cu concentrations. However, activity and mRNA level of lipoprotein lipase (LPL) gene in liver increased. In VAT, G6PD, ME and LPL activities as well as the mRNA levels of FAS, LPL and PPARγ genes decreased in fish exposed to higher Cu concentrations. The differential Pearson correlations between transcription factors (SREBP-1 and peroxisome proliferators-activated receptor-γ (PPARγ)), and the activities and mRNA expression of lipogenic enzymes and their genes were observed between liver and VAT. Thus, our study indicated that reduced lipid contents in liver and VAT after Cu exposure were attributable to the reduced activities and mRNA expression of lipogenic enzymes and their genes in these tissues. Different response patterns of several tested enzymes and genes to waterborne Cu

Differential induction of enzymes and genes involved in lipid metabolism in liver and visceral adipose tissue of juvenile yellow catfish Pelteobagrus fulvidraco exposed to copper

Energy Technology Data Exchange (ETDEWEB)

Chen, Qi-Liang; Luo, Zhi, E-mail: luozhi99@yahoo.com.cn; Pan, Ya-Xiong; Zheng, Jia-Lang; Zhu, Qing-Ling; Sun, Lin-Dan; Zhuo, Mei-Qin; Hu, Wei

2013-07-15

Highlights: •Cu downregulates lipogenesis and reduces lipid deposition in liver and adipose tissue. •Mechanism of Cu affecting lipid metabolism is determined at the enzymatic and molecular levels. •Cu exposure differentially influences lipid metabolism between liver and adipose tissue. -- Abstract: The present study was conducted to determine the mechanism of waterborne Cu exposure influencing lipid metabolism in liver and visceral adipose tissue (VAT) of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to four waterborne copper (Cu) concentrations (2 (control), 24 (low), 71 (medium), 198 (high) μg Cu/l, respectively) for 6 weeks. Waterborne Cu exposure had a negative effect on growth and several condition indices (condition factor, viscerosomatic index, hepatosomatic index and visceral adipose index). In liver, lipid content, activities of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and fatty acid synthase (FAS)) as well as mRNA levels of 6PGD, G6PD, FAS and sterol-regulator element-binding protein-1 (SREBP-1) genes decreased with increasing Cu concentrations. However, activity and mRNA level of lipoprotein lipase (LPL) gene in liver increased. In VAT, G6PD, ME and LPL activities as well as the mRNA levels of FAS, LPL and PPARγ genes decreased in fish exposed to higher Cu concentrations. The differential Pearson correlations between transcription factors (SREBP-1 and peroxisome proliferators-activated receptor-γ (PPARγ)), and the activities and mRNA expression of lipogenic enzymes and their genes were observed between liver and VAT. Thus, our study indicated that reduced lipid contents in liver and VAT after Cu exposure were attributable to the reduced activities and mRNA expression of lipogenic enzymes and their genes in these tissues. Different response patterns of several tested enzymes and genes to waterborne Cu

Energy metabolism in Desulfovibrio vulgaris Hildenborough: insights from transcriptome analysis

Energy Technology Data Exchange (ETDEWEB)

Pereira, Patricia M.; He, Qiang; Valente, Filipa M.A.; Xavier, Antonio V.; Zhou, Jizhong; Pereira, Ines A.C.; Louro, Ricardo O.

2007-11-01

Sulphate-reducing bacteria are important players in the global sulphur and carbon cycles, with considerable economical and ecological impact. However, the process of sulphate respiration is still incompletely understood. Several mechanisms of energy conservation have been proposed, but it is unclear how the different strategies contribute to the overall process. In order to obtain a deeper insight into the energy metabolism of sulphate-reducers whole-genome microarrays were used to compare the transcriptional response of Desulfovibrio vulgaris Hildenborough grown with hydrogen/sulphate, pyruvate/sulphate, pyruvate with limiting sulphate, and lactate/thiosulphate, relative to growth in lactate/sulphate. Growth with hydrogen/sulphate showed the largest number of differentially expressed genes and the largest changes in transcript levels. In this condition the most up-regulated energy metabolism genes were those coding for the periplasmic [NiFeSe]hydrogenase, followed by the Ech hydrogenase. The results also provide evidence for the involvement of formate cycling and the recently proposed ethanol pathway during growth in hydrogen. The pathway involving CO cycling is relevant during growth on lactate and pyruvate, but not during growth in hydrogen as the most down-regulated genes were those coding for the CO-induced hydrogenase. Growth on lactate/thiosulphate reveals a down-regulation of several energymetabolism genes similar to what was observed in the presence of nitrite. This study identifies the role of several proteins involved in the energy metabolism of D. vulgaris and highlights several novel genes related to this process, revealing a more complex bioenergetic metabolism than previously considered.

Stem Cell Metabolism in Cancer and Healthy Tissues: Pyruvate in the Limelight

Directory of Open Access Journals (Sweden)

Cyril Corbet

2018-01-01

Full Text Available Normal and cancer stem cells (CSCs share the remarkable potential to self-renew and differentiate into many distinct cell types. Although most of the stem cells remain under quiescence to maintain their undifferentiated state, they can also undergo cell divisions as required to regulate tissue homeostasis. There is now a growing evidence that cell fate determination from stem cells implies a fine-tuned regulation of their energy balance and metabolic status. Stem cells can shift their metabolic substrate utilization, between glycolysis and mitochondrial oxidative metabolism, during specification and/or differentiation, as well as in order to adapt their microenvironmental niche. Pyruvate appears as a key metabolite since it is at the crossroads of cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. This Review describes how metabolic reprogramming, focusing on pyruvate utilization, drives the fate of normal and CSCs by modulating their capacity for self-renewal, clonal expansion/differentiation, as well as metastatic potential and treatment resistance in cancer. This Review also explores potential therapeutic strategies to restore or manipulate stem cell function through the use of small molecules targeting the pyruvate metabolism.

Metabolic aspects of growth in HU-treated crown-gall tissue cultures. I. Nicotiana tabacum

Directory of Open Access Journals (Sweden)

Aldona Rennert

2015-01-01

Full Text Available An influence of hydroxyurea (HU on the growth, DNA and RNA contents and protein synthesis in the tobacco tumour tissue culture was studied in comparison with a homologous callus tissue. In conformity with expectations considerable decrease of DNA level in both tissues is a primary effect of HU activity. This results in the growth inhibition and in the secondary metabolic effects; these effects depend not only on the concentration of inhibitor but also on the age of tissue. In spite of some common features the character of these changes shows a distinct differentiation depending on the tissue type. TMs points to specific modifications of the biochemical regulation of growth in a tumour.

Late gestation under- and overnutrition have differential impacts when combined with a post-natal obesogenic diet on glucose-lactate-insulin adaptations during metabolic challenges in adolescent sheep

DEFF Research Database (Denmark)

Khanal, Prabhat; Axel, Anne Marie Dixen; Kongsted, Anna Hauntoft

2015-01-01

AIM: To determine whether late gestation under- and overnutrition programme metabolic plasticity in a similar way, and whether metabolic responses to an obesogenic diet in early post-natal life depend on the foetal nutrition history. METHODS: In a 3 × 2 factorial design, twin-pregnant ewes were......) or conventional (CONV; N = 35) diets from 3 days to 6 months of age (around puberty). Then intravenous glucose (GTT; overnight fasted), insulin (ITT; fed) and propionate (gluconeogenetic precursor; PTT; both fed and fasted) tolerance tests were conducted to evaluate (hepatic) metabolic plasticity. RESULTS......: Prenatal malnutrition differentially impacted adaptations of particularly plasma lactate followed by glucose, cholesterol and insulin. This was most clearly expressed during PTT in fasted lambs and much less during ITT and GTT. In fasted lambs, propionate induced more dramatic increases in lactate than...

Genome-wide identification and expression profiling reveal tissue-specific expression and differentially-regulated genes involved in gibberellin metabolism between Williams banana and its dwarf mutant.

Science.gov (United States)

Chen, Jingjing; Xie, Jianghui; Duan, Yajie; Hu, Huigang; Hu, Yulin; Li, Weiming

2016-05-27

Dwarfism is one of the most valuable traits in banana breeding because semi-dwarf cultivars show good resistance to damage by wind and rain. Moreover, these cultivars present advantages of convenient cultivation, management, and so on. We obtained a dwarf mutant '8818-1' through EMS (ethyl methane sulphonate) mutagenesis of Williams banana 8818 (Musa spp. AAA group). Our research have shown that gibberellins (GAs) content in 8818-1 false stems was significantly lower than that in its parent 8818 and the dwarf type of 8818-1 could be restored by application of exogenous GA3. Although GA exerts important impacts on the 8818-1 dwarf type, our understanding of the regulation of GA metabolism during banana dwarf mutant development remains limited. Genome-wide screening revealed 36 candidate GA metabolism genes were systematically identified for the first time; these genes included 3 MaCPS, 2 MaKS, 1 MaKO, 2 MaKAO, 10 MaGA20ox, 4 MaGA3ox, and 14 MaGA2ox genes. Phylogenetic tree and conserved protein domain analyses showed sequence conservation and divergence. GA metabolism genes exhibited tissue-specific expression patterns. Early GA biosynthesis genes were constitutively expressed but presented differential regulation in different tissues in Williams banana. GA oxidase family genes were mainly transcribed in young fruits, thus suggesting that young fruits were the most active tissue involved in GA metabolism, followed by leaves, bracts, and finally approximately mature fruits. Expression patterns between 8818 and 8818-1 revealed that MaGA20ox4, MaGA20ox5, and MaGA20ox7 of the MaGA20ox gene family and MaGA2ox7, MaGA2ox12, and MaGA2ox14 of the MaGA2ox gene family exhibited significant differential expression and high-expression levels in false stems. These genes are likely to be responsible for the regulation of GAs content in 8818-1 false stems. Overall, phylogenetic evolution, tissue specificity and differential expression analyses of GA metabolism genes can provide a

Metabolic and cardiovascular risk in patients with a history of differentiated thyroid carcinoma: A case-controlled cohort study.

Science.gov (United States)

Giusti, Massimo; Mortara, Lorenzo; Degrandi, Roberta; Cecoli, Francesca; Mussap, Michele; Rodriguez, Guido; Ferone, Diego; Minuto, Francesco

2008-09-29

Hyperthyroidism seems to increase metabolic and cardiovascular risk, while the effects of sub-clinical hyperthyroidism are controversial. We evaluated metabolic and cardiovascular parameters in differentiated thyroid carcinoma (DTC) patients with suppressed thyrotropin (TSH) due to levo-thyroxine (L-T4) therapy. We studied DTC patients and, as a control group, patients with a history of surgery for non-malignant thyroid pathology. Significantly higher insulin and lower HDL-cholesterol levels were recorded in DTC subjects. In both groups, insulin levels were significantly related with body mass index (BMI) but not with age or L-T4 dosage. In DTC patients, a significant negative correlation was seen between HDL-cholesterol and BMI or L-T4 dosage. In both groups, intima-media thickness (IMT) correlated positively with age, BMI, glucose levels and systolic blood pressure. In DTC patients, increased IMT was significantly correlated with glycated hemoglobin (HbA1c), cholesterol and triglycerides. In DTC patients, C-reactive protein correlated positively with insulin, insulin resistance, triglycerides and systolic blood pressure, and negatively with HDL-cholesterol. In both DTC and control subjects, fibrinogen correlated positively with age, BMI, increased IMT, HbA1c and systolic blood pressure. In DTC subjects, plasma fibrinogen concentrations correlated positively with insulin resistance, cholesterol and LDL-cholesterol, and negatively with TSH levels. Our data confirm that the favorable evolution of DTC can be impaired by a high incidence of abnormal metabolic and cardiovascular data that are, at least in part, related to L-T4 therapy. These findings underline the need for adequate L-T4 titration.

Nutritional conditioning : The effect of fasting on drug metabolism

NARCIS (Netherlands)

Lammers, L.A.

2018-01-01

The studies described in this thesis focus on the effect of fasting, as nutritional modulator, on drug metabolism. Drug metabolism varies considerably between and within patients, which may result in treatment failure or, conversely, in untoward side effects. Many factors contribute to the

SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress

OpenAIRE

Gao, Jing; Feng, Zhihui; Wang, Xueqiang; Zeng, Mengqi; Liu, Jing; Han, Shujun; Xu, Jie; Chen, Lei; Cao, Ke; Long, Jiangang; Li, Zongfang; Shen, Weili; Liu, Jiankang

2017-01-01

Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by in...

Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes

DEFF Research Database (Denmark)

Nilsson, Emma; Jansson, Per Anders; Perfilyev, Alexander

2014-01-01

Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent...... case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed...... genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution...

Inborn Errors of Metabolism with Acidosis: Organic Acidemias and Defects of Pyruvate and Ketone Body Metabolism.

Science.gov (United States)

Schillaci, Lori-Anne P; DeBrosse, Suzanne D; McCandless, Shawn E

2018-04-01

When a child presents with high-anion gap metabolic acidosis, the pediatrician can proceed with confidence by recalling some basic principles. Defects of organic acid, pyruvate, and ketone body metabolism that present with acute acidosis are reviewed. Flowcharts for identifying the underlying cause and initiating life-saving therapy are provided. By evaluating electrolytes, blood sugar, lactate, ammonia, and urine ketones, the provider can determine the likelihood of an inborn error of metabolism. Freezing serum, plasma, and urine samples during the acute presentation for definitive diagnostic testing at the provider's convenience aids in the differential diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Exercise training dose differentially alters muscle and heart capillary density and metabolic functions in an obese rat with metabolic syndrome.

Science.gov (United States)

Machado, Marcus Vinicius; Vieira, Aline Bomfim; da Conceição, Fabiana Gomes; Nascimento, Alessandro Rodrigues; da Nóbrega, Antonio Claudio Lucas; Tibirica, Eduardo

2017-12-01

What is the central question of this study? Regular exercise is recommended as a non-pharmacological approach for the prevention and treatment of metabolic syndrome. However, the impact of different combinations of intensity, duration and frequency of exercise on metabolic syndrome and microvascular density has not been reported. What is the main finding and its importance? We provide evidence on the impact of aerobic exercise dose on metabolic and microvascular alterations in an experimental model of metabolic syndrome induced by high-fat diet. We found that the exercise frequency and duration were the main factors affecting anthropometric and metabolic parameters and microvascular density in the skeletal muscle. Exercise intensity was related only to microvascular density in the heart. We evaluated the effect of the frequency, duration and intensity of exercise training on metabolic parameters and structural capillary density in obese rats with metabolic syndrome. Wistar-Kyoto rats were fed either a standard commercial diet (CON) or a high-fat diet (HFD). Animals that received the HFD were randomly separated into either a sedentary (SED) group or eight different exercise groups that varied according to the frequency, duration and intensity of training. After 12 weeks of aerobic exercise training, the body composition, aerobic capacity, haemodynamic variables, metabolic parameters and capillary density in the heart and skeletal muscle were evaluated. All the exercise training groups showed reduced resting systolic blood pressure and heart rate and normalized fasting glucose. The minimal amount of exercise (90 min per week) produced little effect on metabolic syndrome parameters. A moderate amount of exercise (150 min per week) was required to reduce body weight and improve capillary density. However, only the high amount of exercise (300 min per week) significantly reduced the amount of body fat depots. The three-way ANOVA showed a main effect of exercise

A hybrid credibility-based fuzzy multiple objective optimisation to differential pricing and inventory policies with arbitrage consideration

Science.gov (United States)

Ghasemy Yaghin, R.; Fatemi Ghomi, S. M. T.; Torabi, S. A.

2015-10-01

In most markets, price differentiation mechanisms enable manufacturers to offer different prices for their products or services in different customer segments; however, the perfect price discrimination is usually impossible for manufacturers. The importance of accounting for uncertainty in such environments spurs an interest to develop appropriate decision-making tools to deal with uncertain and ill-defined parameters in joint pricing and lot-sizing problems. This paper proposes a hybrid bi-objective credibility-based fuzzy optimisation model including both quantitative and qualitative objectives to cope with these issues. Taking marketing and lot-sizing decisions into account simultaneously, the model aims to maximise the total profit of manufacturer and to improve service aspects of retailing simultaneously to set different prices with arbitrage consideration. After applying appropriate strategies to defuzzify the original model, the resulting non-linear multi-objective crisp model is then solved by a fuzzy goal programming method. An efficient stochastic search procedure using particle swarm optimisation is also proposed to solve the non-linear crisp model.

Differential regulation of c-di-GMP metabolic enzymes by environmental signals modulates biofilm formation in Yersinia pestis

Directory of Open Access Journals (Sweden)

Gai-Xian eRen

2016-06-01

Full Text Available Cyclic diguanylate (c-di-GMP is essential for Yersinia pestis biofilm formation, which is important for flea-borne blockage-dependent plague transmission. Two diguanylate cyclases (DGCs, HmsT and HmsD and one phosphodiesterase (PDE, HmsP are responsible for the synthesis and degradation of c-di-GMP in Y. pestis. Here, we systematically analyzed the effect of various environmental signals on regulation of the biofilm phenotype, the c-di-GMP levels, and expression of HmsT, HmsD and HmsP in Y. pestis. Biofilm formation was higher in the presence of nonlethal high concentration of CaCl2, MgCl2, CuSO4, sucrose, sodium dodecyl sulfonate, or dithiothreitol, and was lower in the presence of FeCl2 or NaCl. In addition, we found that HmsD plays a major role in biofilm formation in acidic or redox environments. These environmental signals differentially regulated expression of HmsT, HmsP and HmsD, resulting in changes in the intracellular levels of c-di-GMP in Y. pestis. Our results suggest that bacteria can sense various environmental signals, and differentially regulates their DGCs and PDEs to coordinately regulate and adapt metabolism of c-di-GMP and biofilm formation to changing environments.

The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes

Directory of Open Access Journals (Sweden)

Fan Xing

2017-01-01

Full Text Available Summary: Glioblastoma multiforme (GBM is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells. : Xing et al. show that the metabolic shift from glycolysis to oxidative phosphorylation drives differentiation of GBM cells into astrocytes by cAMP activation. Mechanistically, the cAMP-CREB-PGC1α signal mediates mitochondrial biogenesis, which leads to metabolic reprogramming, induced differentiation, and tumor growth inhibition. Keywords: glioblastoma, induced differentiation, Warburg effect, metabolic reprogramming, oxidative phosphorylation, glycolysis, mitochondrial biogenesis, cyclic adenosine monophosphate, cAMP, PPARγ coactivator-1α, PGC1α

Primary Metabolism during Biosynthesis of Secondary Wall Polymers of Protoxylem Vessel Elements1[OPEN

Science.gov (United States)

Morisaki, Keiko; Sawada, Yuji; Sano, Ryosuke; Yamamoto, Atsushi; Kurata, Tetsuya; Suzuki, Shiro; Matsuda, Mami; Hasunuma, Tomohisa; Hirai, Masami Yokota

2016-01-01

Xylem vessels, the water-conducting cells in vascular plants, undergo characteristic secondary wall deposition and programmed cell death. These processes are regulated by the VASCULAR-RELATED NAC-DOMAIN (VND) transcription factors. Here, to identify changes in metabolism that occur during protoxylem vessel element differentiation, we subjected tobacco (Nicotiana tabacum) BY-2 suspension culture cells carrying an inducible VND7 system to liquid chromatography-mass spectrometry-based wide-target metabolome analysis and transcriptome analysis. Time-course data for 128 metabolites showed dynamic changes in metabolites related to amino acid biosynthesis. The concentration of glyceraldehyde 3-phosphate, an important intermediate of the glycolysis pathway, immediately decreased in the initial stages of cell differentiation. As cell differentiation progressed, specific amino acids accumulated, including the shikimate-related amino acids and the translocatable nitrogen-rich amino acid arginine. Transcriptome data indicated that cell differentiation involved the active up-regulation of genes encoding the enzymes catalyzing fructose 6-phosphate biosynthesis from glyceraldehyde 3-phosphate, phosphoenolpyruvate biosynthesis from oxaloacetate, and phenylalanine biosynthesis, which includes shikimate pathway enzymes. Concomitantly, active changes in the amount of fructose 6-phosphate and phosphoenolpyruvate were detected during cell differentiation. Taken together, our results show that protoxylem vessel element differentiation is associated with changes in primary metabolism, which could facilitate the production of polysaccharides and lignin monomers and, thus, promote the formation of the secondary cell wall. Also, these metabolic shifts correlate with the active transcriptional regulation of specific enzyme genes. Therefore, our observations indicate that primary metabolism is actively regulated during protoxylem vessel element differentiation to alter the cell’s metabolic

NADPH oxidases differentially regulate ROS metabolism and nutrient uptake under cadmium toxicity.

Science.gov (United States)

Gupta, D K; Pena, L B; Romero-Puertas, M C; Hernández, A; Inouhe, M; Sandalio, L M

2017-04-01

The role of NADPH oxidases under cadmium (Cd) toxicity was studied using Arabidopsis thaliana mutants AtrbohC, AtrbohD and AtrbohF, which were grown under hydroponic conditions with 25 and 100 μM Cd for 1 and 5 days. Cadmium reduced the growth of leaves in WT, AtrbohC and D, but not in AtrbohF. A time-dependent increase in H 2 O 2 and lipid peroxidation was observed in all genotypes, with AtrbohC showing the smallest increase. An opposite behaviour was observed with NO accumulation. Cadmium increased catalase activity in WT plants and decreased it in Atrboh mutants, while glutathione reductase and glycolate oxidase activities increased in Atrboh mutants, and superoxide dismutases were down-regulated in AtrbohC. The GSH/GSSG and ASA/DHA couples were also affected by the treatment, principally in AtrbohC and AtrbohF, respectively. Cadmium translocation to the leaves was severely reduced in Atrboh mutants after 1 day of treatment and even after 5 days in AtrbohF. Similar results were observed for S, P, Ca, Zn and Fe accumulation, while an opposite trend was observed for K accumulation, except in AtrbohF. Thus, under Cd stress, RBOHs differentially regulate ROS metabolism, redox homeostasis and nutrient balance and could be of potential interest in biotechnology for the phytoremediation of polluted soils. © 2016 John Wiley & Sons Ltd.

MicroRNAs in Metabolism

DEFF Research Database (Denmark)

Vienberg, Sara; Geiger, Julian; Madsen, Søren

2017-01-01

roles in cholesterol and lipid metabolism, whereas miR-103 and -107 regulates hepatic insulin sensitivity. In muscle tissue a defined number of miRNAs (miR-1, miR-133, mir-206) control myofiber type switch and induce myogenic differentiation programs. Similarly, in adipose tissue a defined number of mi...

Metabolic and cardiovascular risk in patients with a history of differentiated thyroid carcinoma: A case-controlled cohort study

Directory of Open Access Journals (Sweden)

Giusti Massimo

2008-09-01

Full Text Available Abstract Hyperthyroidism seems to increase metabolic and cardiovascular risk, while the effects of sub-clinical hyperthyroidism are controversial. We evaluated metabolic and cardiovascular parameters in differentiated thyroid carcinoma (DTC patients with suppressed thyrotropin (TSH due to levo-thyroxine (L-T4 therapy. We studied DTC patients and, as a control group, patients with a history of surgery for non-malignant thyroid pathology. Significantly higher insulin and lower HDL-cholesterol levels were recorded in DTC subjects. In both groups, insulin levels were significantly related with body mass index (BMI but not with age or L-T4 dosage. In DTC patients, a significant negative correlation was seen between HDL-cholesterol and BMI or L-T4 dosage. In both groups, intima-media thickness (IMT correlated positively with age, BMI, glucose levels and systolic blood pressure. In DTC patients, increased IMT was significantly correlated with glycated hemoglobin (HbA1c, cholesterol and triglycerides. In DTC patients, C-reactive protein correlated positively with insulin, insulin resistance, triglycerides and systolic blood pressure, and negatively with HDL-cholesterol. In both DTC and control subjects, fibrinogen correlated positively with age, BMI, increased IMT, HbA1c and systolic blood pressure. In DTC subjects, plasma fibrinogen concentrations correlated positively with insulin resistance, cholesterol and LDL-cholesterol, and negatively with TSH levels. Our data confirm that the favorable evolution of DTC can be impaired by a high incidence of abnormal metabolic and cardiovascular data that are, at least in part, related to L-T4 therapy. These findings underline the need for adequate L-T4 titration.

Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

Science.gov (United States)

Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

2017-07-01

The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action

International Nuclear Information System (INIS)

McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda A.; Alaee, Mehran; Simpson, Andre J.; Simpson, Myrna J.

2011-01-01

Nuclear magnetic resonance (NMR) - based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms. - Highlights: → NMR-based earthworm metabolomic analysis of the toxic mode of action of various environmental contaminants. → Organic chemicals with different toxic modes of action resulted in varied metabolomic responses for E. fetida. → NMR-based metabolomics differentiates between the different modes of action associated with sub-lethal toxicity. - 1 H NMR metabolomics was used to identify potential biomarkers of organic contaminant exposure in Eisenia fetida earthworms.

Introduction to ordinary differential equations

CERN Document Server

Rabenstein, Albert L

1966-01-01

Introduction to Ordinary Differential Equations is a 12-chapter text that describes useful elementary methods of finding solutions using ordinary differential equations. This book starts with an introduction to the properties and complex variable of linear differential equations. Considerable chapters covered topics that are of particular interest in applications, including Laplace transforms, eigenvalue problems, special functions, Fourier series, and boundary-value problems of mathematical physics. Other chapters are devoted to some topics that are not directly concerned with finding solutio

Differentiate or Die: 3-Bromopyruvate and Pluripotency in Mouse Embryonic Stem Cells.

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Ana Sofia Rodrigues

Full Text Available Pluripotent embryonic stem cells grown under standard conditions (ESC have a markedly glycolytic profile, which is shared with many different types of cancer cells. Thus, some therapeutic strategies suggest that pharmacologically shifting cancer cells towards an oxidative phenotype, using glycolysis inhibitors, may reduce cancer aggressiveness. Given the metabolic parallels between cancer and stemness would chemotherapeutical agents have an effect on pluripotency, and could a strategy involving these agents be envisioned to modulate stem cell fate in an accessible manner? In this manuscript we attempted to determine the effects of 3-bromopyruvate (3BrP in pluripotency. Although it has other intracellular targets, this compound is a potent inhibitor of glycolysis enzymes thought to be important to maintain a glycolytic profile. The goal was also to determine if we could contribute towards a pharmacologically accessible metabolic strategy to influence cell differentiation.Mouse embryonic stem cells (mESC grown under standard pluripotency conditions (in the presence of Leukemia Inducing Factor- LIF were treated with 3BrP. As a positive control for differentiation other mESCs were grown without LIF. Overall our results demonstrate that 3BrP negatively affects pluripotency, forcing cells to become less glycolytic and with more active mitochondria. These changes in metabolism are correlated with increased differentiation, even under pluripotency conditions (i.e. in the presence of LIF. However, 3BrP also significantly impaired cell function, and may have other roles besides affecting the metabolic profile of mESCs.Treatment of mESCs with 3BrP triggered a metabolic switch and loss of pluripotency, even in the presence of LIF. Interestingly, the positive control for differentiation allowed for a distinction between 3BrP effects and changes associated with spontaneous differentiation/loss of pluripotency in the absence of LIF. Additionally, there was a

Differentiate or Die: 3-Bromopyruvate and Pluripotency in Mouse Embryonic Stem Cells.

Science.gov (United States)

Rodrigues, Ana Sofia; Pereira, Sandro L; Correia, Marcelo; Gomes, Andreia; Perestrelo, Tânia; Ramalho-Santos, João

2015-01-01

Pluripotent embryonic stem cells grown under standard conditions (ESC) have a markedly glycolytic profile, which is shared with many different types of cancer cells. Thus, some therapeutic strategies suggest that pharmacologically shifting cancer cells towards an oxidative phenotype, using glycolysis inhibitors, may reduce cancer aggressiveness. Given the metabolic parallels between cancer and stemness would chemotherapeutical agents have an effect on pluripotency, and could a strategy involving these agents be envisioned to modulate stem cell fate in an accessible manner? In this manuscript we attempted to determine the effects of 3-bromopyruvate (3BrP) in pluripotency. Although it has other intracellular targets, this compound is a potent inhibitor of glycolysis enzymes thought to be important to maintain a glycolytic profile. The goal was also to determine if we could contribute towards a pharmacologically accessible metabolic strategy to influence cell differentiation. Mouse embryonic stem cells (mESC) grown under standard pluripotency conditions (in the presence of Leukemia Inducing Factor- LIF) were treated with 3BrP. As a positive control for differentiation other mESCs were grown without LIF. Overall our results demonstrate that 3BrP negatively affects pluripotency, forcing cells to become less glycolytic and with more active mitochondria. These changes in metabolism are correlated with increased differentiation, even under pluripotency conditions (i.e. in the presence of LIF). However, 3BrP also significantly impaired cell function, and may have other roles besides affecting the metabolic profile of mESCs. Treatment of mESCs with 3BrP triggered a metabolic switch and loss of pluripotency, even in the presence of LIF. Interestingly, the positive control for differentiation allowed for a distinction between 3BrP effects and changes associated with spontaneous differentiation/loss of pluripotency in the absence of LIF. Additionally, there was a slight

Xenobiotic Metabolism and Gut Microbiomes.

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Anubhav Das

Full Text Available Humans are exposed to numerous xenobiotics, a majority of which are in the form of pharmaceuticals. Apart from human enzymes, recent studies have indicated the role of the gut bacterial community (microbiome in metabolizing xenobiotics. However, little is known about the contribution of the plethora of gut microbiome in xenobiotic metabolism. The present study reports the results of analyses on xenobiotic metabolizing enzymes in various human gut microbiomes. A total of 397 available gut metagenomes from individuals of varying age groups from 8 nationalities were analyzed. Based on the diversities and abundances of the xenobiotic metabolizing enzymes, various bacterial taxa were classified into three groups, namely, least versatile, intermediately versatile and highly versatile xenobiotic metabolizers. Most interestingly, specific relationships were observed between the overall drug consumption profile and the abundance and diversity of the xenobiotic metabolizing repertoire in various geographies. The obtained differential abundance patterns of xenobiotic metabolizing enzymes and bacterial genera harboring them, suggest their links to pharmacokinetic variations among individuals. Additional analyses of a few well studied classes of drug modifying enzymes (DMEs also indicate geographic as well as age specific trends.

Improving lactate metabolism in an intensified CHO culture process: productivity and product quality considerations.

Science.gov (United States)

Xu, Sen; Hoshan, Linda; Chen, Hao

2016-11-01

In this study, we discussed the development and optimization of an intensified CHO culture process, highlighting medium and control strategies to improve lactate metabolism. A few strategies, including supplementing glucose with other sugars (fructose, maltose, and galactose), controlling glucose level at Productivity and product quality attributes differences between batch, fed-batch, and concentrated fed-batch cultures were discussed. The importance of process and cell metabolism understanding when adapting the existing process to a new operational mode was demonstrated in the study.

Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal.

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Bernadett Pintér-Kübler

Full Text Available Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH, urocortin 2 (UCN2 and proopiomelanocortin (POMC compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY and arginine vasopressin (AVP mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls.

Differential Reliance on Lipid Metabolism as a Salvage Pathway Underlies Functional Differences of T Cell Subsets in Poor Nutrient Environments

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Christopher Ecker

2018-04-01

Full Text Available Summary: T cells compete with malignant cells for limited nutrients within the solid tumor microenvironment. We found that effector memory CD4 T cells respond distinctly from other T cell subsets to limiting glucose and can maintain high levels of interferon-γ (IFN-γ production in a nutrient-poor environment. Unlike naive (TN or central memory T (TCM cells, effector memory T (TEM cells fail to upregulate fatty acid synthesis, oxidative phosphorylation, and reductive glutaminolysis in limiting glucose. Interference of fatty acid synthesis in naive T cells dramatically upregulates IFN-γ, while increasing exogenous lipids in media inhibits production of IFN-γ by all subsets, suggesting that relative ratio of fatty acid metabolism to glycolysis is a direct predictor of T cell effector activity. Together, these data suggest that effector memory T cells are programmed to have limited ability to synthesize and metabolize fatty acids, which allows them to maintain T cell function in nutrient-depleted microenvironments. : Ecker et al. distinguish unique metabolic and functional properties of naive and memory T cell subsets during glucose limitation. During glucose starvation, T cells begin to differentially rely on fatty acid synthesis and glutamine utilization to survive. Unexpectedly, reliance on fatty acid synthesis alters the ability to produce IFN-γ. Keywords: lipid droplets, IFN-γ, oxidative phosphorylation, reductive glutaminolysis, serum-free media, naive T cell, glycolysis, effector memory T cell, fatty acid synthesis

Metabolic and Pharmacokinetic Differentiation of STX209 and Racemic Baclofen in Humans

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Raymundo Sanchez-Ponce

2012-09-01

Full Text Available STX209 is an exploratory drug comprising the single, active R-enantiomer of baclofen which is in later stage clinical trials for the treatment of fragile x syndrome (FXS and autism spectrum disorders (ASD. New clinical data in this article on the metabolism and pharmacokinetics of the R- and S-enantiomers of baclofen presents scientific evidence for stereoselective metabolism of only S-baclofen to an abundant oxidative deamination metabolite that is sterically resolved as the S-enantiomeric configuration. This metabolite undergoes some further metabolism by glucuronide conjugation. Consequences of this metabolic difference are a lower Cmax and lower early plasma exposure of S-baclofen compared to R-baclofen and marginally lower urinary excretion of S-baclofen after racemic baclofen administration. These differences introduce compound-related exposure variances in humans in which subjects dosed with racemic baclofen are exposed to a prominent metabolite of baclofen whilst subjects dosed with STX209 are not. For potential clinical use, our findings suggest that STX209 has the advantage of being a biologically defined and active enantiomer.

Global changes in transcription orchestrate metabolic differentiation during symbiotic nitrogen fixation in Lotus japonicus

DEFF Research Database (Denmark)

Colebatch, Gillian; Desbrosses, Guilhem; Ott, Thomas

2004-01-01

Research on legume nodule metabolism has contributed greatly to our knowledge of primary carbon and nitrogen metabolism in plants in general, and in symbiotic nitrogen fixation in particular. However, most previous studies focused on one or a few genes/enzymes involved in selected metabolic...

[Metabolic myopathies].

Science.gov (United States)

Papazian, Óscar; Rivas-Chacón, Rafael

2013-09-06

To review the metabolic myopathies manifested only by crisis of myalgias, cramps and rigidity of the muscles with decreased voluntary contractions and normal inter crisis neurologic examination in children and adolescents. These metabolic myopathies are autosomic recessive inherited enzymatic deficiencies of the carbohydrates and lipids metabolisms. The end result is a reduction of intra muscle adenosine triphosphate, mainly through mitochondrial oxidative phosphorylation, with decrease of available energy for muscle contraction. The one secondary to carbohydrates intra muscle metabolism disorders are triggered by high intensity brief (fatty acids metabolism disorders are triggered by low intensity prolonged (> 10 min) exercises. The conditions in the first group in order of decreasing frequency are the deficiencies of myophosforilase (GSD V), muscle phosphofructokinase (GSD VII), phosphoglycerate mutase 1 (GSD X) and beta enolase (GSD XIII). The conditions in the second group in order of decreasing frequency are the deficiencies of carnitine palmitoyl transferase II and very long chain acyl CoA dehydrogenase. The differential characteristics of patients in each group and within each group will allow to make the initial presumptive clinical diagnosis in the majority and then to order only the necessary tests to achieve the final diagnosis. Treatment during the crisis includes hydration, glucose and alkalinization of urine if myoglobin in blood and urine are elevated. Prevention includes avoiding exercise which may induce the crisis and fasting. The prognosis is good with the exception of rare cases of acute renal failure due to hipermyoglobinemia because of severe rabdomyolisis.

Statistical and extra-statistical considerations in differential item functioning analyses

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G. K. Huysamen

2004-10-01

Full Text Available This article briefly describes the main procedures for performing differential item functioning (DIF analyses and points out some of the statistical and extra-statistical implications of these methods. Research findings on the sources of DIF, including those associated with translated tests, are reviewed. As DIF analyses are oblivious of correlations between a test and relevant criteria, the elimination of differentially functioning items does not necessarily improve predictive validity or reduce any predictive bias. The implications of the results of past DIF research for test development in the multilingual and multi-cultural South African society are considered. Opsomming Hierdie artikel beskryf kortliks die hoofprosedures vir die ontleding van differensiële itemfunksionering (DIF en verwys na sommige van die statistiese en buite-statistiese implikasies van hierdie metodes. ’n Oorsig word verskaf van navorsingsbevindings oor die bronne van DIF, insluitend dié by vertaalde toetse. Omdat DIF-ontledings nie die korrelasies tussen ’n toets en relevante kriteria in ag neem nie, sal die verwydering van differensieel-funksionerende items nie noodwendig voorspellingsgeldigheid verbeter of voorspellingsydigheid verminder nie. Die implikasies van vorige DIF-navorsingsbevindings vir toetsontwikkeling in die veeltalige en multikulturele Suid-Afrikaanse gemeenskap word oorweeg.

A Urinary Metabolic Signature for Multiple Sclerosis and Neuromyelitis Optica

DEFF Research Database (Denmark)

Gebregiworgis, Teklab; Nielsen, Helle H; Massilamany, Chandirasegaran

2016-01-01

a statistically distinct metabolic signature from healthy and NMO-SD controls. A total of 27 metabolites were differentially altered in the urine from MS and NMO-SD patients and were associated with synthesis and degradation of ketone bodies, amino acids, propionate and pyruvate metabolism, tricarboxylic acid...

[{sup 18}F]FE-SUPPY and [{sup 18}F]FE-SUPPY:2 - metabolic considerations

Energy Technology Data Exchange (ETDEWEB)

Haeusler, Daniela [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Pharmaceutical Technology and Biopharmaceutics, Univ. of Vienna, A-1090 Vienna (Austria); Nics, Lukas [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Nutritional Sciences, Univ. of Vienna, A-1090 Vienna (Austria); Mien, Leonhard-Key [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Pharmaceutical Technology and Biopharmaceutics, Univ. of Vienna, A-1090 Vienna (Austria); Ungersboeck, Johanna [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Inorganic Chemistry, Univ. of Vienna, A-1090 Vienna (Austria); Lanzenberger, Rupert R. [Dept. of Psychiatry and Psychotherapy, Medical Univ. of Vienna, A-1090 Vienna (Austria); Shanab, Karem [Dept. of Drug and Natural Product Synthesis, Univ. of Vienna, A-1090 Vienna (Austria); Sindelar, Karoline M. [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Viernstein, Helmut [Dept. of Pharmaceutical Technology and Biopharmaceutics, Univ. of Vienna, A-1090 Vienna (Austria); Wagner, Karl-Heinz [Dept. of Nutritional Sciences, Univ. of Vienna, A-1090 Vienna (Austria); Dudczak, Robert; Kletter, Kurt [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Wadsak, Wolfgang [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Inorganic Chemistry, Univ. of Vienna, A-1090 Vienna (Austria); Mitterhauser, Markus [Dept. of Nuclear Medicine, Medical Univ. of Vienna, A-1090 Vienna (Austria); Dept. of Pharmaceutical Technology and Biopharmaceutics, Univ. of Vienna, A-1090 Vienna (Austria); Hospital Pharmacy of the General Hospital of Vienna, A-1090 Vienna (Austria)], E-mail: markus.mitterhauser@meduniwien.ac.at

2010-05-15

Introduction: Recently, [{sup 18}F]FE-SUPPY and [{sup 18}F]FE-SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A{sub 3} receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A{sub 3} receptor PET tracers. Methods: In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points (n=3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol. Results: The rate of enzymatic hydrolysis by CES demonstrated Michaelis-Menten constants in a micromolar range (FE-SUPPY, 20.15 {mu}M, and FE-SUPPY:2, 13.11 {mu}M) and limiting velocities of 0.035 and 0.015 {mu}M/min for FE-SUPPY and FE-SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [{sup 18}F]FE-SUPPY was intact compared to 33.1% of [{sup 18}F]FE-SUPPY:2; 30 min pi 30.3% intact [{sup 18}F]FE-SUPPY was found compared to 15.6% [{sup 18}F]FE-SUPPY:2. In brain, [{sup 18}F]FE-SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [{sup 18}F]FE-SUPPY was not observed before 30 min pi Conclusion: Knowing that metabolism in rats is several times faster than in human, we conclude that [{sup 18}F]FE-SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [{sup 18}F]FE-SUPPY.

Kinetic modeling of cell metabolism for microbial production.

Science.gov (United States)

Costa, Rafael S; Hartmann, Andras; Vinga, Susana

2016-02-10

Kinetic models of cellular metabolism are important tools for the rational design of metabolic engineering strategies and to explain properties of complex biological systems. The recent developments in high-throughput experimental data are leading to new computational approaches for building kinetic models of metabolism. Herein, we briefly survey the available databases, standards and software tools that can be applied for kinetic models of metabolism. In addition, we give an overview about recently developed ordinary differential equations (ODE)-based kinetic models of metabolism and some of the main applications of such models are illustrated in guiding metabolic engineering design. Finally, we review the kinetic modeling approaches of large-scale networks that are emerging, discussing their main advantages, challenges and limitations. Copyright © 2015 Elsevier B.V. All rights reserved.

Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: Form food intake to metabolic disease

NARCIS (Netherlands)

Koopmans, S.J.; Schuurman, T.

2015-01-01

(Mini)pigs have proven to be a valuable animal model in nutritional, metabolic and cardiovascular research and in some other biomedical research areas (toxicology, neurobiology). The large resemblance of (neuro)anatomy, the gastro-intestinal tract, body size, body composition, and the omnivorous

Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate

OpenAIRE

Ward, Patrick S.; Thompson, Craig B.

2012-01-01

Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria, but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-ass...

Metabolic differentiation in biofilms as indicated by carbon dioxide production rates.

Science.gov (United States)

Bester, Elanna; Kroukamp, Otini; Wolfaardt, Gideon M; Boonzaaier, Leandro; Liss, Steven N

2010-02-01

The measurement of carbon dioxide production rates as an indication of metabolic activity was applied to study biofilm development and response of Pseudomonas sp. biofilms to an environmental disturbance in the form of a moving air-liquid interface (i.e., shear). A differential response in biofilm cohesiveness was observed after bubble perturbation, and the biofilm layers were operationally defined as either shear-susceptible or non-shear-susceptible. Confocal laser scanning microscopy and image analysis showed a significant reduction in biofilm thickness and biomass after the removal of the shear-susceptible biofilm layer, as well as notable changes in the roughness coefficient and surface-to-biovolume ratio. These changes were accompanied by a 72% reduction of whole-biofilm CO2 production; however, the non-shear-susceptible region of the biofilm responded rapidly after the removal of the overlying cells and extracellular polymeric substances (EPS) along with the associated changes in nutrient and O2 flux, with CO2 production rates returning to preperturbation levels within 24 h. The adaptable nature and the ability of bacteria to respond to environmental conditions were further demonstrated by the outer shear-susceptible region of the biofilm; the average CO2 production rate of cells from this region increased within 0.25 h from 9.45 +/- 5.40 fmol of CO2 x cell(-1) x h(-1) to 22.6 +/- 7.58 fmol of CO2 x cell(-1) x h(-1) when cells were removed from the biofilm and maintained in suspension without an additional nutrient supply. These results also demonstrate the need for sufficient monitoring of biofilm recovery at the solid substratum if mechanical methods are used for biofouling control.

Differential glucose metabolism in mice and humans affected by McArdle disease

DEFF Research Database (Denmark)

Krag, Thomas O; Pinós, Tomàs; Nielsen, Tue L

2016-01-01

McArdle disease (muscle glycogenosis type V) is a disease caused by myophosphorylase deficiency leading to "blocked" glycogen breakdown. A significant but varying glycogen accumulation in especially distal hind limb muscles of mice affected by McArdle disease has recently been demonstrated......, which could lead to lower glycogen accumulation. In comparison, tibialis anterior, extensor digitorum longus, and soleus had massive glycogen accumulation, but few, if any, changes or adaptations in glucose metabolism compared with wild-type mice. The findings suggest plasticity in glycogen metabolism....... In this study, we investigated how myophosphorylase deficiency affects glucose metabolism in hind limb muscle of 20-wk-old McArdle mice and vastus lateralis muscles from patients with McArdle disease. Western blot analysis and activity assay demonstrated that glycogen synthase was inhibited in glycolytic muscle...

MicroRNAs in Obesity, Metabolic Syndrome and Diabetes Mellitus

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Anna Meiliana

2011-04-01

Full Text Available BACKGROUND: MicroRNAs (miRNAs are small regulatory RNAs that play important roles in development of diseases. Several studies have provided evidences showing that miRNAs affect pathways that are fundamental for metabolic control in adipocyte and skeletal muscle differentiations. Some miRNAs have been implicated in lipid, amino acid, and glucose homeostasis. This leads to the possibility that miRNAs may contribute to common metabolic diseases and point to novel therapeutic opportunities based on targeting of miRNAs. CONTENT: miRNAs have been recognized as a class of epigenetic regulators of metabolism and energy homeostasis, primarily because the simultaneous regulation of a large number of target genes can be accomplished by a single miRNA. Emerging evidences suggest that miRNAs play a key role in the pathological development of obesity by affecting adipocyte differentiation. miRNAs have been implicated as novel protagonists in the pathogenesis of Diabetes Mellitus (DM, regulation of insulin production, secretion and action. They also appear to play a role in the development of diabetic complications such as nephropathy and cardiac hypertrophy. SUMMARY: Involvement of miRNAs in glucose and lipid metabolism has provided strong evidences to confirm their roles as key players in regulation of complex metabolic pathways. Additionally, it indicates potential outlook for novel therapeutic strategies in the management of obesity, metabolic syndrome and DM. Further research in this field is needed to ascertain the full potential of miRNAs as novel metabolic biomarkers and potent therapeutic agents against obesity and its metabolic disorders. KEYWORDS: obesity, metabolic syndrome, diabetes, miRNAs, adipogenesis, insulin, pancreatic cells.

Comprehensive Mapping of Pluripotent Stem Cell Metabolism Using Dynamic Genome-Scale Network Modeling

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Sriram Chandrasekaran

2017-12-01

Full Text Available Summary: Metabolism is an emerging stem cell hallmark tied to cell fate, pluripotency, and self-renewal, yet systems-level understanding of stem cell metabolism has been limited by the lack of genome-scale network models. Here, we develop a systems approach to integrate time-course metabolomics data with a computational model of metabolism to analyze the metabolic state of naive and primed murine pluripotent stem cells. Using this approach, we find that one-carbon metabolism involving phosphoglycerate dehydrogenase, folate synthesis, and nucleotide synthesis is a key pathway that differs between the two states, resulting in differential sensitivity to anti-folates. The model also predicts that the pluripotency factor Lin28 regulates this one-carbon metabolic pathway, which we validate using metabolomics data from Lin28-deficient cells. Moreover, we identify and validate metabolic reactions related to S-adenosyl-methionine production that can differentially impact histone methylation in naive and primed cells. Our network-based approach provides a framework for characterizing metabolic changes influencing pluripotency and cell fate. : Chandrasekaran et al. use computational modeling, metabolomics, and metabolic inhibitors to discover metabolic differences between various pluripotent stem cell states and infer their impact on stem cell fate decisions. Keywords: systems biology, stem cell biology, metabolism, genome-scale modeling, pluripotency, histone methylation, naive (ground state, primed state, cell fate, metabolic network

Enantiomeric metabolic interactions and stereoselective human methadone metabolism.

Science.gov (United States)

Totah, Rheem A; Allen, Kyle E; Sheffels, Pamela; Whittington, Dale; Kharasch, Evan D

2007-04-01

Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6- but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic

Metabolism of murine TH 17 cells: Impact on cell fate and function.

Science.gov (United States)

Wang, Ran; Solt, Laura A

2016-04-01

An effective adaptive immune response relies on the ability of lymphocytes to rapidly act upon a variety of insults. In T lymphocytes, this response includes cell growth, clonal expansion, differentiation, and cytokine production, all of which place a significant energy burden on the cell. Recent evidence shows that T-cell metabolic reprogramming is an essential component of the adaptive immune response and specific metabolic pathways dictate T-cell fate decisions, including the development of TH 17 versus T regulatory (Treg) cells. TH 17 cells have garnered significant attention due to their roles in the pathology of immune-mediated inflammatory diseases. Attempts to characterize TH 17 cells have demonstrated that they are highly dynamic, adjusting their function to environmental cues, which dictate their metabolic program. In this review, we highlight recent data demonstrating the impact of cellular metabolism on the TH 17/Treg balance and present factors that mediate TH 17-cell metabolism. Some examples of these include the differential impact of the mTOR signaling complexes on T-helper-cell differentiation, hypoxia inducible factor 1 alpha (HIF1α) promotion of glycolysis to favor TH 17-cell development, and ACC1-dependent de novo fatty acid synthesis favoring TH 17-cell development over Treg cells. Finally, we discuss the potential therapeutic options and the implications of modulating TH 17-cell metabolism for the treatment of TH 17-mediated diseases. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Programmed mitophagy is essential for the glycolytic switch during cell differentiation.

Science.gov (United States)

Esteban-Martínez, Lorena; Sierra-Filardi, Elena; McGreal, Rebecca S; Salazar-Roa, María; Mariño, Guillermo; Seco, Esther; Durand, Sylvère; Enot, David; Graña, Osvaldo; Malumbres, Marcos; Cvekl, Ales; Cuervo, Ana María; Kroemer, Guido; Boya, Patricia

2017-06-14

Retinal ganglion cells (RGCs) are the sole projecting neurons of the retina and their axons form the optic nerve. Here, we show that embryogenesis-associated mouse RGC differentiation depends on mitophagy, the programmed autophagic clearance of mitochondria. The elimination of mitochondria during RGC differentiation was coupled to a metabolic shift with increased lactate production and elevated expression of glycolytic enzymes at the mRNA level. Pharmacological and genetic inhibition of either mitophagy or glycolysis consistently inhibited RGC differentiation. Local hypoxia triggered expression of the mitophagy regulator BCL2/adenovirus E1B 19-kDa-interacting protein 3-like (BNIP3L, best known as NIX) at peak RGC differentiation. Retinas from NIX-deficient mice displayed increased mitochondrial mass, reduced expression of glycolytic enzymes and decreased neuronal differentiation. Similarly, we provide evidence that NIX-dependent mitophagy contributes to mitochondrial elimination during macrophage polarization towards the proinflammatory and more glycolytic M1 phenotype, but not to M2 macrophage differentiation, which primarily relies on oxidative phosphorylation. In summary, developmentally controlled mitophagy promotes a metabolic switch towards glycolysis, which in turn contributes to cellular differentiation in several distinct developmental contexts. © 2017 The Authors.

Bone scintigraphy in systemic and metabolic diseases

International Nuclear Information System (INIS)

Engels, H.J.; Schmidt, H.A.E.

1984-01-01

Bone scintigraphy is a very sensitive method to identify pathological processes affecting the bone. Its specificity is, however, considerably lower than its sensitivity, particularly in systemic diseases. We therefore investigated the possibilities of differential diagnosis based on typical sites or patterns of distribution. The Paget syndrome with characteristic manifestation in the pelvic region, including crutch-shaped accumulation in the proximal femur, may be diagnosed by scintigraphy alone. If these typical sites are absent, however, differential diagnosis is difficult. Differential diagnosis for multiple myeloma, fibrous dysplasia, enchondromatosis, hyperparathyroidism, osteopathies, osteomalacia, inflammatory rheumatic diseases is also required and should be based on further examinations, taking into consideration the history, clinical signs and course. In this connexion scintigraphy is relevant both for early assessment and documentation of the spread of pathological processes and for the follow-up. (orig.) [de

Application of Circuit Simulation Method for Differential Modeling of TIM-2 Iron Uptake and Metabolism in Mouse Kidney Cells

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Zhijian eXie

2013-06-01

Full Text Available Circuit simulation is a powerful methodology to generate differential mathematical models. Due to its highly accurate modelling capability, circuit simulation can be used to investigate interactions between the parts and processes of a cellular system. Circuit simulation has become a core technology for the field of electrical engineering, but its application in biology has not yet been fully realized. As a case study for evaluating the more advanced features of a circuit simulation tool called Advanced Design System (ADS, we collected and modeled laboratory data for iron metabolism in mouse kidney cells for a H ferritin (HFt receptor, T cell immunoglobulin and mucin domain-2 (TIM-2. The internal controlling parameters of TIM-2 associated iron metabolism were extracted and the ratios of iron movement among cellular compartments were quantified by ADS. The differential model processed by circuit simulation demonstrated a capability to identify variables and predict outcomes that could not be readily measured by in vitro experiments. For example, an initial rate of uptake of iron-loaded HFt was 2.17 pmol per million cells. TIM-2 binding probability with iron-loaded HFt was 16.6%. An average of 8.5 minutes was required for the complex of TIM-2 and iron-loaded HFt to form an endosome. The endosome containing HFt lasted roughly 2 hours. At the end of endocytosis, about 28% HFt remained intact and the rest was degraded. Iron released from degraded HFt was in the labile iron pool (LIP and stimulated the generation of endogenous HFt for new storage. Both experimental data and the model showed that TIM-2 was not involved in the process of iron export. The extracted internal controlling parameters successfully captured the complexity of TIM-2 pathway and the use of circuit simulation-based modeling across a wider range of cellular systems is the next step for validating the significance and utility of this method.

The metabolic score: A decision making tool in diabetes care.

Science.gov (United States)

Kalra, Sanjay; Gupta, Yashdeep

2015-11-01

The heterogeneity of diabetes mellitus, and the various metabolic abnormalities associated with it, are well known. Current management guidelines used to help choose glucose-lowering drugs in diabetes mellitus describe various drug classes in detail, but do not take the overall metabolic profile into consideration. To help physicians choose appropriate oral therapy, we propose a discrete metabolic score, based upon the presence and absence of metabolic comorbidities included in the definition of metabolic syndrome. This communication describes how to choose an appropriate oral antidiabetic drug using such a score. The metabolic score based decision making aid should be able to prove its utility in all health care settings, especially resource constrained societies.

Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

International Nuclear Information System (INIS)

Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir; Richardson, Jason R.; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

2014-01-01

The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage

Differential metabolism of 4-hydroxynonenal in liver, lung and brain of mice and rats

Energy Technology Data Exchange (ETDEWEB)

Zheng, Ruijin; Dragomir, Ana-Cristina; Mishin, Vladimir [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Richardson, Jason R. [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States); Heck, Diane E. [Environmental Science, School of Health Sciences and Practice, New York Medical College, Valhalla, NY (United States); Laskin, Debra L. [Pharmacology and Toxicology, Rutgers University-Ernest Mario School of Pharmacy, Piscataway, NJ (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Environmental and Occupational Medicine, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ (United States)

2014-08-15

The lipid peroxidation end-product 4-hydroxynonenal (4-HNE) is generated in tissues during oxidative stress. As a reactive aldehyde, it forms Michael adducts with nucleophiles, a process that disrupts cellular functioning. Liver, lung and brain are highly sensitive to xenobiotic-induced oxidative stress and readily generate 4-HNE. In the present studies, we compared 4-HNE metabolism in these tissues, a process that protects against tissue injury. 4-HNE was degraded slowly in total homogenates and S9 fractions of mouse liver, lung and brain. In liver, but not lung or brain, NAD(P)+ and NAD(P)H markedly stimulated 4-HNE metabolism. Similar results were observed in rat S9 fractions from these tissues. In liver, lung and brain S9 fractions, 4-HNE formed protein adducts. When NADH was used to stimulate 4-HNE metabolism, the formation of protein adducts was suppressed in liver, but not lung or brain. In both mouse and rat tissues, 4-HNE was also metabolized by glutathione S-transferases. The greatest activity was noted in livers of mice and in lungs of rats; relatively low glutathione S-transferase activity was detected in brain. In mouse hepatocytes, 4-HNE was rapidly taken up and metabolized. Simultaneously, 4-HNE-protein adducts were formed, suggesting that 4-HNE metabolism in intact cells does not prevent protein modifications. These data demonstrate that, in contrast to liver, lung and brain have a limited capacity to metabolize 4-HNE. The persistence of 4-HNE in these tissues may increase the likelihood of tissue injury during oxidative stress. - Highlights: • Lipid peroxidation generates 4-hydroxynonenal, a highly reactive aldehyde. • Rodent liver, but not lung or brain, is efficient in degrading 4-hydroxynonenal. • 4-hydroxynonenal persists in tissues with low metabolism, causing tissue damage.

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

Energy Technology Data Exchange (ETDEWEB)

Choi, Yoon Jung [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Lee, Jue Yeon [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Lee, Seung Jin [Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Chung, Chong-Pyoung [Department of Periodontology, School of Dentistry, Seoul National University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Park, Yoon Jeong, E-mail: parkyj@snu.ac.kr [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of)

2011-12-16

Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

International Nuclear Information System (INIS)

Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

2011-01-01

Highlights: ► Doxazocin directly up-regulated bone metabolism at a low dose. ► Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. ► This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor γ, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone

Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.

Science.gov (United States)

Ward, Patrick S; Thompson, Craig B

2012-03-20

Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. Copyright © 2012 Elsevier Inc. All rights reserved.

Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals.

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Anja Böhm

Full Text Available Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.10 insulin-resistant (IR vs. 10 insulin-sensitive (IS non-diabetic morbidly obese (BMI >40 kg/m2 Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma.Among others, aspartate was reduced intracellularly to one third (p = 0.0039 in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHO's and MHO's adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs were lower in MUHO's extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA metabolism was found: 15(S-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014, AA (1.5-fold; p = 0.0055 and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033 were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO.We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.

Plant-derived therapeutics for the treatment of metabolic syndrome.

Science.gov (United States)

Graf, Brittany L; Raskin, Ilya; Cefalu, William T; Ribnicky, David M

2010-10-01

Metabolic syndrome is defined as a set of coexisting metabolic disorders that increase an individual's likelihood of developing type 2 diabetes, cardiovascular disease and stroke. Medicinal plants, some of which have been used for thousands of years, serve as an excellent source of bioactive compounds for the treatment of metabolic syndrome because they contain a wide range of phytochemicals with diverse metabolic effects. In order for botanicals to be effectively used against metabolic syndrome, however, botanical preparations must be characterized and standardized through the identification of their active compounds and respective modes of action, followed by validation in controlled clinical trials with clearly defined endpoints. This review assesses examples of commonly known and partially characterized botanicals to describe specific considerations for the phytochemical, preclinical and clinical characterization of botanicals associated with metabolic syndrome.

Protein profiling of plastoglobules in chloroplasts and chromoplasts. A surprising site for differential accumulation of metabolic enzymes.

Science.gov (United States)

Ytterberg, A Jimmy; Peltier, Jean-Benoit; van Wijk, Klaas J

2006-03-01

Plastoglobules (PGs) are oval or tubular lipid-rich structures present in all plastid types, but their specific functions are unclear. PGs contain quinones, alpha-tocopherol, and lipids and, in chromoplasts, carotenoids as well. It is not known whether PGs contain any enzymes or regulatory proteins. Here, we determined the proteome of PGs from chloroplasts of stressed and unstressed leaves of Arabidopsis (Arabidopsis thaliana) as well as from pepper (Capsicum annuum) fruit chromoplasts using mass spectrometry. Together, this showed that the proteome of chloroplast PGs consists of seven fibrillins, providing a protein coat and preventing coalescence of the PGs, and an additional 25 proteins likely involved in metabolism of isoprenoid-derived molecules (quinines and tocochromanols), lipids, and carotenoid cleavage. Four unknown ABC1 kinases were identified, possibly involved in regulation of quinone monooxygenases. Most proteins have not been observed earlier but have predicted N-terminal chloroplast transit peptides and lack transmembrane domains, consistent with localization in the PG lipid monolayer particles. Quantitative differences in PG composition in response to high light stress and degreening were determined by differential stable-isotope labeling using formaldehyde. More than 20 proteins were identified in the PG proteome of pepper chromoplasts, including four enzymes of carotenoid biosynthesis and several homologs of proteins observed in the chloroplast PGs. Our data strongly suggest that PGs in chloroplasts form a functional metabolic link between the inner envelope and thylakoid membranes and play a role in breakdown of carotenoids and oxidative stress defense, whereas PGs in chromoplasts are also an active site for carotenoid conversions.

Determining the Control Circuitry of Redox Metabolism at the Genome-Scale

DEFF Research Database (Denmark)

Federowicz, Stephen; Kim, Donghyuk; Ebrahim, Ali

2014-01-01

-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes...

Exercise Intensity Modulation of Hepatic Lipid Metabolism

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Fábio S. Lira

2012-01-01

Full Text Available Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL, ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge.

Metabolic syndrome and cardiovascular risk among adults

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Reem Hunain

2018-03-01

Full Text Available Background: Mortality and morbidity due cardiovascular diseases in India is on the rise. Metabolic Syndrome which is a collection of risk factors of metabolic origin, can greatly contribute to its rising burden. Aims & Objectives: The present study was conducted with the objective of estimating the prevalence of metabolic syndrome and 10-year cardiovascular risk among adults. Material & Methods: This hospital-based study included 260 adults aged 20-60 years. Metabolic Syndrome was defined using National Cholesterol Education Program –Adult Treatment Panel -3 criteria. The 10 year cardiovascular risk was estimated using Framingham risk scoring. Results: The overall prevalence of metabolic syndrome among the study participants was 38.8%. Age (41-60yrs, male gender and daily consumption of high salt items were positively associated with metabolic syndrome whereas consumption of occasional high sugar items showed an inverse association with metabolic syndrome. According to Framingham Risk Scoring, 14.3% of the participants belonged to intermediate/high risk category. Conclusion: With a high prevalence of metabolic syndrome and a considerable proportion of individuals with intermediate to high 10 yr CVD risk, there is a need to design strategies to prevent future cardiovascular events.

Positron emission tomography for measuring metabolism in vivo

International Nuclear Information System (INIS)

Feinendegen, L.E.

1985-01-01

Nuclear medical imaging always relates to changes at the cellular or molecular level of organization of the body. For years, such changes, summarily called metabolism, permitted radionuclides as tracers to produce information on rather gross organ structure and function. Yet, more recently, increasing emphasis is placed on metabolic reactions themselves; this development is of considerable promise to the clinician, because disease begins and nearly always expresses itself by alterations of metabolism. PET greatly helps to investigate and describe in vivo individual steps within the complex network of enzyme catalized reactions that maintain life; in fact, PET allows studies of biochemistry in vivo. (Author)

Metabolic neural mapping in neonatal rats

International Nuclear Information System (INIS)

DiRocco, R.J.; Hall, W.G.

1981-01-01

Functional neural mapping by 14 C-deoxyglucose autoradiography in adult rats has shown that increases in neural metabolic rate that are coupled to increased neurophysiological activity are more evident in axon terminals and dendrites than neuron cell bodies. Regions containing architectonically well-defined concentrations of terminals and dendrites (neuropil) have high metabolic rates when the neuropil is physiologically active. In neonatal rats, however, we find that regions containing well-defined groupings of neuron cell bodies have high metabolic rates in 14 C-deoxyglucose autoradiograms. The striking difference between the morphological appearance of 14 C-deoxyglucose autoradiograms obtained from neonatal and adult rats is probably related to developmental changes in morphometric features of differentiating neurons, as well as associated changes in type and locus of neural work performed

Rewiring carbohydrate catabolism differentially affects survival of pancreatic cancer cell lines with diverse metabolic profiles

Science.gov (United States)

Tataranni, Tiziana; Agriesti, Francesca; Ruggieri, Vitalba; Mazzoccoli, Carmela; Simeon, Vittorio; Laurenzana, Ilaria; Scrima, Rosella; Pazienza, Valerio; Capitanio, Nazzareno; Piccoli, Claudia

2017-01-01

An increasing body of evidence suggests that targeting cellular metabolism represents a promising effective approach to treat pancreatic cancer, overcome chemoresistance and ameliorate patient's prognosis and survival. In this study, following whole-genome expression analysis, we selected two pancreatic cancer cell lines, PANC-1 and BXPC-3, hallmarked by distinct metabolic profiles with specific concern to carbohydrate metabolism. Functional comparative analysis showed that BXPC-3 displayed a marked deficit of the mitochondrial respiratory and oxidative phosphorylation activity and a higher production of reactive oxygen species and a reduced NAD+/NADH ratio, indicating their bioenergetic reliance on glycolysis and a different redox homeostasis as compared to PANC-1. Both cell lines were challenged to rewire their metabolism by substituting glucose with galactose as carbon source, a condition inhibiting the glycolytic flux and fostering full oxidation of the sugar carbons. The obtained data strikingly show that the mitochondrial respiration-impaired-BXPC-3 cell line was unable to sustain the metabolic adaptation required by glucose deprivation/substitution, thereby resulting in a G2\\M cell cycle shift, unbalance of the redox homeostasis, apoptosis induction. Conversely, the mitochondrial respiration-competent-PANC-1 cell line did not show clear evidence of cell sufferance. Our findings provide a strong rationale to candidate metabolism as a promising target for cancer therapy. Defining the metabolic features at time of pancreatic cancer diagnosis and likely of other tumors, appears to be crucial to predict the responsiveness to therapeutic approaches or coadjuvant interventions affecting metabolism. PMID:28476035

Preadipocyte factor-1 is associated with metabolic profile in severe obesity.

LENUS (Irish Health Repository)

O'Connell, J

2011-04-01

Dysfunctional adipose tissue has been proposed as a key pathological process linking obesity and metabolic disease. Preadipocyte factor-1 (Pref-1) has been shown to inhibit differentiation in adipocyte precursor cells and could thereby play a role in determining adipocyte size, adipose tissue functioning, and metabolic profile in obese individuals.

Integration of genome-scale metabolic networks into whole-body PBPK models shows phenotype-specific cases of drug-induced metabolic perturbation.

Science.gov (United States)

Cordes, Henrik; Thiel, Christoph; Baier, Vanessa; Blank, Lars M; Kuepfer, Lars

2018-01-01

Drug-induced perturbations of the endogenous metabolic network are a potential root cause of cellular toxicity. A mechanistic understanding of such unwanted side effects during drug therapy is therefore vital for patient safety. The comprehensive assessment of such drug-induced injuries requires the simultaneous consideration of both drug exposure at the whole-body and resulting biochemical responses at the cellular level. We here present a computational multi-scale workflow that combines whole-body physiologically based pharmacokinetic (PBPK) models and organ-specific genome-scale metabolic network (GSMN) models through shared reactions of the xenobiotic metabolism. The applicability of the proposed workflow is illustrated for isoniazid, a first-line antibacterial agent against Mycobacterium tuberculosis , which is known to cause idiosyncratic drug-induced liver injuries (DILI). We combined GSMN models of a human liver with N-acetyl transferase 2 (NAT2)-phenotype-specific PBPK models of isoniazid. The combined PBPK-GSMN models quantitatively describe isoniazid pharmacokinetics, as well as intracellular responses, and changes in the exometabolome in a human liver following isoniazid administration. Notably, intracellular and extracellular responses identified with the PBPK-GSMN models are in line with experimental and clinical findings. Moreover, the drug-induced metabolic perturbations are distributed and attenuated in the metabolic network in a phenotype-dependent manner. Our simulation results show that a simultaneous consideration of both drug pharmacokinetics at the whole-body and metabolism at the cellular level is mandatory to explain drug-induced injuries at the patient level. The proposed workflow extends our mechanistic understanding of the biochemistry underlying adverse events and may be used to prevent drug-induced injuries in the future.

Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process

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Alexandre Vallée

2017-11-01

Full Text Available Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-β and WNT/β-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-β and WNT/β-catenin pathways underlying in fibrosis.

Metabolic Syndrome

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Sevil Ikinci

2010-10-01

Full Text Available Metabolic Syndrome is a combination of risk factors including common etiopathogenesis. These risk factors play different roles in occurence of atherosclerotic diseases, type 2 diabetes, and cancers. Although a compromise can not be achieved on differential diagnosis for MS, the existence of any three criterias enable to diagnose MS. These are abdominal obesity, dislipidemia (hypertrigliceridemia, hypercholesterolemia, and reduced high density lipoprotein hypertension, and elevated fasting blood glucose. According to the results of Metabolic Syndrome Research (METSAR, the overall prevalence of MS in Turkey is 34%; in females 40%, and in males it is 28%. As a result of “Western” diet, and increased frequency of obesity, MS is observed in children and in adolescents both in the world and in Turkey. Resulting in chronic diseases, it is thought that the syndrome can be prevented by healthy lifestyle behaviours. [TAF Prev Med Bull 2010; 9(5.000: 535-540

Severe metabolic alkalosis due to pyloric obstruction: case presentation, evaluation, and management.

Science.gov (United States)

McCauley, Meredith; Gunawardane, Manjula; Cowan, Mark J

2006-12-01

A 46-year-old man presented to the emergency room with severe metabolic alkalosis, hypokalemia, and respiratory failure requiring intubation and mechanical ventilation. The cause of his acid-base disorder was initially unclear. Although alkalosis is common in the intensive care unit, metabolic alkalosis of this severity is unusual, carries a very high mortality rate, and requires careful attention to the pathophysiology and differential diagnosis to effectively evaluate and treat the patient. A central concept in the diagnosis of metabolic alkalosis is distinguishing chloride responsive and chloride nonresponsive states. Further studies are then guided by the history and physical examination in most cases. By using a systematic approach to the differential diagnosis, we were able to determine that a high-grade gastric outlet obstruction was the cause of the patients' alkalosis and to offer effective therapy for his condition. A literature review and algorithm for the diagnosis and management of metabolic alkalosis are also presented.

Solving Differential Equations in R

Science.gov (United States)

Although R is still predominantly applied for statistical analysis and graphical representation, it is rapidly becoming more suitable for mathematical computing. One of the fields where considerable progress has been made recently is the solution of differential equations. Here w...

Hepatic differentiation of human pluripotent stem cells in miniaturized format suitable for high-throughput screen

Directory of Open Access Journals (Sweden)

Arnaud Carpentier

2016-05-01

Full Text Available The establishment of protocols to differentiate human pluripotent stem cells (hPSCs including embryonic (ESC and induced pluripotent (iPSC stem cells into functional hepatocyte-like cells (HLCs creates new opportunities to study liver metabolism, genetic diseases and infection of hepatotropic viruses (hepatitis B and C viruses in the context of specific genetic background. While supporting efficient differentiation to HLCs, the published protocols are limited in terms of differentiation into fully mature hepatocytes and in a smaller-well format. This limitation handicaps the application of these cells to high-throughput assays. Here we describe a protocol allowing efficient and consistent hepatic differentiation of hPSCs in 384-well plates into functional hepatocyte-like cells, which remain differentiated for more than 3 weeks. This protocol affords the unique opportunity to miniaturize the hPSC-based differentiation technology and facilitates screening for molecules in modulating liver differentiation, metabolism, genetic network, and response to infection or other external stimuli.

Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

Energy Technology Data Exchange (ETDEWEB)

Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L. [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States); Piroli, Gerardo G.; Frizzell, Norma [Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Tseng, Yu-Hua; Goodyear, Laurie J. [Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215 (United States); Koh, Ho-Jin, E-mail: kohh@mailbox.sc.edu [Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208 (United States)

2016-02-19

Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. - Highlights: • TRB3 is expressed in brown adipose tissue and its expression is increased during differentiation. • Overexpression of TRB3 inhibits differentiation and its activity. • Overexpression of TRB3 in brown preadipocytes inhibits insulin signaling. • TRB3KO mice displays improved insulin signaling in brown adipose tissue. • Insulin signaling is required for the effects of TRB3 to regulate brown adipose tissue differentiation and

Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

International Nuclear Information System (INIS)

Jeong, Ha-Won; Choi, Ran Hee; McClellan, Jamie L.; Piroli, Gerardo G.; Frizzell, Norma; Tseng, Yu-Hua; Goodyear, Laurie J.; Koh, Ho-Jin

2016-01-01

Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function. - Highlights: • TRB3 is expressed in brown adipose tissue and its expression is increased during differentiation. • Overexpression of TRB3 inhibits differentiation and its activity. • Overexpression of TRB3 in brown preadipocytes inhibits insulin signaling. • TRB3KO mice displays improved insulin signaling in brown adipose tissue. • Insulin signaling is required for the effects of TRB3 to regulate brown adipose tissue differentiation and

Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling.

Science.gov (United States)

Doody, Erin E; Groebner, Jennifer L; Walker, Jetta R; Frizol, Brittnee M; Tuma, Dean J; Fernandez, David J; Tuma, Pamela L

2017-12-01

-exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P 450 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway. Copyright © 2017 the American Physiological Society.

Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions.

Science.gov (United States)

Guitart, Amelie V; Panagopoulou, Theano I; Villacreces, Arnaud; Vukovic, Milica; Sepulveda, Catarina; Allen, Lewis; Carter, Roderick N; van de Lagemaat, Louie N; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; Gonzalez, Marta Vila; Lawson, Hannah; Paris, Jasmin; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O'Carroll, Donal; Vernimmen, Douglas; Rodrigues, Neil P; Pollard, Patrick J; Morton, Nicholas M; Finch, Andrew; Kranc, Kamil R

2017-03-06

Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role of fumarate hydratase (Fh1), a key component of the mitochondrial tricarboxylic acid (TCA) cycle and cytosolic fumarate metabolism, in normal and leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting in endogenous fumarate accumulation and a genetic TCA cycle block reflected by decreased maximal mitochondrial respiration) caused lethal fetal liver hematopoietic defects and hematopoietic stem cell (HSC) failure. Reexpression of extramitochondrial Fh1 (which normalized fumarate levels but not maximal mitochondrial respiration) rescued these phenotypes, indicating the causal role of cellular fumarate accumulation. However, HSCs lacking mitochondrial Fh1 (which had normal fumarate levels but defective maximal mitochondrial respiration) failed to self-renew and displayed lymphoid differentiation defects. In contrast, leukemia-initiating cells lacking mitochondrial Fh1 efficiently propagated Meis1 / Hoxa9 -driven leukemia. Thus, we identify novel roles for fumarate metabolism in HSC maintenance and hematopoietic differentiation and reveal a differential requirement for mitochondrial Fh1 in normal hematopoiesis and leukemia propagation. © 2017 Guitart et al.

The absolute differential calculus calculus of tensors

CERN Document Server

Levi-Cività, Tullio

1926-01-01

Written by a towering figure of twentieth-century mathematics, this classic examines the mathematical background necessary for a grasp of relativity theory. Tullio Levi-Civita provides a thorough treatment of the introductory theories that form the basis for discussions of fundamental quadratic forms and absolute differential calculus, and he further explores physical applications.Part one opens with considerations of functional determinants and matrices, advancing to systems of total differential equations, linear partial differential equations, algebraic foundations, and a geometrical intro

Lipid Metabolism, Apoptosis and Cancer Therapy

Directory of Open Access Journals (Sweden)

Chunfa Huang

2015-01-01

Full Text Available Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy.

Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering

DEFF Research Database (Denmark)

Starokozhko, Viktoriia; Hemmingsen, Mette; Larsen, Layla

2018-01-01

and to perform functional comparisons with fresh human precision-cut liver slices (hPCLS), an excellent benchmark for the human liver in vivo. The majority of the mRNA expression of CYP isoenzymes and transporters and the tested CYP activities, Phase II metabolism, and albumin, urea, and bile acid synthesis...... in the hiPSC-derived cells reached values that overlap those of hPCLS, which indicates a higher degree of hepatic differentiation than observed until now. Differentiation under flow compared with static conditions had a strong inducing effect on Phase II metabolism and suppressed AFP expression but resulted...... in slightly lower activity of some of the Phase I metabolism enzymes. Gene expression data indicate that hiPSCs differentiated into both hepatic and biliary directions. In conclusion, the hiPSC differentiated under flow conditions towards hepatocytes express a wide spectrum of liver functions at levels...

[Study on gene differential expressions of substance and energy metabolism in chronic superficial gastritis patients of Pi deficiency syndrome and of pi-wei hygropyrexia syndrome].

Science.gov (United States)

Yang, Ze-Min; Chen, Wei-Wen; Wang, Ying-Fang

2012-09-01

To analyze the metabolic levels of energy and substance in chronic superficial gastritis (CSG) patients of Pi deficiency syndrome (PDS) and of Pi-Wei hygropyrexia syndrome (PWHS), including lipid, protein, nucleic acid, carbohydrate, trace element, and energy metabolism, and to study the pathogenesis mechanism of PDS from substance and energy metabolisms. Recruited were 8 CSG patients who visited at First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine and Guangdong Provincial Hospital of Traditional Chinese Medicine from June 2004 to March 2005, including 4 patients of PDS and 4 of PWHS. Their gastric mucosae were used for experiments of DNA microarray. The dual-channel DNA microarray data were bioinformatically analyzed by BRB ArrayTools and IPA Software. Obtained were fifty-six differentially expressed genes involved in substance and energy metabolisms with the expression fold more than 2, including 11 genes up-regulated and 45 genes down-regulated. Of them, genes correlated to lipid metabolism included CRLS1, LRP11, FUT9, GPCPD1, PIGL, SULT1A4, B3GNT1, ST8SIA4, and ACADVL, mainly involved in the metabolic processes of fatty acid, cholesterol, phospholipids, and glycolipid. Genes correlated to protein metabolism included ASRGL1, AARSD1, EBNA1BP2, PUM2, MRPL52, C120RF65, PSMB8, PSME2, UBA7, RNF11, FBXO44, ZFYVE26, CHMP2A, SSR4, SNX4, RAB3B, RABL2A, GOLGA2, KDELR1, PHPT1, ACPP, PTPRF, CRKL, HDAC7, ADPRHL2, B3GNT1, ST8SIA4, DDOST, and FUT9, mainly involved in the biosynthesis processes of protein, ubiquitination, targeted transport and post-translation modification. Genes correlated to nucleic acid metabolism included DFFB, FLJ35220, TOP2A, SF3A3, CREB3, CRTC2, NR1D2, MED6, GTF2IRD1, C1ORF83, ZNF773, and ZMYND11, mainly involved in DNA replication and repair, transcription regulation. Genes correlated to carbohydrate metabolism included AGL, B3GNT1, FUT9, ST8SIA4, SULT1A4, DDOST, and PIGL, mainly involved in glucogen degradation and

Cellular energy metabolism in T-lymphocytes.

Science.gov (United States)

Gaber, Timo; Strehl, Cindy; Sawitzki, Birgit; Hoff, Paula; Buttgereit, Frank

2015-01-01

Energy homeostasis is a hallmark of cell survival and maintenance of cell function. Here we focus on the impact of cellular energy metabolism on T-lymphocyte differentiation, activation, and function in health and disease. We describe the role of transcriptional and posttranscriptional regulation of lymphocyte metabolism on immune functions of T cells. We also summarize the current knowledge about T-lymphocyte adaptations to inflammation and hypoxia, and the impact on T-cell behavior of pathophysiological hypoxia (as found in tumor tissue, chronically inflamed joints in rheumatoid arthritis and during bone regeneration). A better understanding of the underlying mechanisms that control immune cell metabolism and immune response may provide therapeutic opportunities to alter the immune response under conditions of either immunosuppression or inflammation, potentially targeting infections, vaccine response, tumor surveillance, autoimmunity, and inflammatory disorders.

Metabolic changes during B cell differentiation for the production of intestinal IgA antibody.

Science.gov (United States)

Kunisawa, Jun

2017-04-01

To sustain the bio-energetic demands of growth, proliferation, and effector functions, the metabolism of immune cells changes dramatically in response to immunologic stimuli. In this review, I focus on B cell metabolism, especially regarding the production of intestinal IgA antibody. Accumulating evidence has implicated not only host-derived factors (e.g., cytokines) but also gut environmental factors, including the possible involvement of commensal bacteria and diet, in the control of B cell metabolism during intestinal IgA antibody production. These findings yield new insights into the regulation of immunosurveillance and homeostasis in the gut.

In vivo metabolic phenotyping of myocardial substrate metabolism in rodents: differential efficacy of metformin and rosiglitazone monotherapy.

Science.gov (United States)

Shoghi, Kooresh I; Finck, Brian N; Schechtman, Kenneth B; Sharp, Terry; Herrero, Pilar; Gropler, Robert J; Welch, Michael J

2009-09-01

Cardiovascular disease is the leading cause of death among diabetic patients, with alteration in myocardial substrate metabolism being a likely contributor. We aimed to assess noninvasively the efficacy of metformin and rosiglitazone monotherapy in normalizing myocardial substrate metabolism in an animal model of type 2 diabetes mellitus. The study used 18 male ZDF rats (fa/fa) with 6 rats in each group: an untreated group; a group treated with metformin (16.6 mg/kg/d), and a group treated with rosiglitazone (4 mg/kg). Each rat was scanned at age 14 weeks (baseline) and subsequently at 19 weeks with small-animal positron emission tomography to estimate myocardial glucose utilization (MGU) and myocardial utilization (MFAU), oxidation (MFAO), and esterification (MFAE). Treatment lasted for 5 weeks after baseline imaging. At week 19, rats were euthanized and hearts were extracted for expression analysis of select genes encoding for GLUT transporters and fatty acid transport and oxidation genes. In addition, echocardiography measurements were obtained at weeks 13 and 18 to characterize cardiac function. Metformin had no significant effect on either MGU or MFAU and MFAO. In contrast, rosiglitazone tended to enhance MGU and significantly reduced MFAU and MFAO. Rosiglitazone-induced increase in glucose uptake correlated significantly with increased expression of GLUT4, whereas diminished MFAO correlated significantly with decreased expression of FATP-1 and MCAD. Finally, changes in fractional shortening as a measure of cardiac function were unchanged throughout the study. Treatment with rosiglitazone enhanced glucose utilization and diminished MFAO, thus reversing the metabolic phenotype of the diabetic heart.

Non-photosynthetic plastids as hosts for metabolic engineering.

Science.gov (United States)

Mellor, Silas Busck; Behrendorff, James B Y H; Nielsen, Agnieszka Zygadlo; Jensen, Poul Erik; Pribil, Mathias

2018-04-13

Using plants as hosts for production of complex, high-value compounds and therapeutic proteins has gained increasing momentum over the past decade. Recent advances in metabolic engineering techniques using synthetic biology have set the stage for production yields to become economically attractive, but more refined design strategies are required to increase product yields without compromising development and growth of the host system. The ability of plant cells to differentiate into various tissues in combination with a high level of cellular compartmentalization represents so far the most unexploited plant-specific resource. Plant cells contain organelles called plastids that retain their own genome, harbour unique biosynthetic pathways and differentiate into distinct plastid types upon environmental and developmental cues. Chloroplasts, the plastid type hosting the photosynthetic processes in green tissues, have proven to be suitable for high yield protein and bio-compound production. Unfortunately, chloroplast manipulation often affects photosynthetic efficiency and therefore plant fitness. In this respect, plastids of non-photosynthetic tissues, which have focused metabolisms for synthesis and storage of particular classes of compounds, might prove more suitable for engineering the production and storage of non-native metabolites without affecting plant fitness. This review provides the current state of knowledge on the molecular mechanisms involved in plastid differentiation and focuses on non-photosynthetic plastids as alternative biotechnological platforms for metabolic engineering. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

[Rhabdomyolysis - may it be a metabolic myopathy? Case report and diagnostic algorithm].

Science.gov (United States)

Sebők, Ágnes; Pál, Endre; Molnár, Gergő Attila; Wittmann, István; Berenténé Bene, Judit; Melegh, Béla; Komoly, Sámuel; Hidvégi, Tibor; Balogh, Lídia; Szabó, Attila; Zsidegh, Petra

2017-11-01

We report the case of a 46-year-old female patient with recurrent rhabdomyolysis. In the background of her metabolic myopathy an inherited metabolic disorder of the fatty acid oxidation, very long-chain acyl-coenzyme A-dehydrogenase deficiency was diagnosed. The diagnosis was based on abnormal acyl-carnitine- and urine organic-acid profile in addition to low residual enzyme activity, and was confirmed by genetic testing. After introduction of dietotherapy metabolic crisis necessitating hospital admission has not occurred neither have fixed myopathic changes developed. We present here the differential diagnosis of rhabdomyolysis and exertional muscle complaints, with the metabolic myopathies in focus. The main features of fatty acid oxidation disorders are highlighted, acute and chronic managements of very long-chain acyl-coenzyme A-dehydrogenase deficiency are discussed. Metabolic myopathies respond well to treatment, so good quality of life can be achieved. However, especially in fatty acid oxidation disorders, a metabolic crisis may develop quickly and can be fatal, albeit rarely. Some of these disorders can be identified by newborn screening, but occasionally the symptoms may manifest only in adulthood. With the presentation of this case we would like to point out that in the differential diagnosis of recurrent rhabdomyolysis inherited metabolic disorders should be considered regardless of the patient's age. Orv Hetil. 2017; 158(46): 1873-1882.

Comparison of 1H-MRS-detected metabolic characteristics in single metastatic brain tumors of different origin

International Nuclear Information System (INIS)

Chernov, M.F.; Ono, Yuko; Kubo, Osami; Hori, Tomokatsu

2006-01-01

Various types of intracranial metastases exhibit different growth patterns, which can be reflected in their metabolic characteristics and investigated noninvasively by proton magnetic resonance spectroscopy ( 1 H-MRS). The objective of the present study was comparison of the 1 H-MRS-detected metabolic parameters in brain metastases of different origin. Twenty-five patients (15 men and 10 women; mean age, 62.0 years) with single, previously nontreated metastatic brain tumors were investigated by long-echo single-voxel volume-selected 1 H-MRS. The primary cancer was located in the lungs (10 cases), colon and rectum (8 cases), breast (3 cases), kidney (2 cases), prostate (1 case), and cardiac muscle (1 case). Comparison of clinical and radiological variables, including type of tumor contrast enhancement and extension of peritumoral edema, did not disclose statistically significant differences in metastatic brain tumors of different origin. At the same time, comparison of 1 H-MRS-detected metabolic characteristics revealed that metastases of colorectal carcinoma have greater content of mobile lipids (Lip) compared to other neoplasms. In conclusion, high Lip content in the viable brain metastases of colorectal carcinoma can be used as an additional diagnostic clue for noninvasive identification of these tumors and should be taken into consideration in cases of 1 H-MRS-based differentiation of their recurrence and radiation-induced necrosis after radiosurgical or radiotherapeutic treatment. (author)

Exponentially Convergent Algorithms for Abstract Differential Equations

CERN Document Server

Gavrilyuk, Ivan; Vasylyk, Vitalii

2011-01-01

This book presents new accurate and efficient exponentially convergent methods for abstract differential equations with unbounded operator coefficients in Banach space. These methods are highly relevant for the practical scientific computing since the equations under consideration can be seen as the meta-models of systems of ordinary differential equations (ODE) as well as the partial differential equations (PDEs) describing various applied problems. The framework of functional analysis allows one to obtain very general but at the same time transparent algorithms and mathematical results which

A workflow for mathematical modeling of subcellular metabolic pathways in leaf metabolism of Arabidopsis thaliana

Directory of Open Access Journals (Sweden)

Thomas eNägele

2013-12-01

Full Text Available During the last decade genome sequencing has experienced a rapid technological development resulting in numerous sequencing projects and applications in life science. In plant molecular biology, the availability of sequence data on whole genomes has enabled the reconstruction of metabolic networks. Enzymatic reactions are predicted by the sequence information. Pathways arise due to the participation of chemical compounds as substrates and products in these reactions. Although several of these comprehensive networks have been reconstructed for the genetic model plant Arabidopsis thaliana, the integration of experimental data is still challenging. Particularly the analysis of subcellular organization of plant cells limits the understanding of regulatory instances in these metabolic networks in vivo. In this study, we develop an approach for the functional integration of experimental high-throughput data into such large-scale networks. We present a subcellular metabolic network model comprising 524 metabolic intermediates and 548 metabolic interactions derived from a total of 2769 reactions. We demonstrate how to link the metabolite covariance matrix of different Arabidopsis thaliana accessions with the subcellular metabolic network model for the inverse calculation of the biochemical Jacobian, finally resulting in the calculation of a matrix which satisfies a Lyaponov equation involving a covariance matrix. In this way, differential strategies of metabolite compartmentation and involved reactions were identified in the accessions when exposed to low temperature.

Computational methods in metabolic engineering for strain design.

Science.gov (United States)

Long, Matthew R; Ong, Wai Kit; Reed, Jennifer L

2015-08-01

Metabolic engineering uses genetic approaches to control microbial metabolism to produce desired compounds. Computational tools can identify new biological routes to chemicals and the changes needed in host metabolism to improve chemical production. Recent computational efforts have focused on exploring what compounds can be made biologically using native, heterologous, and/or enzymes with broad specificity. Additionally, computational methods have been developed to suggest different types of genetic modifications (e.g. gene deletion/addition or up/down regulation), as well as suggest strategies meeting different criteria (e.g. high yield, high productivity, or substrate co-utilization). Strategies to improve the runtime performances have also been developed, which allow for more complex metabolic engineering strategies to be identified. Future incorporation of kinetic considerations will further improve strain design algorithms. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dense bone - too much bone: Radiological considerations and differential diagnosis. Pt. 2

Energy Technology Data Exchange (ETDEWEB)

Jacobson, H.G.

1985-02-01

In conclusion, the attempt has been made to demonstrate that three major forms of new bone formation exist: reactive, neoplastic, and the newborn or relative skeletal sclerosis in congenital (developmental) disorders. A classification of skeletal disorders has been presented and four major groups have been selected from the nine categories in this classification. These are: congenital-developmental, metabolic and endocrine, benign neoplasms and malignant neoplasms. In all four categories a large group of entities which may present with new bone (sclerosis) are listed and are discussed in some, but limited, detail. A number of these entities in each of the four categories are illustrated. Some difficulty is encountered in considering the mechanisms for the production of bony sclerosis in the group of congenital-developmental disorders. In such entities as osteopetrosis, the overproduction of cartilage cords and subsequent excessive mineralization is known to be responsible for the dense bone. However, in various skeletal dysplasias (e.g. pyknodysostosis, van Bucherm disease), the exact mechanism for the development of the diffuse sclerotic process is not clearly understood. In the metabolic and endocrine category, the situation as to mechanism is less unclear in considering the reason for the development of bony sclerosis. Yet even in evaluating disorders such as renal osteodystrophy, the reactive bony sclerosis in the presence of secondary hyperparathyroidism and osteomalacia is a source of speculation with no definite proof, as yet.

Metabolic topography of Parkinsonism

Energy Technology Data Exchange (ETDEWEB)

Kim, Jae Seung [Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

2007-04-15

Parkinson's disease is one of the most frequent neurodegenerative diseases, which mainly affects the elderly. Parkinson's disease is often difficult to differentiate from atypical parkinson disorder such as progressive supranuclear palsy, multiple system atrophy, dementia with Lewy body, and corticobasal ganglionic degeneration, based on the clinical findings because of the similarity of phenotypes and lack of diagnostic markers. The accurate diagnosis of Parkinson's disease and atypical Parkinson disorders is not only important for deciding on treatment regimens and providing prognosis, but also it is critical for studies designed to investigate etiology and pathogenesis of parkinsonism and to develop new therapeutic strategies. Although degeneration of the nigrostriatal dopamine system results in marked loss of striatal dopamine content in most of the diseases causing parkinsonism, pathologic studies revealed different topographies of the neuronal cell loss in Parkinsonism. Since the regional cerebral glucose metabolism is a marker of integrated local synaptic activity and as such is sensitive to both direct neuronal/synaptic damage and secondary functional disruption at synapses distant from the primary site of pathology, and assessment of the regional cerebral glucose metabolism with F-18 FDG PET is useful in the differential diagnosis of parkinsonism and evaluating the pathophysiology of Parkinsonism.

Metabolic topography of Parkinsonism

International Nuclear Information System (INIS)

Kim, Jae Seung

2007-01-01

Parkinson's disease is one of the most frequent neurodegenerative diseases, which mainly affects the elderly. Parkinson's disease is often difficult to differentiate from atypical parkinson disorder such as progressive supranuclear palsy, multiple system atrophy, dementia with Lewy body, and corticobasal ganglionic degeneration, based on the clinical findings because of the similarity of phenotypes and lack of diagnostic markers. The accurate diagnosis of Parkinson's disease and atypical Parkinson disorders is not only important for deciding on treatment regimens and providing prognosis, but also it is critical for studies designed to investigate etiology and pathogenesis of parkinsonism and to develop new therapeutic strategies. Although degeneration of the nigrostriatal dopamine system results in marked loss of striatal dopamine content in most of the diseases causing parkinsonism, pathologic studies revealed different topographies of the neuronal cell loss in Parkinsonism. Since the regional cerebral glucose metabolism is a marker of integrated local synaptic activity and as such is sensitive to both direct neuronal/synaptic damage and secondary functional disruption at synapses distant from the primary site of pathology, and assessment of the regional cerebral glucose metabolism with F-18 FDG PET is useful in the differential diagnosis of parkinsonism and evaluating the pathophysiology of Parkinsonism

Consideration of myocardial FDG uptake in differentiation of mediastinal lymph node of non-small cell lung cancer

International Nuclear Information System (INIS)

Eo, Jae Seon; Lee, Won Woo; Chung, Jin Haeng; So, Young; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul; Kim, Sang Eun

2004-01-01

The whole body FDG PET suffers from poor diagnostic competency in differentiation of mediastinal lymph node (LN) in non-small cell lung cancer. In addition to LN FDG uptake. We considered myocardial FDG uptake in mediastinal lymph node staging. Thirty-nine non-small cell lung cancer patients (male: female = 32: 7, age = 63±11 years) who underwent preoperative whole body FDG PET were enrolled. There were 18 squamous cell cancer, 13 adenocarcinoma, and 8 others. Maximum standard uptake values (maxSUVs) of myocardium and LNs using lean body weight were measured and compared with pathological results. Among 187 LNs which were confirmed postoperatively, 31 were malignant, and 156 benign. Of 31 malignant LNs, only 11 were visible on FDG PET (sensitivity : 35.5% = 11/31) but majority of 20 nonvisible metastatic LNs had relevant cause of false negative (11 peribroncheal, 3 mucine producing adenocarcinoma, or 6 low amount of tumor cells). Of 156 benign LNs, 137 were nonvisible (specificity : 87.8% 137/156) and 19 visible. Under subgroup analysis of 30 visible LNs on whole body FDG PET (11 malignant, and 19 benign), maxSUV of myocardium (p = 0.020) as well as maxSUV of LN (p = 0.002) were significant predictor of malignant LN in multivariate analysis. Using the ROC curve, a cut-off value of LN maxSUV > 2.4 provided sensitivity of 81.8% and specificity of 63.2% (AUC 0.775, 95% confidence interval = 0.586 to 0.906). Meanwhile, the composite criterion of LN maxSUV plus square root of myocardial maxSUV > 4.65 provided slightly improved diagnostic competencies (sensitivity 90.9%, specificity 84.2%, AUC 0.876, 95% confidence interval 0.704 to 0.966) (p = 0.08). Taking into consideration myocardial FDG uptake may improve the diagnostic competency of whole body FDG PET in differentiation of mediastinal LNs of non-small cell lung cancer

Autophagic pathways and metabolic stress.

Science.gov (United States)

Kaushik, S; Singh, R; Cuervo, A M

2010-10-01

Autophagy is an essential intracellular process that mediates degradation of intracellular proteins and organelles in lysosomes. Autophagy was initially identified for its role as alternative source of energy when nutrients are scarce but, in recent years, a previously unknown role for this degradative pathway in the cellular response to stress has gained considerable attention. In this review, we focus on the novel findings linking autophagic function with metabolic stress resulting either from proteins or lipids. Proper autophagic activity is required in the cellular defense against proteotoxicity arising in the cytosol and also in the endoplasmic reticulum, where a vast amount of proteins are synthesized and folded. In addition, autophagy contributes to mobilization of intracellular lipid stores and may be central to lipid metabolism in certain cellular conditions. In this review, we focus on the interrelation between autophagy and different types of metabolic stress, specifically the stress resulting from the presence of misbehaving proteins within the cytosol or in the endoplasmic reticulum and the stress following a lipogenic challenge. We also comment on the consequences that chronic exposure to these metabolic stressors could have on autophagic function and on how this effect may underlie the basis of some common metabolic disorders. © 2010 Blackwell Publishing Ltd.

Differential rotation in magnetic stars

International Nuclear Information System (INIS)

Moss, D.

1981-01-01

The possibility that large-scale magnetic fields in stars are the product of a contemporary dynamo situated in the convective stellar core, rather than being a fossil from an earlier stage in the history of the star, is investigated. It is demonstrated that then the envelope will almost inevitably be in a state of differential rotation. Some simple models are constructed to illustrate the magnitude of the effects on the structure of the envelope and magnetic field. It is found that, for models which are relatively rapidly rotating, a modest differential rotation at the surface of the core may increase considerably the ratio of internal to surface field, but only give rise to a small surface differential rotation. (author)

Metabolic Profiling in Patients with Pneumonia on Intensive Care.

Science.gov (United States)

Antcliffe, David; Jiménez, Beatriz; Veselkov, Kirill; Holmes, Elaine; Gordon, Anthony C

2017-04-01

Clinical features and investigations lack predictive value when diagnosing pneumonia, especially when patients are ventilated and when patients develop ventilator associated pneumonia (VAP). New tools to aid diagnosis are important to improve outcomes. This pilot study examines the potential for metabolic profiling to aid the diagnosis in critical care. In this prospective observational study ventilated patients with brain injuries or pneumonia were recruited in the intensive care unit and serum samples were collected soon after the start of ventilation. Metabolic profiles were produced using 1D 1 H NMR spectra. Metabolic data were compared using multivariate statistical techniques including Principal Component Analysis (PCA) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). We recruited 15 patients with pneumonia and 26 with brain injuries, seven of whom went on to develop VAP. Comparison of metabolic profiles using OPLS-DA differentiated those with pneumonia from those with brain injuries (R 2 Y=0.91, Q 2 Y=0.28, p=0.02) and those with VAP from those without (R 2 Y=0.94, Q 2 Y=0.27, p=0.05). Metabolites that differentiated patients with pneumonia included lipid species, amino acids and glycoproteins. Metabolic profiling shows promise to aid in the diagnosis of pneumonia in ventilated patients and may allow a more timely diagnosis and better use of antibiotics. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Bioavailability and in vivo metabolism of intact glucosinolates

DEFF Research Database (Denmark)

Sørensen, Jens Christian; Frandsen, Heidi Blok; Jensen, Søren Krogh

2016-01-01

Health benefits associated with consumption of cruciferous vegetables have received considerable attention with a hitherto focus on the role and bioactivity of glucosinolate degradation products. We investigated the in vivo metabolism of intact glucosinolates by following their fate in digesta an...

MR spectroscopy in metabolic disorders of the brain

International Nuclear Information System (INIS)

Yilmaz, U.

2017-01-01

Metabolic disorders of the brain often present a particular challenge for the neuroradiologist, since the disorders are rare, changes on conventional MR are often non-specific and there are numerous differential diagnoses for the white substance lesions. As a complementary method to conventional brain MRI, MR spectroscopy may help to reduce the scope of the differential diagnosis. Entities with specific MR spectroscopy patterns are Canavan disease, maple syrup urine disease, nonketotic hyperglycinemia and creatine deficiency. (orig.) [de

Tumor macroenvironment and metabolism.

Science.gov (United States)

Al-Zoughbi, Wael; Al-Zhoughbi, Wael; Huang, Jianfeng; Paramasivan, Ganapathy S; Till, Holger; Pichler, Martin; Guertl-Lackner, Barbara; Hoefler, Gerald

2014-04-01

In this review we introduce the concept of the tumor macroenvironment and explore it in the context of metabolism. Tumor cells interact with the tumor microenvironment including immune cells. Blood and lymph vessels are the critical components that deliver nutrients to the tumor and also connect the tumor to the macroenvironment. Several factors are then released from the tumor itself but potentially also from the tumor microenvironment, influencing the metabolism of distant tissues and organs. Amino acids, and distinct lipid and lipoprotein species can be essential for further tumor growth. The role of glucose in tumor metabolism has been studied extensively. Cancer-associated cachexia is the most important tumor-associated systemic syndrome and not only affects the quality of life of patients with various malignancies but is estimated to be the cause of death in 15%-20% of all cancer patients. On the other hand, systemic metabolic diseases such as obesity and diabetes are known to influence tumor development. Furthermore, the clinical implications of the tumor macroenvironment are explored in the context of the patient's outcome with special consideration for pediatric tumors. Finally, ways to target the tumor macroenvironment that will provide new approaches for therapeutic concepts are described. Copyright © 2014 Elsevier Inc. All rights reserved.

Oxidative stress status, antioxidant metabolism and polypeptide patterns in Juncus maritimus shoots exhibiting differential mercury burdens in Ria de Aveiro coastal lagoon (Portugal).

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Anjum, Naser A; Duarte, Armando C; Pereira, Eduarda; Ahmad, Iqbal

2014-05-01

This study assessed the oxidative stress status, antioxidant metabolism and polypeptide patterns in salt marsh macrophyte Juncus maritimus shoots exhibiting differential mercury burdens in Ria de Aveiro coastal lagoon at reference and the sites with highest, moderate and the lowest mercury contamination. In order to achieve these goals, shoot-mercury burden and the responses of representative oxidative stress indices, and the components of both non-glutathione- and glutathione-based H2O2-metabolizing systems were analyzed and cross-talked with shoot-polypeptide patterns. Compared to the reference site, significant elevations in J. maritimus shoot mercury and the oxidative stress indices such as H2O2, lipid peroxidation, electrolyte leakage and reactive carbonyls were maximum at the site with highest followed by moderate and the lowest mercury contamination. Significantly elevated activity of non-glutathione-based H2O2-metabolizing enzymes such as ascorbate peroxidase and catalase accompanied the studied damage-endpoint responses, whereas the activity of glutathione-based H2O2-scavenging enzymes glutathione peroxidase and glutathione sulfo-transferase was inhibited. Concomitantly, significantly enhanced glutathione reductase activity and the contents of both reduced and oxidized glutathione were perceptible in high mercury-exhibiting shoots. It is inferred that high mercury-accrued elevations in oxidative stress indices were obvious, where non-glutathione-based H2O2-decomposing enzyme system was dominant over the glutathione-based H2O2-scavenging enzyme system. In particular, the glutathione-based H2O2-scavenging system failed to coordinate with elevated glutathione reductase which in turn resulted into increased pool of oxidized glutathione and the ratio of oxidized glutathione-to-reduced glutathione. The substantiation of the studied oxidative stress indices and antioxidant metabolism with approximately 53-kDa polypeptide warrants further studies.

Identification of Discriminating Metabolic Pathways and Metabolites in Human PBMCs Stimulated by Various Pathogenic Agents

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Xiang Zhang

2018-02-01

Full Text Available Immunity and cellular metabolism are tightly interconnected but it is not clear whether different pathogens elicit specific metabolic responses. To address this issue, we studied differential metabolic regulation in peripheral blood mononuclear cells (PBMCs of healthy volunteers challenged by Candida albicans, Borrelia burgdorferi, lipopolysaccharide, and Mycobacterium tuberculosis in vitro. By integrating gene expression data of stimulated PBMCs of healthy individuals with the KEGG pathways, we identified both common and pathogen-specific regulated pathways depending on the time of incubation. At 4 h of incubation, pathogenic agents inhibited expression of genes involved in both the glycolysis and oxidative phosphorylation pathways. In contrast, at 24 h of incubation, particularly glycolysis was enhanced while genes involved in oxidative phosphorylation remained unaltered in the PBMCs. In general, differential gene expression was less pronounced at 4 h compared to 24 h of incubation. KEGG pathway analysis allowed differentiation between effects induced by Candida and bacterial stimuli. Application of genome-scale metabolic model further generated a Candida-specific set of 103 reporter metabolites (e.g., desmosterol that might serve as biomarkers discriminating Candida-stimulated PBMCs from bacteria-stimuated PBMCs. Our analysis also identified a set of 49 metabolites that allowed discrimination between the effects of Borrelia burgdorferi, lipopolysaccharide and Mycobacterium tuberculosis. We conclude that analysis of pathogen-induced effects on PBMCs by a combination of KEGG pathways and genome-scale metabolic model provides deep insight in the metabolic changes coupled to host defense.

From gametogenesis and stem cells to cancer: common metabolic themes.

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Pereira, Sandro L; Rodrigues, Ana Sofia; Sousa, Maria Inês; Correia, Marcelo; Perestrelo, Tânia; Ramalho-Santos, João

2014-01-01

Both pluripotent stem cells (PSCs) and cancer cells have been described as having similar metabolic pathways, most notably a penchant for favoring glycolysis even under aerobiosis, suggesting common themes that might be explored for both stem cell differentiation and anti-oncogenic purposes. A search of the scientific literature available in the PubMed/Medline was conducted for studies on metabolism and mitochondrial function related to gametogenesis, early development, stem cells and cancers in the reproductive system, notably breast, prostate, ovarian and testicular cancers. Both PSCs and some types of cancer cells, particularly reproductive cancers, were found to obtain energy mostly by glycolysis, often reducing mitochondrial activity and oxidative phosphorylation. This strategy links proliferating cells, allowing for the biosynthesis reactions necessary for cell division. Interventions that affect metabolic pathways, and force cells to change their preferences, can lead to shifts in cell status, increasing either pluripotency or differentiation of stem cells, and causing cancer cells to become more or less aggressive. Interestingly metabolic changes in many cases seemed to lead to cell transformation, not necessarily follow it, suggesting a direct role of metabolic choices in influencing the (epi)genetic program of different cell types. There are uncanny similarities between PSCs and cancer cells at the metabolic level. Furthermore, metabolism may also play a direct role in cell status and targeting metabolic pathways could therefore be a promising strategy for both the control of cancer cell proliferation and the regulation of stem cell physiology, in terms of manipulating stem cells toward relevant phenotypes that may be important for tissue engineering, or making cancer cells become less tumorigenic. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For

Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH

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Eric L. Allen

2016-10-01

Full Text Available Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors. These findings highlight an anaplerotic role of aspartate and, more broadly, suggest that differential nutrient utilization patterns can identify subsets of cancers with distinct metabolic dependencies for potential pharmacological intervention.

Rumen microbial communities influence metabolic phenotypes in lambs

DEFF Research Database (Denmark)

Morgavi, Diego P.; Rahahao-Paris, Estelle; Popova, Milka

2015-01-01

and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted...

Highly efficient differentiation of embryonic stem cells into adipocytes by ascorbic acid

OpenAIRE

Ixchelt Cuaranta-Monroy; Zoltan Simandi; Zsuzsanna Kolostyak; Quang-Minh Doan-Xuan; Szilard Poliska; Attila Horvath; Gergely Nagy; Zsolt Bacso; Laszlo Nagy

2014-01-01

Adipocyte differentiation and function have become the major research targets due to the increasing interest in obesity and related metabolic conditions. Although, late stages of adipogenesis have been extensively studied, the early phases remain poorly understood. Here we present that supplementing ascorbic acid (AsA) to the adipogenic differentiation cocktail enables the robust and efficient differentiation of mouse embryonic stem cells (mESCs) to mature adipocytes. Such ESC-derived adipocy...

Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling.

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Wen, Shi; Zhan, Bohan; Feng, Jianghua; Hu, Weize; Lin, Xianchao; Bai, Jianxi; Huang, Heguang

2017-11-02

The differentiation of pancreatic ductal adenocarcinoma (PDAC) could be associated with prognosis and may influence the choices of clinical management. No applicable methods could reliably predict the tumor differentiation preoperatively. Thus, the aim of this study was to compare the metabonomic profiling of pancreatic ductal adenocarcinoma with different differentiations and assess the feasibility of predicting tumor differentiations through metabonomic strategy based on nuclear magnetic resonance spectroscopy. By implanting pancreatic cancer cell strains Panc-1, Bxpc-3 and SW1990 in nude mice in situ, we successfully established the orthotopic xenograft models of PDAC with different differentiations. The metabonomic profiling of serum from different PDAC was achieved and analyzed by using 1 H nuclear magnetic resonance (NMR) spectroscopy combined with the multivariate statistical analysis. Then, the differential metabolites acquired were used for enrichment analysis of metabolic pathways to get a deep insight. An obvious metabonomic difference was demonstrated between all groups and the pattern recognition models were established successfully. The higher concentrations of amino acids, glycolytic and glutaminolytic participators in SW1990 and choline-contain metabolites in Panc-1 relative to other PDAC cells were demonstrated, which may be served as potential indicators for tumor differentiation. The metabolic pathways and differential metabolites identified in current study may be associated with specific pathways such as serine-glycine-one-carbon and glutaminolytic pathways, which can regulate tumorous proliferation and epigenetic regulation. The NMR-based metabonomic strategy may be served as a non-invasive detection method for predicting tumor differentiation preoperatively.

Metabolic Plasticity of Stem Cells and Macrophages in Cancer

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Jelena Krstic

2017-08-01

Full Text Available In addition to providing essential molecules for the overall function of cells, metabolism plays an important role in cell fate and can be affected by microenvironmental stimuli as well as cellular interactions. As a specific niche, tumor microenvironment (TME, consisting of different cell types including stromal/stem cells and immune cells, is characterized by distinct metabolic properties. This review will be focused on the metabolic plasticity of mesenchymal stromal/stem cells (MSC and macrophages in TME, as well as on how the metabolic state of cancer stem cells (CSC, as key drivers of oncogenesis, affects their generation and persistence. Namely, heterogenic metabolic phenotypes of these cell populations, which include various levels of dependence on glycolysis or oxidative phosphorylation are closely linked to their complex roles in cancer progression. Besides well-known extrinsic factors, such as cytokines and growth factors, the differentiation and activation states of CSC, MSC, and macrophages are coordinated by metabolic reprogramming in TME. The significance of mutual metabolic interaction between tumor stroma and cancer cells in the immune evasion and persistence of CSC is currently under investigation.

Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation.

Science.gov (United States)

Taipaleenmäki, Hanna; Bjerre Hokland, Lea; Chen, Li; Kauppinen, Sakari; Kassem, Moustapha

2012-03-01

Osteoblast differentiation and bone formation (osteogenesis) are regulated by transcriptional and post-transcriptional mechanisms. Recently, a novel class of regulatory factors termed micro-RNAs (miRNAs) has been identified as playing an important role in the regulation of many aspects of osteoblast biology including proliferation, differentiation, metabolism and apoptosis. Also, preliminary data from animal disease models suggest that targeting miRNAs in bone can be a novel approach to increase bone mass. This review highlights the current knowledge of miRNA biology and their role in bone formation and discusses their potential use in future therapeutic applications for metabolic bone diseases.

Genetic and metabolic biodiversity of Trichoderma from Colombia and adjacent neotropic regions.

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Hoyos-Carvajal, Lilliana; Orduz, Sergio; Bissett, John

2009-09-01

The genus Trichoderma has been studied for production of enzymes and other metabolites, as well as for exploitation as effective biological control agents. The biodiversity of Trichoderma has seen relatively limited study over much of the neotropical region. In the current study we assess the biodiversity of 183 isolates from Mexico, Guatemala, Panama, Ecuador, Peru, Brazil and Colombia, using morphological, metabolic and genetic approaches. A comparatively high diversity of species was found, comprising 29 taxa: Trichoderma asperellum (60 isolates), Trichoderma atroviride (3), Trichoderma brevicompactum (5), Trichoderma crassum (3), Trichoderma erinaceum (3), Trichoderma gamsii (2), Trichoderma hamatum (2), Trichoderma harzianum (49), Trichoderma koningiopsis (6), Trichoderma longibrachiatum (3), Trichoderma ovalisporum (1), Trichoderma pubescens (2), Trichoderma rossicum (4), Trichoderma spirale (1), Trichoderma tomentosum (3), Trichoderma virens (8), Trichoderma viridescens (7) and Hypocrea jecorina (3) (anamorph: Trichoderma reesei), along with 11 currently undescribed species. T. asperellum was the prevalent species and was represented by two distinct genotypes with different metabolic profiles and habitat preferences. The second predominant species, T. harzianum, was represented by three distinct genotypes. The addition of 11 currently undescribed species is evidence of the considerable unresolved biodiversity of Trichoderma in neotropical regions. Sequencing of the internal transcribed spacer regions (ITS) of the ribosomal repeat could not differentiate some species, and taken alone gave several misidentifications in part due to the presence of nonorthologous copies of the ITS in some isolates.

Troglitazone induces differentiation in Trypanosoma brucei

International Nuclear Information System (INIS)

Denninger, Viola; Figarella, Katherine; Schoenfeld, Caroline; Brems, Stefanie; Busold, Christian; Lang, Florian; Hoheisel, Joerg; Duszenko, Michael

2007-01-01

Trypanosoma brucei, a protozoan parasite causing sleeping sickness, is transmitted by the tsetse fly and undergoes a complex lifecycle including several defined stages within the insect vector and its mammalian host. In the latter, differentiation from the long slender to the short stumpy form is induced by a yet unknown factor of trypanosomal origin. Here we describe that some thiazolidinediones are also able to induce differentiation. In higher eukaryotes, thiazolidinediones are involved in metabolism and differentiation processes mainly by binding to the intracellular receptor peroxisome proliferator activated receptor γ. Our studies focus on the effects of troglitazone on bloodstream form trypanosomes. Differentiation was monitored using mitochondrial markers (membrane potential, succinate dehydrogenase activity, inhibition of oxygen uptake by KCN, amount of cytochrome transcripts), morphological changes (Transmission EM and light microscopy), and transformation experiments (loss of the Variant Surface Glycoprotein coat and increase of dihydroliponamide dehydrogenase activity). To further investigate the mechanisms responsible for these changes, microarray analyses were performed, showing an upregulation of expression site associated gene 8 (ESAG8), a potential differentiation regulator

Studies of liver-specific metabolic reactions with /sup 15/N. 1. Metabolism of /sup 15/N-ammonium chloride in pigs

Energy Technology Data Exchange (ETDEWEB)

Hirschberg, K; Jung, K; Faust, H; Matkowitz, R

1987-07-01

The /sup 15/N tracer technique was used to investigate liver-specific reactions (urea and hippurate synthesis) for studying the metabolism in the healthy and damaged pig liver. After (/sup 15/N)ammonium chloride administration the tracer distribution on non-protein compounds of serum and urine was followed. Blood samplings before and after liver passage rendered possible a direct analysis of the (/sup 15/N)ammonium metabolism. The thioacetamide-induced liver damage was used as model for an acute liver intoxication. The capacity for urea synthesis was not influenced by means of this noxious substance, but the metabolism of amino acids and hippuric acid. The considerably depressed excretion of (/sup 15/N)hippurate seems to be a suitable indicator of liver disfunction.

Differential CT Attenuation of Metabolically Active and Inactive Adipose Tissues — Preliminary Findings

Science.gov (United States)

Hu, Houchun H.; Chung, Sandra A.; Nayak, Krishna S.; Jackson, Hollie A.; Gilsanz, Vicente

2010-01-01

This study investigates differences in CT Hounsfield units (HUs) between metabolically active (brown fat) and inactive adipose tissues (white fat) due to variations in their densities. PET/CT data from 101 pediatric and adolescent patients were analyzed. Regions of metabolically active and inactive adipose tissues were identified and standard uptake values (SUVs) and HUs were measured. HUs of active brown fat were more positive (p<0.001) than inactive fat (−62.4±5.3 versus −86.7±7.0) and the difference was observed in both males and females. PMID:21245691

Differential expression analysis of genic male sterility by cDNA-AFLP in maize

International Nuclear Information System (INIS)

Zhang Linbi; Rong Tingzhao; Pan Guangtang; Cao Moju

2009-01-01

The differential expression of male sterility induced by space flight with male fertility was studied using cDNA-AFLP technology. Total RNA was isolated from anther of male sterility and male fertility. Nine differential expression cDNA fragments were obtained with 16 primer combinations. The differential cDNA fragments were eluted, cloned and sequenced. Then half-quantitative RT-PCR was used to stuy the differential expressions of 4 development stages between sterility and fertility. Sequencing analysis shown 2 fragments from male sterility might be novel genes. Four fragments from male fertility were homology as chalcone and stilbene synthases, putative acyl CoA dehydrogenase, putative protein kinases and putative glycine decarboxylase. All these proteins might participate in the energy metabolisms, substance metabolisms or signal pollen development, Z8 took on increasing expression during the middle period of pollen development. These results just met the demand of more energy and more substance during the pollen development. (authors)

T2 black lesions on routine knee MRI: differential considerations

International Nuclear Information System (INIS)

Wadhwa, Vibhor; Cho, Gina; Moore, Daniel; Pezeshk, Parham; Coyner, Katherine; Chhabra, Avneesh

2016-01-01

The majority of abnormal findings or lesions on T2-weighted fast spin-echo (FSE) magnetic resonance imaging (MRI) are hyperintense due to increased perfusion or fluid content, such as infections, tumours or synovitis. Hypointense lesions on T2-weighted images (both fat-suppressed and non-fat-suppressed) are less common and can sometimes be overlooked. Such lesions have limited differential diagnostic possibilities, and include vacuum phenomenon, loose body, tenosynovial giant cell tumour, rheumatoid arthritis, haemochromatosis, gout, amyloid, chondrocalcinosis, hydroxyapetite deposition disease, lipoma arborescens, arthrofibrosis and iatrogenic lesions. These lesions often show characteristic appearances and predilections in the knee. In this article, the authors describe the MRI features of hypointense T2 lesions on routine knee MRI and outline a systematic diagnostic approach towards their evaluation. (orig.)

Urinary Metabolite Profiling Offers Potential for Differentiation of Liver-Kidney Yin Deficiency and Dampness-Heat Internal Smoldering Syndromes in Posthepatitis B Cirrhosis Patients

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Xiaoning Wang

2015-01-01

Full Text Available Zheng is the basic theory and essence of traditional Chinese medicine (TCM in diagnosing diseases. However, there are no biological evidences to support TCM Zheng differentiation. In this study we elucidated the biological alteration of cirrhosis with TCM “Liver-Kidney Yin Deficiency (YX” or “Dampness-Heat Internal Smoldering (SR” Zheng and the potential of urine metabonomics in TCM Zheng differentiation. Differential metabolites contributing to the intergroup variation between healthy controls and liver cirrhosis patients were investigated, respectively, and mainly participated in energy metabolism, gut microbiota metabolism, oxidative stress, and bile acid metabolism. Three metabolites, aconitate, citrate, and 2-pentendioate, altered significantly in YX Zheng only, representing the abnormal energy metabolism. Contrarily, hippurate and 4-pyridinecarboxylate altered significantly in SR Zheng only, representing the abnormalities of gut microbiota metabolism. Moreover, there were significant differences between two TCM Zhengs in three metabolites, glycoursodeoxycholate, cortolone-3-glucuronide, and L-aspartyl-4-phosphate, among all differential metabolites. Metabonomic profiling, as a powerful approach, provides support to the understanding of biological mechanisms of TCM Zheng stratification. The altered urinary metabolites constitute a panel of reliable biological evidence for TCM Zheng differentiation in patients with posthepatitis B cirrhosis and may be used for the potential biomarkers of TCM Zheng stratification.

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments.

Science.gov (United States)

Srivastava, Anubhav; Philip, Nisha; Hughes, Katie R; Georgiou, Konstantina; MacRae, James I; Barrett, Michael P; Creek, Darren J; McConville, Malcolm J; Waters, Andrew P

2016-12-01

Malaria parasites (Plasmodium spp.) encounter markedly different (nutritional) environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA) metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design.

Stage-Specific Changes in Plasmodium Metabolism Required for Differentiation and Adaptation to Different Host and Vector Environments.

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Anubhav Srivastava

2016-12-01

Full Text Available Malaria parasites (Plasmodium spp. encounter markedly different (nutritional environments during their complex life cycles in the mosquito and human hosts. Adaptation to these different host niches is associated with a dramatic rewiring of metabolism, from a highly glycolytic metabolism in the asexual blood stages to increased dependence on tricarboxylic acid (TCA metabolism in mosquito stages. Here we have used stable isotope labelling, targeted metabolomics and reverse genetics to map stage-specific changes in Plasmodium berghei carbon metabolism and determine the functional significance of these changes on parasite survival in the blood and mosquito stages. We show that glutamine serves as the predominant input into TCA metabolism in both asexual and sexual blood stages and is important for complete male gametogenesis. Glutamine catabolism, as well as key reactions in intermediary metabolism and CoA synthesis are also essential for ookinete to oocyst transition in the mosquito. These data extend our knowledge of Plasmodium metabolism and point towards possible targets for transmission-blocking intervention strategies. Furthermore, they highlight significant metabolic differences between Plasmodium species which are not easily anticipated based on genomics or transcriptomics studies and underline the importance of integration of metabolomics data with other platforms in order to better inform drug discovery and design.

New peptides players in metabolic disorders

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Agata Mierzwicka

2016-08-01

Full Text Available Among new peptides responsible for the pathogenesis of metabolic disorders and carbohydrate metabolism, adipokines are of great importance. Adipokines are substances of hormonal character, secreted by adipose tissue. Apart from the well-known adipokines, adropin and preptin are relatively newly discovered, hence their function is not fully understood. They are peptides not secreted by adipose tissue but their role in the metabolic regulations seems to be significant. Preptin is a 34-amino acid peptide, a derivative of proinsulin growth factor II (pro-IGF-II, secreted by pancreatic β cells, considered to be a physiological enhancer of insulin secretion. Additionally, preptin has a stimulating effect on osteoblasts, inducing their proliferation, differentiation and survival. Adropin is a 76-amino acid peptide, encoded by the energy homeostasis associated gene (Enho, mainly in liver and brain, and its expression is dependent on a diet. Adropin is believed to play an important role in metabolic homeostasis, fatty acids metabolism control, insulin resistance prevention, dyslipidemia, and impaired glucose tolerance. The results of studies conducted so far show that the diseases resulting from metabolic syndrome, such as obesity, type 2 diabetes mellitus, polycystic ovary syndrome, non-alcoholic fatty liver disease, or cardiovascular disease are accompanied by significant changes in the concentration of these peptides. It is also important to note that preptin has an anabolic effect on bone tissue, which might be preventive in osteoporosis.

Protein Profiling of Plastoglobules in Chloroplasts and Chromoplasts. A Surprising Site for Differential Accumulation of Metabolic Enzymes1[W

Science.gov (United States)

Ytterberg, A. Jimmy; Peltier, Jean-Benoit; van Wijk, Klaas J.

2006-01-01

Plastoglobules (PGs) are oval or tubular lipid-rich structures present in all plastid types, but their specific functions are unclear. PGs contain quinones, α-tocopherol, and lipids and, in chromoplasts, carotenoids as well. It is not known whether PGs contain any enzymes or regulatory proteins. Here, we determined the proteome of PGs from chloroplasts of stressed and unstressed leaves of Arabidopsis (Arabidopsis thaliana) as well as from pepper (Capsicum annuum) fruit chromoplasts using mass spectrometry. Together, this showed that the proteome of chloroplast PGs consists of seven fibrillins, providing a protein coat and preventing coalescence of the PGs, and an additional 25 proteins likely involved in metabolism of isoprenoid-derived molecules (quinines and tocochromanols), lipids, and carotenoid cleavage. Four unknown ABC1 kinases were identified, possibly involved in regulation of quinone monooxygenases. Most proteins have not been observed earlier but have predicted N-terminal chloroplast transit peptides and lack transmembrane domains, consistent with localization in the PG lipid monolayer particles. Quantitative differences in PG composition in response to high light stress and degreening were determined by differential stable-isotope labeling using formaldehyde. More than 20 proteins were identified in the PG proteome of pepper chromoplasts, including four enzymes of carotenoid biosynthesis and several homologs of proteins observed in the chloroplast PGs. Our data strongly suggest that PGs in chloroplasts form a functional metabolic link between the inner envelope and thylakoid membranes and play a role in breakdown of carotenoids and oxidative stress defense, whereas PGs in chromoplasts are also an active site for carotenoid conversions. PMID:16461379

Differential interaction of hGDH1 and hGDH2 with manganese: Implications for metabolism and toxicity.

Science.gov (United States)

Dimovasili, Christina; Aschner, Michael; Plaitakis, Andreas; Zaganas, Ioannis

2015-09-01

Manganese (Mn) is an essential trace element that serves as co-factor for many important mammalian enzymes. In humans, the importance of this cation is highlighted by the fact that low levels of Mn cause developmental and metabolic abnormalities and, on the other hand, chronic exposure to excessive amounts of Mn is characterized by neurotoxicity, possibly mediated by perturbation of astrocytic mitochondrial energy metabolism. Here we sought to study the effect of Mn on the two human glutamate dehydrogenases (hGDH1 and hGDH2, respectively), key mitochondrial enzymes involved in numerous cellular processes, including mitochondrial metabolism, glutamate homeostasis and neurotransmission, and cell signaling. Our studies showed that, compared to magnesium (Mg) and calcium (Ca), Mn exerted a significant inhibitory effect on both human isoenzymes with hGDH2 being more sensitive than hGDH1, especially under conditions of low ADP levels. Specifically, in the presence of 0.25 mM ADP, the Mn IC50 was 1.14 ± 0.02 mM and 1.54 ± 0.08 mM for hGDH2 and for hGDH1, respectively (p = 0.0001). Increasing Mn levels potentiated this differential effect, with 3 mM Mn inhibiting hGDH2 by 96.5% and hGDH1 by 70.2%. At 1 mM ADP, the Mn IC50 was 1.84 ± 0.02 mM and 2.04 ± 0.07 mM (p = 0.01) for hGDH2 and hGDH1, respectively, with 3 mM Mn inhibiting hGDH2 by 93.6% and hGDH1 by 70.9%. These results were due to the sigmoidal inhibitory curve of Mn that was more pronounced for hGDH2 than for hGDH1. Indeed, at 0.25 mM, the Hill coefficient value was higher for hGDH2 (3.42 ± 0.20) than for hGDH1 (1.94 ± 0.25; p = 0.0002) indicating that interaction of Mn with hGDH2 was substantially more co-operative than for hGDH1. These findings, showing an enhanced sensitivity of the hGDH2 isoenzyme to Mn, especially at low ADP levels, might be of pathophysiological relevance under conditions of Mn neurotoxicity. Copyright © 2015 Elsevier Ltd. All

Actin depolymerization enhances adipogenic differentiation in human stromal stem cells

DEFF Research Database (Denmark)

Chen, Li; Hu, Huimin; Qiu, Weimin

2018-01-01

Human stromal stem cells (hMSCs) differentiate into adipocytes that play a role in skeletal tissue homeostasis and whole body energy metabolism. During adipocyte differentiation, hMSCs exhibit significant changes in cell morphology suggesting changes in cytoskeletal organization. Here, we examined...... the effect of direct modulation of actin microfilament dynamics on adipocyte differentiation. Stabilizing actin filaments in hMSCs by siRNA-mediated knock down of the two main actin depolymerizing factors (ADFs): Cofilin 1 (CFL1) and Destrin (DSTN) or treating the cells by Phalloidin reduced adipocyte...

Cerebellar involvement in metabolic disorders: a pattern-recognition approach

International Nuclear Information System (INIS)

Steinlin, M.; Boltshauser, E.; Blaser, S.

1998-01-01

Inborn errors of metabolism can affect the cerebellum during development, maturation and later during life. We have established criteria for pattern recognition of cerebellar abnormalities in metabolic disorders. The abnormalities can be divided into four major groups: cerebellar hypoplasia (CH), hyperplasia, cerebellar atrophy (CA), cerebellar white matter abnormalities (WMA) or swelling, and involvement of the dentate nuclei (DN) or cerebellar cortex. CH can be an isolated typical finding, as in adenylsuccinase deficiency, but is also occasionally seen in many other disorders. Differentiation from CH and CA is often difficult, as in carbohydrate deficient glycoprotein syndrome or 2-l-hydroxyglutaric acidaemia. In cases of atrophy the relationship of cerebellar to cerebral atrophy is important. WMA may be diffuse or patchy, frequently predominantly around the DN. Severe swelling of white matter is present during metabolic crisis in maple syrup urine disease. The DN can be affected by metabolite deposition, necrosis, calcification or demyelination. Involvement of cerebellar cortex is seen in infantile neuroaxonal dystrophy. Changes in DN and cerebellar cortex are rather typical and therefore most helpful; additional features should be sought as they are useful in narrowing down the differential diagnosis. (orig.)

The glycogen metabolism via Akt signaling is important for the secretion of enamel matrix in tooth development.

Science.gov (United States)

Ida-Yonemochi, Hiroko; Otsu, Keishi; Ohshima, Hayato; Harada, Hidemitsu

2016-02-01

Cells alter their energy metabolism depending on the stage of differentiation or various environments. In the ameloblast differentiation of continuous growing mouse incisors, we found temporary glycogen storage in preameloblasts before the start of enamel matrix secretion and investigated the relationship between enamel matrix secretion and glycogen metabolism. Immunohistochemistry showed that in the transitional stage from preameloblasts to secretory ameloblasts, the glycogen synthase changed from the inactive form to the active form, the expression of glycogen phosphorylase increased, and further, the levels of IGF-1, IGF-1 receptor and activated Akt increased. These results suggested that the activation of Akt signaling via IGF is linked to the onset of both glycogen metabolism and enamel matrix deposition. In the experiments using organ culture and ameloblast cell line, the activation of Akt signaling by IGF-1 stimulated glycogen metabolism through the up-regulation of Glut-1,-4 and Gsk-3β and the dephosphorylation of glycogen synthase. Subsequently, they resulted in increased enamel matrix secretion. In contrast, some inhibitors of Akt signals and glycogen synthesis/degradation down-regulated enamel matrix secretion. Taking these findings together, glycogen metabolism via Akt signaling is an essential system for the secretion of enamel matrix in ameloblast differentiation. Copyright © 2016 Elsevier B.V. All rights reserved.

Sirt6 regulates postnatal growth plate differentiation and proliferation via Ihh signaling.

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Piao, Jinying; Tsuji, Kunikazu; Ochi, Hiroki; Iwata, Munetaka; Koga, Daisuke; Okawa, Atsushi; Morita, Sadao; Takeda, Shu; Asou, Yoshinori

2013-10-23

Sirtuin 6 (Sirt6) is a mammalian homologue of NAD⁺-dependent histone deacetylase Sir2. Although Sirt6⁻/⁻ mice exhibit growth retardation, the role of Sirt6 in cartilage metabolism is unclear. The aim of this study was to investigate the Sirt6 signaling pathway in cartilage metabolism. Immunohistological evaluation of the tibial growth plate in Sirt6⁻/⁻ mice exhibited impaired proliferation and differentiation of chondrocytes, reduced expression of Indian hedgehog (Ihh), and a senescent phenotype. When Sirt6 was knocked down in chondrocytes in vitro, expression of Ihh and its downstream genes were reduced. Impaired differentiation by Sirt6 silencing was completely rescued by administration of a Hh signal agonist. When sirtuins were activated, chondrocyte differentiation was enhanced together with activation of Ihh signal, and these effects were abrogated by Sirt6 silencing. ChIP assay revealed the affinity of ATF4 to the Ihh promoter was markedly decreased by Sirt6 knockdown. These data indicate Sirt6 directly controls proliferation and differentiation of chondrocytes.

Actin depolymerization enhances adipogenic differentiation in human stromal stem cells

DEFF Research Database (Denmark)

Chen, Li; Hu, Huimin; Qiu, Weimin

2018-01-01

Human stromal stem cells (hMSCs) differentiate into adipocytes that play a role in skeletal tissue homeostasis and whole body energy metabolism. During adipocyte differentiation, hMSCs exhibit significant changes in cell morphology suggesting changes in cytoskeletal organization. Here, we examined...... differentiation as evidenced by decreased number of mature adipocytes and decreased adipocyte specific gene expression (ADIPOQ, LPL, PPARG, FABP4). In contrast, disruption of actin cytoskeleton by Cytochalasin D enhanced adipocyte differentiation. Follow up studies revealed that the effects of CFL1 on adipocyte...... differentiation depended on the activity of LIM domain kinase 1 (LIMK1) which is the major upstream kinase of CFL1. Inhibiting LIMK by its specific chemical inhibitor LIMKi inhibited the phosphorylation of CFL1 and actin polymerization, and enhanced the adipocyte differentiation. Moreover, treating h...

Large-scale transcriptome analysis reveals arabidopsis metabolic pathways are frequently influenced by different pathogens.

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Jiang, Zhenhong; He, Fei; Zhang, Ziding

2017-07-01

Through large-scale transcriptional data analyses, we highlighted the importance of plant metabolism in plant immunity and identified 26 metabolic pathways that were frequently influenced by the infection of 14 different pathogens. Reprogramming of plant metabolism is a common phenomenon in plant defense responses. Currently, a large number of transcriptional profiles of infected tissues in Arabidopsis (Arabidopsis thaliana) have been deposited in public databases, which provides a great opportunity to understand the expression patterns of metabolic pathways during plant defense responses at the systems level. Here, we performed a large-scale transcriptome analysis based on 135 previously published expression samples, including 14 different pathogens, to explore the expression pattern of Arabidopsis metabolic pathways. Overall, metabolic genes are significantly changed in expression during plant defense responses. Upregulated metabolic genes are enriched on defense responses, and downregulated genes are enriched on photosynthesis, fatty acid and lipid metabolic processes. Gene set enrichment analysis (GSEA) identifies 26 frequently differentially expressed metabolic pathways (FreDE_Paths) that are differentially expressed in more than 60% of infected samples. These pathways are involved in the generation of energy, fatty acid and lipid metabolism as well as secondary metabolite biosynthesis. Clustering analysis based on the expression levels of these 26 metabolic pathways clearly distinguishes infected and control samples, further suggesting the importance of these metabolic pathways in plant defense responses. By comparing with FreDE_Paths from abiotic stresses, we find that the expression patterns of 26 FreDE_Paths from biotic stresses are more consistent across different infected samples. By investigating the expression correlation between transcriptional factors (TFs) and FreDE_Paths, we identify several notable relationships. Collectively, the current study

Comparison of metabolic ratios of urinary estrogens between benign and malignant thyroid tumors in postmenopausal women

Science.gov (United States)

2013-01-01

Background Estrogen metabolism may be associated with the pathophysiological development of papillary thyroid carcinoma (PTC). Methods To evaluate the differential estrogen metabolism between benign and malignant PTCs, estrogen profiling by gas chromatography–mass spectrometry was applied to urine samples from postmenopausal patients with 9 benign tumors and 18 malignant stage I and III/IV PTCs. Results The urinary concentration of 2-methoxyestradiol was significantly lower in the stage I malignant patients (3.5-fold; P 3.5-fold difference; P < 0.002). In particular, the estriol/16α-OH-estrone ratio differentiated between the benign and early-stage malignant patients (P < 0.01). Conclusions Increased 16α-hydroxylation and/or a decreased 2-/16α-ratio, as well increased reductive 17β-HSD, with regard to estrogen metabolism could provide potential biomarkers. The devised profiles could be useful for differentiating malignant thyroid carcinomas from benign adenomas in postmenopausal women. PMID:24156385

Differential metabolic rates in prefrontal and temporal Brodmann areas in schizophrenia and schizotypal personality disorder.

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Buchsbaum, Monte S; Nenadic, Igor; Hazlett, Erin A; Spiegel-Cohen, Jacqueline; Fleischman, Michael B; Akhavan, Arash; Silverman, Jeremy M; Siever, Larry J

2002-03-01

In an exploration of the schizophrenia spectrum, we compared cortical metabolic rates in unmedicated patients with schizophrenia and schizotypal personality disorder (SPD) with findings in age- and sex-matched normal volunteers. Coregistered magnetic resonance imaging (MRI) and positron emission tomography (PET) scans were obtained in 27 schizophrenic, 13 SPD, and 32 normal volunteers who performed a serial verbal learning test during tracer uptake. A template of Brodmann areas derived from a whole brain histological section atlas was used to analyze PET findings. Significantly lower metabolic rates were found in prefrontal areas 44-46 in schizophrenic patients than in normal volunteers. SPD patients did not differ from normal volunteers in most lateral frontal regions, but they had values intermediate between those of normal volunteers and schizophrenic patients in lateral temporal regions. SPD patients showed higher than normal metabolic rates in both medial frontal and medial temporal areas. Metabolic rates in Brodmann area 10 were distinctly higher in SPD patients than in either normal volunteers or schizophrenic patients.

Metabolic diversity of the heterotrophic microorganisms and potential link to pollution of the Rouge River

International Nuclear Information System (INIS)

Tiquia, S.M.

2010-01-01

The heterotrophic microbial communities of the Rouge River were tracked using Biolog Ecoplates to understand the metabolic diversity at different temporal and spatial scales, and potential link to river pollution. Site less impacted by anthrophogenic sources (site 1), showed markedly lower metabolic diversity. The only substrates that were utilized in the water samples were carbohydrates. Sites more impacted by anthrophogenic sources (sites 8 and 9) showed higher metabolic diversity. Higher functional diversity was linked to the physico-chemical and biological properties of the water samples (i.e. higher concentrations of DO, DOC, chlorophyll, and bacterial density). Biolog analysis was found to be useful in differentiating metabolic diversity between microbial communities; in determining factors that most influence the separation of communities; and in identifying which substrates were most utilized by the communities. It can also be used as an effective ecological indicator of changes in river function attributable to urbanization and pollution. - BIOLOG differentiated metabolic diversity between microbial communities and can be used as ecological indicator of river function attributable to urbanization and pollution.

Metabolic diversity of the heterotrophic microorganisms and potential link to pollution of the Rouge River

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Tiquia, S.M., E-mail: smtiquia@umd.umich.ed [Department of Natural Sciences, University of Michigan, 115F Science Building, Dearborn, MI 48128 (United States)

2010-05-15

The heterotrophic microbial communities of the Rouge River were tracked using Biolog Ecoplates to understand the metabolic diversity at different temporal and spatial scales, and potential link to river pollution. Site less impacted by anthrophogenic sources (site 1), showed markedly lower metabolic diversity. The only substrates that were utilized in the water samples were carbohydrates. Sites more impacted by anthrophogenic sources (sites 8 and 9) showed higher metabolic diversity. Higher functional diversity was linked to the physico-chemical and biological properties of the water samples (i.e. higher concentrations of DO, DOC, chlorophyll, and bacterial density). Biolog analysis was found to be useful in differentiating metabolic diversity between microbial communities; in determining factors that most influence the separation of communities; and in identifying which substrates were most utilized by the communities. It can also be used as an effective ecological indicator of changes in river function attributable to urbanization and pollution. - BIOLOG differentiated metabolic diversity between microbial communities and can be used as ecological indicator of river function attributable to urbanization and pollution.

BCAA Metabolism and NH3 Homeostasis.

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Conway, M E; Hutson, S M

2016-01-01

The branched chain amino acids (BCAA) are essential amino acids required not only for growth and development, but also as nutrient signals and as nitrogen donors to neurotransmitter synthesis and glutamate/glutamine cycling. Transamination and oxidative decarboxylation of the BCAAs are catalysed by the branched-chain aminotransferase proteins (BCATm, mitochondrial and BCATc, cytosolic) and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively. These proteins show tissue, cell compartmentation, and protein-protein interactions, which call for substrate shuttling or channelling and nitrogen transfer for oxidation to occur. Efficient regulation of these pathways is mediated through the redox environment and phosphorylation in response to dietary and hormonal stimuli. The wide distribution of these proteins allows for effective BCAA utilisation. We discuss how BCAT, BCKDC, and glutamate dehydrogenase operate in supramolecular complexes, allowing for efficient channelling of substrates. The role of BCAAs in brain metabolism is highlighted in rodent and human brain, where differential expression of BCATm indicates differences in nitrogen metabolism between species. Finally, we introduce a new role for BCAT, where a change in function is triggered by oxidation of its redox-active switch. Our understanding of how BCAA metabolism and nitrogen transfer is regulated is important as many studies now point to BCAA metabolic dysregulation in metabolic and neurodegenerative conditions.

Data set of interactomes and metabolic pathways of proteins differentially expressed in brains with Alzheimer׳s disease

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Benito Minjarez

2016-06-01

Full Text Available Alzheimer׳s disease is one of the main causes of dementia in the elderly and its frequency is on the rise worldwide. It is considered the result of complex interactions between genetic and environmental factors, being many of them unknown. Therefore, there is a dire necessity for the identification of novel molecular players for the understanding of this disease. In this data article we determined the protein expression profiles of whole protein extracts from cortex regions of brains from patients with Alzheimer׳s disease in comparison to a normal brain. We identified 721 iTRAQ-labeled polypeptides with more than 95% in confidence. We analyzed all proteins that changed in their expression level and located them in the KEGG metabolic pathways, as well as in the mitochondrial complexes of the electron transport chain and ATP synthase. In addition, we analyzed the over- and sub-expressed polypeptides through IPA software, specifically Core I and Biomarkers I modules. Data in this article is related to the research article “Identification of proteins that are differentially expressed in brains with Alzheimer’s disease using iTRAQ labeling and tandem mass spectrometry” (Minjarez et al., 2016 [1].

Long Non-Coding RNAs Associated with Metabolic Traits in Human White Adipose Tissue

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Hui Gao

2018-04-01

Full Text Available Long non-coding RNAs (lncRNAs belong to a recently discovered class of molecules proposed to regulate various cellular processes. Here, we systematically analyzed their expression in human subcutaneous white adipose tissue (WAT and found that a limited set was differentially expressed in obesity and/or the insulin resistant state. Two lncRNAs herein termed adipocyte-specific metabolic related lncRNAs, ASMER-1 and ASMER-2 were enriched in adipocytes and regulated by both obesity and insulin resistance. Knockdown of either ASMER-1 or ASMER-2 by antisense oligonucleotides in in vitro differentiated human adipocytes revealed that both genes regulated adipogenesis, lipid mobilization and adiponectin secretion. The observed effects could be attributed to crosstalk between ASMERs and genes within the master regulatory pathways for adipocyte function including PPARG and INSR. Altogether, our data demonstrate that lncRNAs are modulators of the metabolic and secretory functions in human fat cells and provide an emerging link between WAT and common metabolic conditions. Keywords: White adipose tissue, Adipocytes, Long non-coding RNAs, Metabolic traits, Lipolysis, Adiponectin

Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

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Chichger, Havovi; Cleasby, Mark E; Srai, Surjit K; Unwin, Robert J; Debnam, Edward S; Marks, Joanne

2016-06-01

What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC

Characterization of differential cocaine metabolism in mouse and rat through metabolomics-guided metabolite profiling.

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Yao, Dan; Shi, Xiaolei; Wang, Lei; Gosnell, Blake A; Chen, Chi

2013-01-01

Rodent animal models have been widely used for studying neurologic and toxicological events associated with cocaine abuse. It is known that the mouse is more susceptible to cocaine-induced hepatotoxicity (CIH) than the rat. However, the causes behind this species-dependent sensitivity to cocaine have not been elucidated. In this study, cocaine metabolism in the mouse and rat was characterized through LC-MS-based metabolomic analysis of urine samples and were further compared through calculating the relative abundance of individual cocaine metabolites. The results showed that the levels of benzoylecgonine, a major cocaine metabolite from ester hydrolysis, were comparable in the urine from the mice and rats treated with the same dose of cocaine. However, the levels of the cocaine metabolites from oxidative metabolism, such as N-hydroxybenzoylnorecgonine and hydroxybenzoylecgonine, differed dramatically between the two species, indicating species-dependent cocaine metabolism. Subsequent structural analysis through accurate mass analysis and LC-MS/MS fragmentation revealed that N-oxidation reactions, including N-demethylation and N-hydroxylation, are preferred metabolic routes in the mouse, while extensive aryl hydroxylation reactions occur in the rat. Through stable isotope tracing and in vitro enzyme reactions, a mouse-specific α-glucoside of N-hydroxybenzoylnorecgonine and a group of aryl hydroxy glucuronides high in the rat were identified and structurally elucidated. The differences in the in vivo oxidative metabolism of cocaine between the two rodent species were confirmed by the in vitro microsomal incubations. Chemical inhibition of P450 enzymes further revealed that different P450-mediated oxidative reactions in the ecgonine and benzoic acid moieties of cocaine contribute to the species-dependent biotransformation of cocaine.

Effects of Different Exercise Modes on the Urinary Metabolic Fingerprint of Men with and without Metabolic Syndrome.

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Siopi, Aikaterina; Deda, Olga; Manou, Vasiliki; Kellis, Spyros; Kosmidis, Ioannis; Komninou, Despina; Raikos, Nikolaos; Christoulas, Kosmas; Theodoridis, Georgios A; Mougios, Vassilis

2017-01-26

Exercise is important in the prevention and treatment of the metabolic syndrome (MetS), a cluster of risk factors that raises morbidity. Metabolomics can facilitate the optimization of exercise prescription. This study aimed to investigate whether the response of the human urinary metabolic fingerprint to exercise depends on the presence of MetS or exercise mode. Twenty-three sedentary men (MetS, n = 9, and Healthy, n = 14) completed four trials: resting, high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE). Urine samples were collected pre-exercise and at 2, 4, and 24 h for targeted analysis by liquid chromatography-mass spectrometry. Time exerted the strongest differentiating effect, followed by exercise mode and health status. The greatest changes were observed in the first post-exercise samples, with a gradual return to baseline at 24 h. RE caused the greatest responses overall, followed by HIIE, while CME had minimal effect. The metabolic fingerprints of the two groups were separated at 2 h, after HIIE and RE; and at 4 h, after HIIE, with evidence of blunted response to exercise in MetS. Our findings show diverse responses of the urinary metabolic fingerprint to different exercise modes in men with and without metabolic syndrome.

Effects of Different Exercise Modes on the Urinary Metabolic Fingerprint of Men with and without Metabolic Syndrome

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Aikaterina Siopi

2017-01-01

Full Text Available Exercise is important in the prevention and treatment of the metabolic syndrome (MetS, a cluster of risk factors that raises morbidity. Metabolomics can facilitate the optimization of exercise prescription. This study aimed to investigate whether the response of the human urinary metabolic fingerprint to exercise depends on the presence of MetS or exercise mode. Twenty-three sedentary men (MetS, n = 9, and Healthy, n = 14 completed four trials: resting, high-intensity interval exercise (HIIE, continuous moderate-intensity exercise (CME, and resistance exercise (RE. Urine samples were collected pre-exercise and at 2, 4, and 24 h for targeted analysis by liquid chromatography-mass spectrometry. Time exerted the strongest differentiating effect, followed by exercise mode and health status. The greatest changes were observed in the first post-exercise samples, with a gradual return to baseline at 24 h. RE caused the greatest responses overall, followed by HIIE, while CME had minimal effect. The metabolic fingerprints of the two groups were separated at 2 h, after HIIE and RE; and at 4 h, after HIIE, with evidence of blunted response to exercise in MetS. Our findings show diverse responses of the urinary metabolic fingerprint to different exercise modes in men with and without metabolic syndrome.

Obesity-driven gut microbiota inflammatory pathways to metabolic syndrome

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Luiz Henrique Agra eCavalcante-Silva

2015-11-01

Full Text Available The intimate interplay between immune system, metabolism and gut microbiota plays an important role in controlling metabolic homeostasis and possible obesity development. Obesity involves impairment of immune response affecting both innate and adaptive immunity. The main factors involved in the relationship of obesity with inflammation have not been completely elucidated. On the other hand, gut microbiota, via innate immune receptors, has emerged as one of the key factors regulating events triggering acute inflammation associated with obesity and metabolic syndrome. Inflammatory disorders lead to several signalling transduction pathways activation, inflammatory cytokine, chemokine production and cell migration, which in turn cause metabolic dysfunction. Inflamed adipose tissue, with increased macrophages infiltration, is associated with impaired preadipocyte development and differentiation to mature adipose cells, leading to ectopic lipid accumulation and insulin resistance. This review focuses on the relationship between obesity and inflammation, which is essential to understand the pathological mechanisms governing metabolic syndrome.

Transcriptome Analysis of Three Sheep Intestinal Regions reveals Key Pathways and Hub Regulatory Genes of Large Intestinal Lipid Metabolism.

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Chao, Tianle; Wang, Guizhi; Ji, Zhibin; Liu, Zhaohua; Hou, Lei; Wang, Jin; Wang, Jianmin

2017-07-13

The large intestine, also known as the hindgut, is an important part of the animal digestive system. Recent studies on digestive system development in ruminants have focused on the rumen and the small intestine, but the molecular mechanisms underlying sheep large intestine metabolism remain poorly understood. To identify genes related to intestinal metabolism and to reveal molecular regulation mechanisms, we sequenced and compared the transcriptomes of mucosal epithelial tissues among the cecum, proximal colon and duodenum. A total of 4,221 transcripts from 3,254 genes were identified as differentially expressed transcripts. Between the large intestine and duodenum, differentially expressed transcripts were found to be significantly enriched in 6 metabolism-related pathways, among which PPAR signaling was identified as a key pathway. Three genes, CPT1A, LPL and PCK1, were identified as higher expression hub genes in the large intestine. Between the cecum and colon, differentially expressed transcripts were significantly enriched in 5 lipid metabolism related pathways, and CEPT1 and MBOAT1 were identified as hub genes. This study provides important information regarding the molecular mechanisms of intestinal metabolism in sheep and may provide a basis for further study.

Patients with old age or proximal tumors benefit from metabolic syndrome in early stage gastric cancer.

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Xiao-li Wei

Full Text Available BACKGROUND: Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated. METHODS: Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed. RESULTS: Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P=0.036. Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P=0.009 in multivariate analysis or patients with proximal gastric cancer (P=0.047 in multivariate analysis. No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P=0.052 in univariate analysis. CONCLUSIONS: Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.

Adenylate kinase I does not affect cellular growth characteristics under normal and metabolic stress conditions.

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de Bruin, Wieke; Oerlemans, Frank; Wieringa, Bé

2004-07-01

Adenylate kinase (AK)-catalyzed phosphotransfer is essential in the maintenance of cellular energetic economy in cells of fully differentiated tissues with highly variable energy demand, such as muscle and brain. To investigate if AK isoenzymes have a comparable function in the energy-demand management of proliferating cells, AK1 and AK1beta were expressed in mouse neuroblastoma N2a cells and in human colon carcinoma SW480 cells. Glucose deprivation, galactose feeding, and metabolic inhibitor tests revealed a differential energy dependency for these two cell lines. N2a cells showed a faster proliferation rate and strongest coupling to mitochondrial activity, SW480 proliferation was more dependent on glycolysis. Despite these differences, ectopic expression of AK1 or AK1beta did not affect their growth characteristics under normal conditions. Also, no differential effects were seen under metabolic stress upon treatment with mitochondrial and glycolytic inhibitors in in vitro culture or in solid tumors grown in vivo. Although many intimate connections have been revealed between cell death and metabolism, our results suggest that AK1- or AK1beta-mediated high-energy phosphoryl transfer is not a modulating factor in the survival of tumor cells during episodes of metabolic crisis.

Organ-specific metabolic responses to drought in Pinus pinaster Ait.

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de Miguel, Marina; Guevara, M Ángeles; Sánchez-Gómez, David; de María, Nuria; Díaz, Luis Manuel; Mancha, Jose A; Fernández de Simón, Brígida; Cadahía, Estrella; Desai, Nalini; Aranda, Ismael; Cervera, María-Teresa

2016-05-01

Drought is an important driver of plant survival, growth, and distribution. Water deficit affects different pathways of metabolism, depending on plant organ. While previous studies have mainly focused on the metabolic drought response of a single organ, analysis of metabolic differences between organs is essential to achieve an integrated understanding of the whole plant response. In this work, untargeted metabolic profiling was used to examine the response of roots, stems, adult and juvenile needles from Pinus pinaster Ait. full-sib individuals, subjected to a moderate and long lasting drought period. Cyclitols content showed a significant alteration, in response to drought in all organs examined, but other metabolites increased or decreased differentially depending on the analyzed organ. While a high number of flavonoids were only detected in aerial organs, an induction of the glutathione pathway was mainly detected in roots. This result may reflect different antioxidant mechanisms activated in aerial organs and roots. Metabolic changes were more remarkable in roots than in the other organs, highlighting its prominent role in the response to water stress. Significant changes in flavonoids and ascorbate metabolism were also observed between adult and juvenile needles, consistent with previously proven differential functional responses between the two developmental stages. Genetic polymorphisms in candidate genes coding for a Myb1 transcription factor and a malate dehydrogenase (EC 1.1.1.37) were associated with different concentration of phenylalanine, phenylpropanoids and malate, respectively. The results obtained will support further research on metabolites and genes potentially involved in functional mechanisms related to drought tolerance in trees. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention.

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Keeney, Jeriel Thomas-Richard; Ibrahimi, Shaher; Zhao, Liqin

2015-01-01

Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-β (Aβ) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aβ dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.

Quantitative rates of brain glucose metabolism distinguish minimally conscious from vegetative state patients.

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Stender, Johan; Kupers, Ron; Rodell, Anders; Thibaut, Aurore; Chatelle, Camille; Bruno, Marie-Aurélie; Gejl, Michael; Bernard, Claire; Hustinx, Roland; Laureys, Steven; Gjedde, Albert

2015-01-01

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.

Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes

DEFF Research Database (Denmark)

Min, Josine L; Nicholson, George; Halgrimsdottir, Ingileif

2012-01-01

Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue...... and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P100,000 individuals; rs10282458, affecting expression of RARRES2...... and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations....

Effect of diosgenin on metabolic dysfunction: Role of ERβ in the regulation of PPARγ

Energy Technology Data Exchange (ETDEWEB)

Wang, Xin, E-mail: xinwang@fmmu.edu.cn [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China); Liu, Jun [Department of Orthopedics, Lanzhou General Hospital of PLA, South Binhe Road, No. 333, Lanzhou 730050 (China); Long, Zi; Sun, Quangui [The First Student Brigade, Fourth Military Medical University, Xi' an, Shaanxi, 710032 (China); Liu, Ying; Wang, Lele; Zhang, Xiaodi [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China); Hai, Chunxu, E-mail: cx-hai@fmmu.edu.cn [Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an 710032 (China)

2015-12-01

The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its target gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation. - Highlights: • Diosgenin (DSG) attenuated metabolic dysfunction in high fat (HF) diet-fed mice. • DSG reduced oxidative stress and lipid accumulation in HF diet-fed mice. • DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size. • DSG induced the binding of ERβ with RXRα. • DSG-induced activation of ERβ dissociated RXRα from PPARγ and reduced PPARγ activity.

Effect of diosgenin on metabolic dysfunction: Role of ERβ in the regulation of PPARγ

International Nuclear Information System (INIS)

Wang, Xin; Liu, Jun; Long, Zi; Sun, Quangui; Liu, Ying; Wang, Lele; Zhang, Xiaodi; Hai, Chunxu

2015-01-01

The present study was designed to investigate the effect of diosgenin (DSG) on metabolic dysfunction and to elucidate the possible molecular mechanisms. High fat (HF) diet-fed mice and 3T3-L1 preadipocytes was used to evaluate the effect of DSG. We showed that DSG attenuated metabolic dysfunction in HF diet-fed mice, as evidenced by reduction of blood glucose level and improvement of glucose and insulin intolerance. DSG ameliorated oxidative stress, reduced body weight, fat pads, and systematic lipid profiles and attenuated lipid accumulation. DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size through regulating key factors. DSG inhibited PPARγ and its target gene expression both in differentiated 3T3-L1 adipocytes and fat tissues in HF diet-fed mice. Overexpression of PPARγ suppressed DSG-inhibited adipocyte differentiation. DSG significantly increased nuclear expression of ERβ. Inhibition of ERβ significantly suppressed DSG-exerted suppression of adipocyte differentiation and PPARγ expression. In response to DSG stimulation, ERβ bound with RXRα and dissociated RXRα from PPARγ, leading to the reduction of transcriptional activity of PPARγ. These data provide new insight into the mechanisms underlying the inhibitory effect of DSG on adipocyte differentiation and demonstrate that ERβ-exerted regulation of PPARγ expression and activity is critical for DSG-inhibited adipocyte differentiation. - Highlights: • Diosgenin (DSG) attenuated metabolic dysfunction in high fat (HF) diet-fed mice. • DSG reduced oxidative stress and lipid accumulation in HF diet-fed mice. • DSG inhibited 3T3-L1 adipocyte differentiation and reduced adipocyte size. • DSG induced the binding of ERβ with RXRα. • DSG-induced activation of ERβ dissociated RXRα from PPARγ and reduced PPARγ activity.

Measurement of metabolism of worker ants by using the elimination of caesium-134

International Nuclear Information System (INIS)

Nielsen, M.G.; Jensen, T.F.

1977-01-01

In order to find a method for measuring field metabolism of worker ants the elimination of 134 Cs by two ant species has been investigated. Equations relating temperature to radiocaesium elimination and metabolism have been found. From these equations the relationship between elimination and metabolism is calculated. Consequently, the elimination of the isotope can be used for measuring metabolism. A pilot field experiment with Lasius alienus (Foerst.) reveals that the traditional methods of estimating field metabolism give values which are considerably lower than the value based on caesium elimination rate. This difference is supposed to be mainly due to greater motor activity of the animals in the field. Consequently, the value of the caesium elimination method is closer to the 'true' value of field metabolism. (orig.) [de

Effect of the neurosphere size on the viability and metabolism of ...

African Journals Online (AJOL)

2012-02-23

Feb 23, 2012 ... substance metabolism mathematic model with which the substance distribution ..... dinucleotide (NADH) back to NAD+ and flavin adenine dinucleotide (FADH2) ... differentiated from rat neurospheres. Brain Res. 1101: 5-11.

Novel hydrated graphene ribbon unexpectedly promotes aged seed germination and root differentiation

Science.gov (United States)

Hu, Xiangang; Zhou, Qixing

2014-01-01

It is well known that graphene (G) induces nanotoxicity towards living organisms. Here, a novel and biocompatible hydrated graphene ribbon (HGR) unexpectedly promoted aged (two years) seed germination. HGR formed at the normal temperature and pressure (120 days hydration), presented 17.1% oxygen, 0.9% nitrogen groups, disorder-layer structure, with 0.38 nm thickness ribbon morphology. Interestingly, there were bulges around the edges of HGR. Compared to G and graphene oxide (GO), HGR increased seed germination by 15% root differentiation between 52 and 59% and enhanced resistance to oxidative stress. The metabonomics analysis discovered that HGR upregulated carbohydrate, amino acid, and fatty acids metabolism that determined secondary metabolism, nitrogen sequestration, cell membrane integrity, permeability, and oxidation resistance. Hexadecanoic acid as a biomarker promoted root differentiation and increased the germination rate. Our discovery is a novel HGR that promotes aged seed germination, illustrates metabolic specificity among graphene-based materials, and inspires innovative concepts in the regulation of seed development.

Metabolic imaging of patients with cardiomyopathy

International Nuclear Information System (INIS)

Geltman, E.M.

1991-01-01

The cardiomyopathies comprise a diverse group of illnesses that can be characterized functionally by several techniques. However, the delineation of derangements of regional perfusion and metabolism have been accomplished only relatively recently with positron emission tomography (PET). Regional myocardial accumulation and clearance of 11C-palmitate, the primary myocardial substrate under most conditions, demonstrate marked spatial heterogeneity when studied under fasting conditions or with glucose loading. PET with 11C-palmitate permits the noninvasive differentiation of patients with nonischemic from ischemic dilated cardiomyopathy, since patients with ischemic cardiomyopathy demonstrate large zones of intensely depressed accumulation of 11C-palmitate, probably reflecting prior infarction. Patients with hypertrophic cardiomyopathy and Duchenne's muscular dystrophy demonstrate relatively unique patterns of myocardial abnormalities of perfusion and metabolism. The availability of new tracers and techniques for the evaluation of myocardial metabolism (11C-acetate), perfusion (H2(15)O), and autonomic tone (11-C-hydroxyephedrine) should facilitate further understanding of the pathogenesis of the cardiomyopathies

Differential equations

CERN Document Server

Tricomi, FG

2013-01-01

Based on his extensive experience as an educator, F. G. Tricomi wrote this practical and concise teaching text to offer a clear idea of the problems and methods of the theory of differential equations. The treatment is geared toward advanced undergraduates and graduate students and addresses only questions that can be resolved with rigor and simplicity.Starting with a consideration of the existence and uniqueness theorem, the text advances to the behavior of the characteristics of a first-order equation, boundary problems for second-order linear equations, asymptotic methods, and diff

Differentiated Learning. Teaching English to Mixed-Ability Classes

Directory of Open Access Journals (Sweden)

Lăcrimioara Năsui

2015-06-01

Full Text Available The present article is dedicated to one of the most important aspects of teaching nowadays- differentiated teaching and instruction for English language learners. Differentiation means directing teaching towards the interests and capacities of all pupils in a class. It is not a simple expedient for keeping pupils busy – although that may prove important – it is a consideration for overcoming any latent barriers to learning.

13C and 31P NMR [Nuclear Magnetic Resonance] studies of prostate tumor metabolism

International Nuclear Information System (INIS)

Sillerud, L.O.; Halliday, K.R.; Freyer, J.P; Griffey, R.H.; Fenoglio-Preiser, C.

1989-01-01

The current research on prostate cancer by NMR spectroscopy and microscopy will most significantly contribute to tumor diagnosis and characterization only if sound biochemical models of tumor metabolism are established and tested. Prior searches focused on universal markers of malignancy, have to date, revealed no universal markers by any method. It is unlikely that NMRS will succeed where other methods have failed, however, NMR spectroscopy does provide a non-invasive means to analyze multiple compounds simultaneously in vivo. In order to fully evaluate the ability of NMRS to differentiate non-malignant from malignant tissues it is necessary to determine sufficient multiple parameters from specific, well-diagnosed, histological tumor types that, in comparison to normal tissue and non-neoplastic, non-normal pathologies from which the given neoplasm must be differentiated, one has enough degrees of freedom to make a mathematically and statistically significant determination. Confounding factors may consist of tumor heterogeneity arising from regional variations in differentiation, ischemia, necrosis, hemorrhage, inflammation and the presence of intermingled normal tissue. One related aspect of our work is the development of { 13 C}- 1 H metabolic imaging of 13 C for metabolic characterization, with enhanced spatial localization (46). This should markedly extend the range of potential clinical NMR uses because the spatial variation in prostate metabolism may prove to be just as important in tumor diagnoses as bulk (volume-averaged) properties themselves. It is our hope that NMRS and spectroscopic imaging will reveal a sound correlation between prostate metabolism and tumor properties that will be clinically straightforward and useful for diagnosis

Differential 3-bromopyruvate inhibition of cytosolic and mitochondrial human serine hydroxymethyltransferase isoforms, key enzymes in cancer metabolic reprogramming.

Science.gov (United States)

Paiardini, Alessandro; Tramonti, Angela; Schirch, Doug; Guiducci, Giulia; di Salvo, Martino Luigi; Fiascarelli, Alessio; Giorgi, Alessandra; Maras, Bruno; Cutruzzolà, Francesca; Contestabile, Roberto

2016-11-01

The cytosolic and mitochondrial isoforms of serine hydroxymethyltransferase (SHMT1 and SHMT2, respectively) are well-recognized targets of cancer research, since their activity is critical for purine and pyrimidine biosynthesis and because of their prominent role in the metabolic reprogramming of cancer cells. Here we show that 3-bromopyruvate (3BP), a potent novel anti-tumour agent believed to function primarily by blocking energy metabolism, differentially inactivates human SHMT1 and SHMT2. SHMT1 is completely inhibited by 3BP, whereas SHMT2 retains a significant fraction of activity. Site directed mutagenesis experiments on SHMT1 demonstrate that selective inhibition relies on the presence of a cysteine residue at the active site of SHMT1 (Cys204) that is absent in SHMT2. Our results show that 3BP binds to SHMT1 active site, forming an enzyme-3BP complex, before reacting with Cys204. The physiological substrate l-serine is still able to bind at the active site of the inhibited enzyme, although catalysis does not occur. Modelling studies suggest that alkylation of Cys204 prevents a productive binding of l-serine, hampering interaction between substrate and Arg402. Conversely, the partial inactivation of SHMT2 takes place without the formation of a 3BP-enzyme complex. The introduction of a cysteine residue in the active site of SHMT2 by site directed mutagenesis (A206C mutation), at a location corresponding to that of Cys204 in SHMT1, yields an enzyme that forms a 3BP-enzyme complex and is completely inactivated. This work sets the basis for the development of selective SHMT1 inhibitors that target Cys204, starting from the structure and reactivity of 3BP. Copyright © 2016 Elsevier B.V. All rights reserved.

Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes.

Science.gov (United States)

Allison, Katrina E; Coomber, Brenda L; Bridle, Byram W

2017-10-01

Altered metabolism is a hallmark of cancers, including shifting oxidative phosphorylation to glycolysis and up-regulating glutaminolysis to divert carbon sources into biosynthetic pathways that promote proliferation and survival. Therefore, metabolic inhibitors represent promising anti-cancer drugs. However, T cells must rapidly divide and survive in harsh microenvironments to mediate anti-cancer effects. Metabolic profiles of cancer cells and activated T lymphocytes are similar, raising the risk of metabolic inhibitors impairing the immune system. Immune checkpoint blockade provides an example of how metabolism can be differentially impacted to impair cancer cells but support T cells. Implications for research with metabolic inhibitors are discussed. © 2017 John Wiley & Sons Ltd.

Novel insights into iron metabolism by integrating deletome and transcriptome analysis in an iron deficiency model of the yeast Saccharomyces cerevisiae

Directory of Open Access Journals (Sweden)

Arkin Adam P

2009-03-01

Full Text Available Abstract Background Iron-deficiency anemia is the most prevalent form of anemia world-wide. The yeast Saccharomyces cerevisiae has been used as a model of cellular iron deficiency, in part because many of its cellular pathways are conserved. To better understand how cells respond to changes in iron availability, we profiled the yeast genome with a parallel analysis of homozygous deletion mutants to identify essential components and cellular processes required for optimal growth under iron-limited conditions. To complement this analysis, we compared those genes identified as important for fitness to those that were differentially-expressed in the same conditions. The resulting analysis provides a global perspective on the cellular processes involved in iron metabolism. Results Using functional profiling, we identified several genes known to be involved in high affinity iron uptake, in addition to novel genes that may play a role in iron metabolism. Our results provide support for the primary involvement in iron homeostasis of vacuolar and endosomal compartments, as well as vesicular transport to and from these compartments. We also observed an unexpected importance of the peroxisome for growth in iron-limited media. Although these components were essential for growth in low-iron conditions, most of them were not differentially-expressed. Genes with altered expression in iron deficiency were mainly associated with iron uptake and transport mechanisms, with little overlap with those that were functionally required. To better understand this relationship, we used expression-profiling of selected mutants that exhibited slow growth in iron-deficient conditions, and as a result, obtained additional insight into the roles of CTI6, DAP1, MRS4 and YHR045W in iron metabolism. Conclusion Comparison between functional and gene expression data in iron deficiency highlighted the complementary utility of these two approaches to identify important functional

A fat option for the pig: Hepatocytic differentiated mesenchymal stem cells for translational research

Energy Technology Data Exchange (ETDEWEB)

Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de [University Hospital Leipzig, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Liebigstraße 21, Leipzig D-04103 (Germany); Tautenhahn, Hans-Michael, E-mail: hans-michael.tautenhahn@medizin.uni-leipzig.de [University Hospital Leipzig, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Liebigstraße 21, Leipzig D-04103 (Germany); TRM, Translational Centre for Regenerative Medicine, Philipp-Rosenthal-Str. 55, Leipzig D-04103 (Germany); Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de [University Hospital Leipzig, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Liebigstraße 21, Leipzig D-04103 (Germany); Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de [University Hospital Leipzig, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Liebigstraße 21, Leipzig D-04103 (Germany); Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de [University Hospital Ulm, First Department of Medicine, Albert-Einstein-Allee 23, Ulm D-89081 (Germany); Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de [University Hospital Leipzig, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Liebigstraße 21, Leipzig D-04103 (Germany); TRM, Translational Centre for Regenerative Medicine, Philipp-Rosenthal-Str. 55, Leipzig D-04103 (Germany)

2014-02-15

Study background: Extended liver resection is the only curative treatment option of liver cancer. Yet, the residual liver may not accomplish the high metabolic and regenerative capacity needed, which frequently leads to acute liver failure. Because of their anti-inflammatory and -apoptotic as well as pro-proliferative features, mesenchymal stem cells differentiated into hepatocyte-like cells might provide functional and regenerative compensation. Clinical translation of basic research requires pre-clinical approval in large animals. Therefore, we characterized porcine mesenchymal stem cells (MSC) from adipose tissue and bone marrow and their hepatocyte differentiation potential for future assessment of functional liver support after surgical intervention in the pig model. Methods: Mesenchymal surface antigens and multi-lineage differentiation potential of porcine MSC isolated by collagenase digestion either from bone marrow or adipose tissue (subcutaneous/visceral) were assessed by flow cytometry. Morphology and functional properties (urea-, glycogen synthesis and cytochrome P450 activity) were determined during culture under differentiation conditions and compared with primary porcine hepatocytes. Results: MSC from porcine adipose tissue and from bone marrow express the typical mesenchymal markers CD44, CD29, CD90 and CD105 but not haematopoietic markers. MSC from both sources displayed differentiation into the osteogenic as well as adipogenic lineage. After hepatocyte differentiation, expression of CD105 decreased significantly and cells adopted the typical polygonal morphology of hepatocytes. Glycogen storage was comparable in adipose tissue- and bone marrow-derived cells. Urea synthesis was about 35% lower in visceral than in subcutaneous adipose tissue-derived MSC. Cytochrome P450 activity increased significantly during differentiation and was twice as high in hepatocyte-like cells generated from bone marrow as from adipose tissue. Conclusion: The hepatocyte

A fat option for the pig: Hepatocytic differentiated mesenchymal stem cells for translational research

International Nuclear Information System (INIS)

Brückner, Sandra; Tautenhahn, Hans-Michael; Winkler, Sandra; Stock, Peggy; Dollinger, Matthias; Christ, Bruno

2014-01-01

Study background: Extended liver resection is the only curative treatment option of liver cancer. Yet, the residual liver may not accomplish the high metabolic and regenerative capacity needed, which frequently leads to acute liver failure. Because of their anti-inflammatory and -apoptotic as well as pro-proliferative features, mesenchymal stem cells differentiated into hepatocyte-like cells might provide functional and regenerative compensation. Clinical translation of basic research requires pre-clinical approval in large animals. Therefore, we characterized porcine mesenchymal stem cells (MSC) from adipose tissue and bone marrow and their hepatocyte differentiation potential for future assessment of functional liver support after surgical intervention in the pig model. Methods: Mesenchymal surface antigens and multi-lineage differentiation potential of porcine MSC isolated by collagenase digestion either from bone marrow or adipose tissue (subcutaneous/visceral) were assessed by flow cytometry. Morphology and functional properties (urea-, glycogen synthesis and cytochrome P450 activity) were determined during culture under differentiation conditions and compared with primary porcine hepatocytes. Results: MSC from porcine adipose tissue and from bone marrow express the typical mesenchymal markers CD44, CD29, CD90 and CD105 but not haematopoietic markers. MSC from both sources displayed differentiation into the osteogenic as well as adipogenic lineage. After hepatocyte differentiation, expression of CD105 decreased significantly and cells adopted the typical polygonal morphology of hepatocytes. Glycogen storage was comparable in adipose tissue- and bone marrow-derived cells. Urea synthesis was about 35% lower in visceral than in subcutaneous adipose tissue-derived MSC. Cytochrome P450 activity increased significantly during differentiation and was twice as high in hepatocyte-like cells generated from bone marrow as from adipose tissue. Conclusion: The hepatocyte

Regulation of Specialized Metabolism by WRKY Transcription Factors

Science.gov (United States)

Schluttenhofer, Craig; Yuan, Ling

2015-01-01

WRKY transcription factors (TFs) are well known for regulating plant abiotic and biotic stress tolerance. However, much less is known about how WRKY TFs affect plant-specialized metabolism. Analysis of WRKY TFs regulating the production of specialized metabolites emphasizes the values of the family outside of traditionally accepted roles in stress tolerance. WRKYs with conserved roles across plant species seem to be essential in regulating specialized metabolism. Overall, the WRKY family plays an essential role in regulating the biosynthesis of important pharmaceutical, aromatherapy, biofuel, and industrial components, warranting considerable attention in the forthcoming years. PMID:25501946

Metabolic alkalosis in children: Study of patients admitted to pediatrics center

OpenAIRE

Sobhani A; Radmehr B; Raji AR

2001-01-01

Metabolic alkalosis is characterized by high HCO3- as it is seen in chronic respiratory acidosis, but PH differentiates the two disorders. There is no characteristic symptom or sign. Orthostatic hypotension may be encountered. Weakness and hyporeflexia occur if serum K+ is markerdly low. Tetany and neuromuscular irritability occur rarely. We report the results of retrospective data analysis of metabolic alkalosis in 15463 patients hospitalized Pediatric Medical Center in Tehran during years 1...

Differential cold-shock resistance among acclimated European mussel populations

NARCIS (Netherlands)

Jansen, J.M.; Wendelaar Bonga, S.E.; Hummel, H.

2007-01-01

To study differential cold-shock resistance of marine mussel populations (Mytilus spp.) from different climatic regions in Europe, we sampled 12 populations, ranging from 43 to 58°N. Minimum critical temperatures for aerobic metabolism (CTmin) were determined before and after 3 months of common

Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism

DEFF Research Database (Denmark)

Nehlin, Jan O; Just, Marlene; Rustan, Arild C

2011-01-01

Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways. As the prolif......Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways...... number and could be explained by reduced incorporation into diacyl- and triacylglycerols. The levels of long-chain acyl-CoA esters decreased with increased passage number. Late-passage, non-proliferating, myoblast cultures showed strong senescence-associated β-galactosidase activity indicating...... that the observed metabolic defects accompany the induction of a senescent state. The main function of SCs is regeneration and skeletal muscle-build up. Thus, the metabolic defects observed during aging of SC-derived myotubes could have a role in sarcopenia, the gradual age-related loss of muscle mass and strength....

Differentiation of real functions

CERN Document Server

Bruckner, Andrew

1994-01-01

Topics related to the differentiation of real functions have received considerable attention during the last few decades. This book provides an efficient account of the present state of the subject. Bruckner addresses in detail the problems that arise when dealing with the class \\Delta ' of derivatives, a class that is difficult to handle for a number of reasons. Several generalized forms of differentiation have assumed importance in the solution of various problems. Some generalized derivatives are excellent substitutes for the ordinary derivative when the latter is not known to exist; others are not. Bruckner studies generalized derivatives and indicates "geometric" conditions that determine whether or not a generalized derivative will be a good substitute for the ordinary derivative. There are a number of classes of functions closely linked to differentiation theory, and these are examined in some detail. The book unifies many important results from the literature as well as some results not previously pub...

Differential lysine acetylation profiles of Erwinia amylovora strains revealed by proteomics

Science.gov (United States)

Wu, Xia; Vellaichamy, Adaikkalam; Wang, Dongping; Zamdborg, Leonid; Kelleher, Neil L.; Huber, Steven C.; Zhao, Youfu

2015-01-01

Protein lysine acetylation (LysAc) has recently been demonstrated to be widespread in E. coli and Salmonella, and to broadly regulate bacterial physiology and metabolism. However, LysAc in plant pathogenic bacteria is largely unknown. Here we first report the lysine acetylome of Erwinia amylovora, an enterobacterium causing serious fire blight disease of apples and pears. Immunoblots using generic anti-lysine acetylation antibodies demonstrated that growth conditions strongly affected the LysAc profiles in E. amylovora. Differential LysAc profiles were also observed for two E. amylovora strains, known to have differential virulence in plants, indicating translational modification of proteins may be important in determining virulence of bacterial strains. Proteomic analysis of LysAc in two E. amylovora strains identified 141 LysAc sites in 96 proteins that function in a wide range of biological pathways. Consistent with previous reports, 44% of the proteins are involved in metabolic processes, including central metabolism, lipopolysaccharide, nucleotide and amino acid metabolism. Interestingly, for the first time, several proteins involved in E. amylovora virulence, including exopolysaccharide amylovoran biosynthesis- and type III secretion-associated proteins, were found to be lysine acetylated, suggesting that LysAc may play a major role in bacterial virulence. Comparative analysis of LysAc sites in E. amylovora and E. coli further revealed the sequence and structural commonality for LysAc in the two organisms. Collectively, these results reinforce the notion that LysAc of proteins is widespread in bacterial metabolism and virulence. PMID:23234799

Some considerations on robotics for environmental friendliness

International Nuclear Information System (INIS)

Pin, F.G.

1993-01-01

This paper presents a series of considerations regarding the use and potential of robotic devices for supporting humans in a variety of tasks, while maintaining, if not improving, environmental friendliness. One of the main considerations brought forward here relates to the type of human-support functions which the robots are, or will be, expected to perform, and from this, a clear differentiation appears between robots designed to replace humans in environments that were engineered in the past for best human functionality, and robots designed to take functions in the future, in environments which could be better engineered for large-scale human-robot synergy. Other considerations discussed involve the ''life-cycle'' cleanliness of robotic systems, including the materials needs for their construction, their operation, their disposal and, more importantly, their energy consumption which will impact the cycle of natural resources utilization. These considerations are discussed using a variety of possible robotic systems applications in contexts varied as manufacturing, energy recovery and production, emergency situations handling, traffic improvement, waste management, agriculture, and space exploration. In all these applications, the operation costs and complexity of the robots seem to vary in inverse proportion to the amount of engineering that is feasible to make the task environment more robot-friendly, but with no seemingly direct impact on the potential for environmental friendliness of the robots

Some considerations on robotics for environmental friendliness

Energy Technology Data Exchange (ETDEWEB)

Pin, F.G.

1993-12-01

This paper presents a series of considerations regarding the use and potential of robotic devices for supporting humans in a variety of tasks, while maintaining, if not improving, environmental friendliness. One of the main considerations brought forward here relates to the type of human-support functions which the robots are, or will be, expected to perform, and from this, a clear differentiation appears between robots designed to replace humans in environments that were engineered in the past for best human functionality, and robots designed to take functions in the future, in environments which could be better engineered for large-scale human-robot synergy. Other considerations discussed involve the ``life-cycle`` cleanliness of robotic systems, including the materials needs for their construction, their operation, their disposal and, more importantly, their energy consumption which will impact the cycle of natural resources utilization. These considerations are discussed using a variety of possible robotic systems applications in contexts varied as manufacturing, energy recovery and production, emergency situations handling, traffic improvement, waste management, agriculture, and space exploration. In all these applications, the operation costs and complexity of the robots seem to vary in inverse proportion to the amount of engineering that is feasible to make the task environment more robot-friendly, but with no seemingly direct impact on the potential for environmental friendliness of the robots.

Lack of differential pattern in central adiposity and metabolic syndrome in Barrett's esophagus and gastroesophageal reflux disease.

LENUS (Irish Health Repository)

Healy, L A

2012-02-01

Obesity is an established risk factor for esophageal adenocarcinoma, although the mechanism is unclear. A pathway from reflux to inflammation through metaplasia is the dominant hypothesis, and an added role relating to visceral adiposity and the metabolic syndrome has been mooted in Barrett\\'s esophagus (BE) patients. Whether BE differs from gastroesophageal reflux disease (GERD) in obesity and metabolic syndrome profiles is unclear, and this was the focus of this study. Patients with proven BE or GERD were randomly selected from the unit data registry and invited to attend for metabolic syndrome screening, anthropometry studies including segmental body composition analysis, and laboratory tests including fasting lipids, insulin, and C-reactive protein. Metabolic syndrome was defined using the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) criteria. One hundred and eighteen BE patients and 113 age- and sex-matched GERD controls were studied. The incidence of obesity (body mass index >30 kg\\/m(2)) was 36% and 38%, respectively, with the pattern of fat deposition predominantly central and an estimated trunk fat mass of 13 and 14 kg, respectively. Using the NCEP criteria, metabolic syndrome was significantly more common in the BE cohort (30% vs 20%, P < 0.05), but there was no significant difference using IDF criteria (42% vs 37%, P= 0.340). Central obesity and the metabolic syndrome are common in both Barrett\\'s and GERD cohorts, but not significantly different, suggesting that central obesity and the metabolic syndrome does not per se impact on the development of BE in a reflux population. In BE, the importance of obesity and the metabolic syndrome in disease progression merits further study.

Microvesicles/exosomes as potential novel biomarkers of metabolic diseases

Directory of Open Access Journals (Sweden)

Müller G

2012-08-01

Full Text Available Günter MüllerDepartment of Biology 1, Genetics, Ludwig-Maximilians University Munich, Biocenter, Munich, GermanyAbstract: Biomarkers are of tremendous importance for the prediction, diagnosis, and observation of the therapeutic success of common complex multifactorial metabolic diseases, such as type II diabetes and obesity. However, the predictive power of the traditional biomarkers used (eg, plasma metabolites and cytokines, body parameters is apparently not sufficient for reliable monitoring of stage-dependent pathogenesis starting with the healthy state via its initiation and development to the established disease and further progression to late clinical outcomes. Moreover, the elucidation of putative considerable differences in the underlying pathogenetic pathways (eg, related to cellular/tissue origin, epigenetic and environmental effects within the patient population and, consequently, the differentiation between individual options for disease prevention and therapy – hallmarks of personalized medicine – plays only a minor role in the traditional biomarker concept of metabolic diseases. In contrast, multidimensional and interdependent patterns of genetic, epigenetic, and phenotypic markers presumably will add a novel quality to predictive values, provided they can be followed routinely along the complete individual disease pathway with sufficient precision. These requirements may be fulfilled by small membrane vesicles, which are so-called exosomes and microvesicles (EMVs that are released via two distinct molecular mechanisms from a wide variety of tissue and blood cells into the circulation in response to normal and stress/pathogenic conditions and are equipped with a multitude of transmembrane, soluble and glycosylphosphatidylinositol-anchored proteins, mRNAs, and microRNAs. Based on the currently available data, EMVs seem to reflect the diverse functional and dysfunctional states of the releasing cells and tissues along the

Pathway elucidation and metabolic engineering of specialized plant metabolites

DEFF Research Database (Denmark)

Salomonsen, Bo

A worldwide need to liberate ourselves from unsustainable petrochemicals has led to numerous metabolic engineering projects, mostly carried out in microbial hosts. Using systems biology for predicting and altering the metabolism of microorganisms towards production of a desired metabolite......, these projects have increased revenues on fermentative production of several biochemicals. The use of systems biology is, however, not limited to microorganisms. Recent advances in biotechnology methods have provided a wealth of data within functional genomics, metabolomics, transcriptomics, proteomics...... and fluxomics for a considerable number of organisms. Unfortunately, transferring the wealth of data to valuable information for metabolic engineering purposes is a non-obvious task. This PhD thesis describes a palate of tools used in generation of cell factories for production of specialized plant metabolites...

HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes.

Directory of Open Access Journals (Sweden)

Beth S Zha

Full Text Available HIV protease inhibitors (PI are core components of Highly Active Antiretroviral Therapy (HAART, the most effective treatment for HIV infection currently available. However, HIV PIs have now been linked to lipodystrophy and dyslipidemia, which are major risk factors for cardiovascular disease and metabolic syndrome. Our previous studies have shown that HIV PIs activate endoplasmic reticulum (ER stress and disrupt lipid metabolism in hepatocytes and macrophages. Yet, little is known on how HIV PIs disrupt lipid metabolism in adipocytes, a major cell type involved in the pathogenesis of metabolic syndrome.Cultured and primary mouse adipocytes and human adipocytes were used to examine the effect of frequently used HIV PIs in the clinic, lopinavir/ritonavir, on adipocyte differentiation and further identify the underlying molecular mechanism of HIV PI-induced dysregulation of lipid metabolism in adipocytes. The results indicated that lopinavir alone or in combination with ritonavir, significantly activated the ER stress response, inhibited cell differentiation, and induced cell apoptosis in adipocytes. In addition, HIV PI-induced ER stress was closely linked to inhibition of autophagy activity. We also identified through the use of primary adipocytes of CHOP(-/- mice that CHOP, the major transcriptional factor of the ER stress signaling pathway, is involved in lopinavir/ritonavir-induced inhibition of cell differentiation in adipocytes. In addition, lopinavir/ritonavir-induced ER stress appears to be associated with inhibition of autophagy activity in adipocytes.Activation of ER stress and impairment of autophagy activity are involved in HIV PI-induced dysregulation of lipid metabolism in adipocytes. The key components of ER stress and autophagy signaling pathways are potential therapeutic targets for HIV PI-induced metabolic side effects in HIV patients.

Hypothyroidism in metabolic syndrome

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Sunil Kumar Kota

2012-01-01

Full Text Available Aim: Metabolic syndrome (MetS and hypothyroidism are well established forerunners of atherogenic cardiovascular disease. Considerable overlap occurs in the pathogenic mechanisms of atherosclerotic cardiovascular disease by metabolic syndrome and hypothyroidism. Insulin resistance has been studied as the basic pathogenic mechanism in metabolic syndrome. [1] This cross sectional study intended to assess thyroid function in patients with metabolic syndrome and to investigate the association between hypothyroidism and metabolic syndrome. Materials and Methods: One hundred patients with metabolic syndrome who fulfilled the National Cholesterol Education Program- Adult Treatment Panel (NCEP-ATP III criteria [ 3 out of 5 criteria positive namely blood pressure ≥ 130/85 mm hg or on antihypertensive medications, fasting plasma glucose > 100 mg/dl or on anti-diabetic medications, fasting triglycerides > 150 mg/dl, high density lipoprotein cholesterol (HDL-C 102 cms in men and 88 cms in women] were included in the study group. [2] Fifty patients who had no features of metabolic syndrome (0 out of 5 criteria for metabolic syndrome were included in the control group. Patients with liver disorders, renal disorders, congestive cardiac failure, pregnant women, patients on oral contraceptive pills, statins and other medications that alter thyroid functions and lipid levels and those who are under treatment for any thyroid related disorder were excluded from the study. Acutely ill patients were excluded taking into account sick euthyroid syndrome. Patients were subjected to anthropometry, evaluation of vital parameters, lipid and thyroid profile along with other routine laboratory parameters. Students t-test, Chi square test and linear regression, multiple logistic regression models were used for statistical analysis. P value < 0.05 was considered significant. Results: Of the 100 patients in study group, 55 were females (55% and 45 were males (45%. Of the 50

SIMULTANEOUS DIFFERENTIAL EQUATION COMPUTER

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Collier, D.M.; Meeks, L.A.; Palmer, J.P.

1960-05-10

A description is given for an electronic simulator for a system of simultaneous differential equations, including nonlinear equations. As a specific example, a homogeneous nuclear reactor system including a reactor fluid, heat exchanger, and a steam boiler may be simulated, with the nonlinearity resulting from a consideration of temperature effects taken into account. The simulator includes three operational amplifiers, a multiplier, appropriate potential sources, and interconnecting R-C networks.

A simple method of screening for metabolic bone disease

International Nuclear Information System (INIS)

Broughton, R.B.K.; Evans, W.D.

1982-01-01

The purpose of this investigation was to find a simple method -to be used as an adjunct to the conventional bone scintigram- that could differentiate between decreased bone metabolism or mass, i.e., osteoporosis -normal bone- and the group of conditions of increased bone metabolism or mass namely, osteomalacia, renal osteodystrophy, hyperparathyroidism and Paget's disease. The Fogelman's method using the bone to soft tissue ratios from region of interest analysis at 4 hours post injection, was adopted. An initial experience in measuring a value for the count rate density in lumbar vertebrae at 1 hr post injection during conventional bone scintigraphy appears to give a clear indication of the overall rate of bone metabolism. The advantage over whole body retention methods is that the scan performed at the end of the metabolic study will reveal localized bone disease that may otherwise not be anticipated

African urbanization in metropolitan South Africa--differential urbanization perspectives.

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Geyer, H S

1993-07-01

"As a potentially important urban development policy consideration, attention is focused in this paper on differential urbanization trends in South Africa at the metropolitan level. Recent informal urban settlement patterns of the African population within the major metropolitan areas are contrasted against these differential urbanization trends to determine the implications of both for residential development in the metropolitan areas during the post-apartheid era." excerpt

Metabolomics reveals metabolic biomarkers of Crohn's disease

Energy Technology Data Exchange (ETDEWEB)

Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

2009-06-01

The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

Metabolic alkalosis in children: Study of patients admitted to pediatrics center

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Sobhani A

2001-07-01

Full Text Available Metabolic alkalosis is characterized by high HCO3- as it is seen in chronic respiratory acidosis, but PH differentiates the two disorders. There is no characteristic symptom or sign. Orthostatic hypotension may be encountered. Weakness and hyporeflexia occur if serum K+ is markerdly low. Tetany and neuromuscular irritability occur rarely. We report the results of retrospective data analysis of metabolic alkalosis in 15463 patients hospitalized Pediatric Medical Center in Tehran during years 1995-1997. We found 50 cases of metabolic alkalosis (rate of 0.32 percent. 64 precent male and 36 percent female. Most of them had growth failure (40% were bellow 3 percentile of height by age, 44% bellow 5 percentile of weight by height. More than 60 percent had hypokalemia, hypocloremia and hyponatremia. The most common cause of Metabolic alkalosis was cystic fibrosis and pyloric stenosis. Fifty percent of cystic fibrosis patients and Bartter cases had metabolic alkalosis. Metabolic alkalosis should be considered in every pediatric patient presented with projectile vomitting.

Muscle differentiation in a colonial ascidian: organisation, gene expression and evolutionary considerations

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Burighel Paolo

2009-09-01

Full Text Available Abstract Background Ascidians are tunicates, the taxon recently proposed as sister group to the vertebrates. They possess a chordate-like swimming larva, which metamorphoses into a sessile adult. Several ascidian species form colonies of clonal individuals by asexual reproduction. During their life cycle, ascidians present three muscle types: striated in larval tail, striated in the heart, and unstriated in the adult body-wall. Results In the colonial ascidian Botryllus schlosseri, we investigated organisation, differentiation and gene expression of muscle beginning from early buds to adults and during zooid regression. We characterised transcripts for troponin T (BsTnT-c, adult muscle-type (BsMA2 and cytoplasmic-type (BsCA1 actins, followed by in situ hybridisation (ISH on sections to establish the spatio-temporal expression of BsTnT-c and BsMA2 during asexual reproduction and in the larva. Moreover, we characterised actin genomic sequences, which by comparison with other metazoans revealed conserved intron patterns. Conclusion Integration of data from ISH, phalloidin staining and TEM allowed us to follow the phases of differentiation of the three muscle kinds, which differ in expression pattern of the two transcripts. Moreover, phylogenetic analyses provided evidence for the close relationship between tunicate and vertebrate muscle genes. The characteristics and plasticity of muscles in tunicates are discussed.

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation

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Price, Nathan L.; Holtrup, Brandon; Kwei, Stephanie L.; Wabitsch, Martin; Rodeheffer, Matthew; Bianchini, Laurence; Suárez, Yajaira

2016-01-01

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting in vitro adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding in vivo assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along with SREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease. PMID:26830228

Metabolic control of the insecticides safety use

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L.I. Solomenko

2016-06-01

Full Text Available The results of the conducted research affirm that the phosphororganic insecticides utilization can lead to the break in the nitrogen metabolism, breaking the protein formation, reducing the protein molecules renewal, causing the amino acid and amides accumulation in the active state. It has been revealed that the translocation and transformation of the insecticides under consideration are more closely connected with the changes of insoluble protein fraction. The stagnation point of the Phosphamide and Kaunter impact on the plant has been determined. And only the use of the preparation in optimal norms can influence stimulatingly the course of the process under consideration.

Skeletal scintigraphy and quantitative tracer studies in metabolic bone disease

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Fogelman, Ignac

Bone scan imaging with the current bone seeking radiopharmaceuticals, the technetium-99m labelled diphosphonates, has dramatically improved our ability to evaluate skeletal pathology. In this thesis, chapter 1 presents a review of the history of bone scanning, summarises present concepts as to the mechanism of uptake of bone seeking agents and briefly illustrates the role of bone scanning in clinical practice. In chapter 2 the applications of bone scan imaging and quantitative tracer techniques derived from the bone scan in the detection of metabolic bone disease are discussed. Since skeletal uptake of Tc-99m diphosphonate depends upon skeletal metabolism one might expect that the bone scan would be of considerable value in the assessment of metabolic bone disease. However in these disorders the whole skeleton is often diffusely involved by the metabolic process and simple visual inspection of the scan image may not reveal the uniformly increased uptake of tracer. Certain patterns of bone scan abnormality have, however, been reported in patients with primary hyperparathyroidism and renal osteo-dystrophy; the present studies extend these observations and introduce the concept of "metabolic features" which are often recognisable in conditions with generalised increased bone turnover. As an aid to systematic recognition of these features on a given bone scan image a semi-quantitative scoring system, the metabolic index, was introduced. The metabolic index allowed differentiation between various groups of patients with metabolic disorders and a control population. In addition, in a bone scan study of patients with acromegaly, it was found that the metabolic index correlated well with disease activity as measured by serum growth hormone levels. The metabolic index was, however, found to be a relatively insensitive means of identifying disease in individual patients. Patients with increased bone turnover will have an absolute increase in skeletal uptake of tracer. As a

Detrimental and protective fat: body fat distribution and its relation to metabolic disease.

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Booth, Andrea; Magnuson, Aaron; Foster, Michelle

2014-01-01

Obesity is linked to numerous comorbidities that include, but are not limited to, glucose intolerance, insulin resistance, dyslipidemia, and cardiovascular disease. Current evidence suggests, however, obesity itself is not an exclusive predictor of metabolic dysregulation but rather adipose tissue distribution. Obesity-related adverse health consequences occur predominately in individuals with upper body fat accumulation, the detrimental distribution, commonly associated with visceral obesity. Increased lower body subcutaneous adipose tissue, however, is associated with a reduced risk of obesity-induced metabolic dysregulation and even enhanced insulin sensitivity, thus, storage in this region is considered protective. The proposed mechanisms that causally relate the differential outcomes of adipose tissue distribution are often attributed to location and/or adipocyte regulation. Visceral adipose tissue effluent to the portal vein drains into the liver where hepatocytes are directly exposed to its metabolites and secretory products, whereas the subcutaneous adipose tissue drains systemically. Adipose depots are also inherently different in numerous ways such as adipokine release, immunity response and regulation, lipid turnover, rate of cell growth and death, and response to stress and sex hormones. Proximal extrinsic factors also play a role in the differential drive between adipose tissue depots. This review focuses on the deleterious mechanisms postulated to drive the differential metabolic response between central and lower body adipose tissue distribution.

DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

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Baroukh, Caroline; Muñoz-Tamayo, Rafael; Steyer, Jean-Philippe; Bernard, Olivier

2014-01-01

Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

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Caroline Baroukh

Full Text Available Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

Autotrophic microbe metagenomes and metabolic pathways differentiate adjacent red sea brine pools

KAUST Repository

Wang, Yong

2013-04-29

In the Red Sea, two neighboring deep-sea brine pools, Atlantis II and Discovery, have been studied extensively, and the results have shown that the temperature and concentrations of metal and methane in Atlantis II have increased over the past decades. Therefore, we investigated changes in the microbial community and metabolic pathways. Here, we compared the metagenomes of the two pools to each other and to those of deep-sea water samples. Archaea were generally absent in the Atlantis II metagenome; Bacteria in the metagenome were typically heterotrophic and depended on aromatic compounds and other extracellular organic carbon compounds as indicated by enrichment of the related metabolic pathways. In contrast, autotrophic Archaea capable of CO2 fixation and methane oxidation were identified in Discovery but not in Atlantis II. Our results suggest that hydrothermal conditions and metal precipitation in the Atlantis II pool have resulted in elimination of the autotrophic community and methanogens.

Differential effects of glyphosate and aminomethylphosphonic acid (AMPA) on photosynthesis and chlorophyll metabolism in willow plants.

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Gomes, Marcelo Pedrosa; Le Manac'h, Sarah Gingras; Maccario, Sophie; Labrecque, Michel; Lucotte, Marc; Juneau, Philippe

2016-06-01

We used a willow species (Salix miyabeana cultivar SX64) to examine the differential secondary-effects of glyphosate and aminomethylphosphonic acid (AMPA), the principal glyphosate by-product, on chlorophyll metabolism and photosynthesis. Willow plants were treated with different concentrations of glyphosate (equivalent to 0, 1.4, 2.1 and 2.8kgha(-1)) and AMPA (equivalent to 0, 0.28, 1.4 and 2.8kgha(-1)) and evaluations of pigment contents, chlorophyll fluorescence, and oxidative stress markers (hydrogen peroxide content and antioxidant enzyme activities) in leaves were performed after 12h of exposure. We observed that AMPA and glyphosate trigger different mechanisms leading to decreases in chlorophyll content and photosynthesis rates in willow plants. Both chemicals induced ROS accumulation in willow leaves although only glyphosate-induced oxidative damage through lipid peroxidation. By disturbing chlorophyll biosynthesis, AMPA induced decreases in chlorophyll contents, with consequent effects on photosynthesis. With glyphosate, ROS increases were higher than the ROS-sensitive threshold, provoking chlorophyll degradation (as seen by pheophytin accumulation) and invariable decreases in photosynthesis. Peroxide accumulation in both AMPA and glyphosate-treated plants was due to the inhibition of antioxidant enzyme activities. The different effects of glyphosate on chlorophyll contents and photosynthesis as described in the literature may be due to various glyphosate:AMPA ratios in those plants. Copyright © 2015 Elsevier Inc. All rights reserved.

Biosynthesis and metabolic fate of phenylalanine in conifers

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María Belén Pascual

2016-07-01

Full Text Available The amino acid phenylalanine (Phe is a critical metabolic node that plays an essential role in the interconnection between primary and secondary metabolism in plants. Phe is used as a protein building block but it is also as a precursor for numerous plant compounds that are crucial for plant reproduction, growth, development and defense against different types of stresses. The metabolism of Phe plays a central role in the channeling of carbon from photosynthesis to the biosynthesis of phenylpropanoids. The study of this metabolic pathway is particularly relevant in trees, which divert large amounts of carbon into the biosynthesis of Phe-derived compounds, particularly lignin, an important constituent of wood. The trunks of trees are metabolic sinks that consume a considerable percentage of carbon and energy from photosynthesis, and carbon is finally immobilized in wood. This paper reviews recent advances in the biosynthesis and metabolic utilization of Phe in conifer trees. Two alternative routes have been identified: the ancient phenylpyruvate pathway that is present in microorganisms, and the arogenate pathway that possibly evolved later during plant evolution. Additionally, an efficient nitrogen recycling mechanism is required to maintain sustained growth during xylem formation. The relevance of phenylalanine metabolic pathways in wood formation, the biotic interactions and ultraviolet protection is discussed. The genetic manipulation and transcriptional regulation of the pathways are also outlined.

Biosynthesis and Metabolic Fate of Phenylalanine in Conifers.

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Pascual, María B; El-Azaz, Jorge; de la Torre, Fernando N; Cañas, Rafael A; Avila, Concepción; Cánovas, Francisco M

2016-01-01

The amino acid phenylalanine (Phe) is a critical metabolic node that plays an essential role in the interconnection between primary and secondary metabolism in plants. Phe is used as a protein building block but it is also as a precursor for numerous plant compounds that are crucial for plant reproduction, growth, development, and defense against different types of stresses. The metabolism of Phe plays a central role in the channeling of carbon from photosynthesis to the biosynthesis of phenylpropanoids. The study of this metabolic pathway is particularly relevant in trees, which divert large amounts of carbon into the biosynthesis of Phe-derived compounds, particularly lignin, an important constituent of wood. The trunks of trees are metabolic sinks that consume a considerable percentage of carbon and energy from photosynthesis, and carbon is finally immobilized in wood. This paper reviews recent advances in the biosynthesis and metabolic utilization of Phe in conifer trees. Two alternative routes have been identified: the ancient phenylpyruvate pathway that is present in microorganisms, and the arogenate pathway that possibly evolved later during plant evolution. Additionally, an efficient nitrogen recycling mechanism is required to maintain sustained growth during xylem formation. The relevance of phenylalanine metabolic pathways in wood formation, the biotic interactions, and ultraviolet protection is discussed. The genetic manipulation and transcriptional regulation of the pathways are also outlined.

Metabolism of phthalates in humans

DEFF Research Database (Denmark)

Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

2007-01-01

on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some...... phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...... (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as...

Studies of liver-specific metabolic reactions with 15N. 1

International Nuclear Information System (INIS)

Hirschberg, K.; Jung, K.; Faust, H.; Matkowitz, R.

1987-01-01

The 15 N tracer technique was used to investigate liver-specific reactions (urea and hippurate synthesis) for studying the metabolism in the healthy and damaged pig liver. After [ 15 N]ammonium chloride administration the tracer distribution on non-protein compounds of serum and urine was followed. Blood samplings before and after liver passage rendered possible a direct analysis of the [ 15 N]ammonium metabolism. The thioacetamide-induced liver damage was used as model for an acute liver intoxication. The capacity for urea synthesis was not influenced by means of this noxious substance, but the metabolism of amino acids and hippuric acid. The considerably depressed excretion of [ 15 N]hippurate seems to be a suitable indicator of liver disfunction. (author)

Endothelial dysfunction in metabolic and vascular disorders.

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Polovina, Marija M; Potpara, Tatjana S

2014-03-01

Vascular endothelium has important regulatory functions in the cardiovascular system and a pivotal role in the maintenance of vascular health and metabolic homeostasis. It has long been recognized that endothelial dysfunction participates in the pathogenesis of atherosclerosis from early, preclinical lesions to advanced, thrombotic complications. In addition, endothelial dysfunction has been recently implicated in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering that states of insulin resistance (eg, metabolic syndrome, impaired fasting glucose, impaired glucose tolerance, and T2DM) represent the most prevalent metabolic disorders and risk factors for atherosclerosis, it is of considerable scientific and clinical interest that both metabolic and vascular disorders have endothelial dysfunction as a common background. Importantly, endothelial dysfunction has been associated with adverse outcomes in patients with established cardiovascular disease, and a growing body of evidence indicates that endothelial dysfunction also imparts adverse prognosis in states of insulin resistance. In this review, we discuss the association of insulin resistance and T2DM with endothelial dysfunction and vascular disease, with a focus on the underlying mechanisms and prognostic implications of the endothelial dysfunction in metabolic and vascular disorders. We also address current therapeutic strategies for the improvement of endothelial dysfunction.

Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

DEFF Research Database (Denmark)

Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

2018-01-01

during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor......Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling...... signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand...

Differential regulation of metabolic parameters by energy deficit and hunger.

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Kitka, Tamás; Tuza, Sebestyén; Varga, Balázs; Horváth, Csilla; Kovács, Péter

2015-10-01

Hypocaloric diet decreases both energy expenditure (EE) and respiratory exchange rate (RER), affecting the efficacy of dieting inversely. Energy deficit and hunger may be modulated separately both in human and animal studies by drug treatment or food restriction. Thus it is important to separate the effects of energy deficit and hunger on EE and RER. Three parallel and analogous experiments were performed using three pharmacologically distinct anorectic drugs: rimonabant, sibutramine and tramadol. Metabolic parameters of vehicle- and drug-treated and pair-fed diet-induced obese mice from the three experiments underwent common statistical analysis to identify effects independent of the mechanisms of action. Diet-induced obesity (DIO) test of tramadol was also performed to examine its anti-obesity efficacy. RER was decreased similarly by drug treatments and paired feeding throughout the experiment irrespective of the cause of reduced food intake. Contrarily, during the passive phase, EE was decreased more by paired feeding than by both vehicle and drug treatment irrespective of the drug used. In the active phase, EE was influenced by the pharmacological mechanisms of action. Tramadol decreased body weight in the DIO test. Our results suggest that RER is mainly affected by the actual state of energy balance; conversely, EE is rather influenced by hunger. Therefore, pharmacological medications that decrease hunger may enhance the efficacy of a hypocaloric diet by maintaining metabolic rate. Furthermore, our results yield the proposal that effects of anorectic drugs on EE and RER should be determined compared to vehicle and pair-fed groups, respectively, in animal models. Copyright © 2015 Elsevier Inc. All rights reserved.

Toward a New Philosophical Anthropology of Education: Fuller Considerations of Social Constructivism

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Fleury, Stephen; Garrison, Jim

2014-01-01

Philosophical anthropology is philosophical inquiry into human nature that seeks to answer the fundamental question of what generally characterizes human beings and differentiates them from other creatures and things. Political theories considerably influence educational theories. We call attention to the fact that the three main political…

Quantitative proteomics and systems analysis of cultured H9C2 cardiomyoblasts during differentiation over time supports a 'function follows form' model of differentiation.

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Kankeu, Cynthia; Clarke, Kylie; Van Haver, Delphi; Gevaert, Kris; Impens, Francis; Dittrich, Anna; Roderick, H Llewelyn; Passante, Egle; Huber, Heinrich J

2018-05-17

The rat cardiomyoblast cell line H9C2 has emerged as a valuable tool for studying cardiac development, mechanisms of disease and toxicology. We present here a rigorous proteomic analysis that monitored the changes in protein expression during differentiation of H9C2 cells into cardiomyocyte-like cells over time. Quantitative mass spectrometry followed by gene ontology (GO) enrichment analysis revealed that early changes in H9C2 differentiation are related to protein pathways of cardiac muscle morphogenesis and sphingolipid synthesis. These changes in the proteome were followed later in the differentiation time-course by alterations in the expression of proteins involved in cation transport and beta-oxidation. Studying the temporal profile of the H9C2 proteome during differentiation in further detail revealed eight clusters of co-regulated proteins that can be associated with early, late, continuous and transient up- and downregulation. Subsequent reactome pathway analysis based on these eight clusters further corroborated and detailed the results of the GO analysis. Specifically, this analysis confirmed that proteins related to pathways in muscle contraction are upregulated early and transiently, and proteins relevant to extracellular matrix organization are downregulated early. In contrast, upregulation of proteins related to cardiac metabolism occurs at later time points. Finally, independent validation of the proteomics results by immunoblotting confirmed hereto unknown regulators of cardiac structure and ionic metabolism. Our results are consistent with a 'function follows form' model of differentiation, whereby early and transient alterations of structural proteins enable subsequent changes that are relevant to the characteristic physiology of cardiomyocytes.

Pluripotent Stem Cell Metabolism and Mitochondria: Beyond ATP

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Jarmon G. Lees

2017-01-01

Full Text Available Metabolism is central to embryonic stem cell (ESC pluripotency and differentiation, with distinct profiles apparent under different nutrient milieu, and conditions that maintain alternate cell states. The significance of altered nutrient availability, particularly oxygen, and metabolic pathway activity has been highlighted by extensive studies of their impact on preimplantation embryo development, physiology, and viability. ESC similarly modulate their metabolism in response to altered metabolite levels, with changes in nutrient availability shown to have a lasting impact on derived cell identity through the regulation of the epigenetic landscape. Further, the preferential use of glucose and anaplerotic glutamine metabolism serves to not only support cell growth and proliferation but also minimise reactive oxygen species production. However, the perinuclear localisation of spherical, electron-poor mitochondria in ESC is proposed to sustain ESC nuclear-mitochondrial crosstalk and a mitochondrial-H2O2 presence, to facilitate signalling to support self-renewal through the stabilisation of HIFα, a process that may be favoured under physiological oxygen. The environment in which a cell is grown is therefore a critical regulator and determinant of cell fate, with metabolism, and particularly mitochondria, acting as an interface between the environment and the epigenome.

Yeast cell differentiation: Lessons from pathogenic and non-pathogenic yeasts.

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Palková, Zdena; Váchová, Libuše

2016-09-01

Yeasts, historically considered to be single-cell organisms, are able to activate different differentiation processes. Individual yeast cells can change their life-styles by processes of phenotypic switching such as the switch from yeast-shaped cells to filamentous cells (pseudohyphae or true hyphae) and the transition among opaque, white and gray cell-types. Yeasts can also create organized multicellular structures such as colonies and biofilms, and the latter are often observed as contaminants on surfaces in industry and medical care and are formed during infections of the human body. Multicellular structures are formed mostly of stationary-phase or slow-growing cells that diversify into specific cell subpopulations that have unique metabolic properties and can fulfill specific tasks. In addition to the development of multiple protective mechanisms, processes of metabolic reprogramming that reflect a changed environment help differentiated individual cells and/or community cell constituents to survive harmful environmental attacks and/or to escape the host immune system. This review aims to provide an overview of differentiation processes so far identified in individual yeast cells as well as in multicellular communities of yeast pathogens of the Candida and Cryptococcus spp. and the Candida albicans close relative, Saccharomyces cerevisiae. Molecular mechanisms and extracellular signals potentially involved in differentiation processes are also briefly mentioned. Copyright © 2016 Elsevier Ltd. All rights reserved.

The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism.

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Becker-Bense, Sandra; Dieterich, Marianne; Buchholz, Hans-Georg; Bartenstein, Peter; Schreckenberger, Mathias; Brandt, Thomas

2014-07-01

The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual-vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits.

Metabolic characterization of isocitrate dehydrogenase (IDH) mutant and IDH wildtype gliomaspheres uncovers cell type-specific vulnerabilities.

Science.gov (United States)

Garrett, Matthew; Sperry, Jantzen; Braas, Daniel; Yan, Weihong; Le, Thuc M; Mottahedeh, Jack; Ludwig, Kirsten; Eskin, Ascia; Qin, Yue; Levy, Rachelle; Breunig, Joshua J; Pajonk, Frank; Graeber, Thomas G; Radu, Caius G; Christofk, Heather; Prins, Robert M; Lai, Albert; Liau, Linda M; Coppola, Giovanni; Kornblum, Harley I

2018-01-01

There is considerable interest in defining the metabolic abnormalities of IDH mutant tumors to exploit for therapy. While most studies have attempted to discern function by using cell lines transduced with exogenous IDH mutant enzyme, in this study, we perform unbiased metabolomics to discover metabolic differences between a cohort of patient-derived IDH1 mutant and IDH wildtype gliomaspheres. Using both our own microarray and the TCGA datasets, we performed KEGG analysis to define pathways differentially enriched in IDH1 mutant and IDH wildtype cells and tumors. Liquid chromatography coupled to mass spectrometry analysis with labeled glucose and deoxycytidine tracers was used to determine differences in overall cellular metabolism and nucleotide synthesis. Radiation-induced DNA damage and repair capacity was assessed using a comet assay. Differences between endogenous IDH1 mutant metabolism and that of IDH wildtype cells transduced with the IDH1 (R132H) mutation were also investigated. Our KEGG analysis revealed that IDH wildtype cells were enriched for pathways involved in de novo nucleotide synthesis, while IDH1 mutant cells were enriched for pathways involved in DNA repair. LC-MS analysis with fully labeled 13 C-glucose revealed distinct labeling patterns between IDH1 mutant and wildtype cells. Additional LC-MS tracing experiments confirmed increased de novo nucleotide synthesis in IDH wildtype cells relative to IDH1 mutant cells. Endogenous IDH1 mutant cultures incurred less DNA damage than IDH wildtype cultures and sustained better overall growth following X-ray radiation. Overexpression of mutant IDH1 in a wildtype line did not reproduce the range of metabolic differences observed in lines expressing endogenous mutations, but resulted in depletion of glutamine and TCA cycle intermediates, an increase in DNA damage following radiation, and a rise in intracellular ROS. These results demonstrate that IDH1 mutant and IDH wildtype cells are easily distinguishable

Transcriptome data modeling for targeted plant metabolic engineering.

Science.gov (United States)

Yonekura-Sakakibara, Keiko; Fukushima, Atsushi; Saito, Kazuki

2013-04-01

The massive data generated by omics technologies require the power of bioinformatics, especially network analysis, for data mining and doing data-driven biology. Gene coexpression analysis, a network approach based on comprehensive gene expression data using microarrays, is becoming a standard tool for predicting gene function and elucidating the relationship between metabolic pathways. Differential and comparative gene coexpression analyses suggest a change in coexpression relationships and regulators controlling common and/or specific biological processes. In conjunction with the newly emerging genome editing technology, network analysis integrated with other omics data should pave the way for robust and practical plant metabolic engineering. Copyright © 2012 Elsevier Ltd. All rights reserved.

Risk Factors for the Development of Metabolic Disorders: A Review ...

African Journals Online (AJOL)

External factors impact on the hormones and enzymes which trigger development of metabolic disorders. The aim of this review was to highlight major hormonal and enzymatic factors that differentially predispose males and females to obesity, diabetes mellitus and hypertension. The research was a literaturebased ...

Non-invasive Assessments of Adipose Tissue Metabolism In Vitro.

Science.gov (United States)

Abbott, Rosalyn D; Borowsky, Francis E; Quinn, Kyle P; Bernstein, David L; Georgakoudi, Irene; Kaplan, David L

2016-03-01

Adipose tissue engineering is a diverse area of research where the developed tissues can be used to study normal adipose tissue functions, create disease models in vitro, and replace soft tissue defects in vivo. Increasing attention has been focused on the highly specialized metabolic pathways that regulate energy storage and release in adipose tissues which affect local and systemic outcomes. Non-invasive, dynamic measurement systems are useful to track these metabolic pathways in the same tissue model over time to evaluate long term cell growth, differentiation, and development within tissue engineering constructs. This approach reduces costs and time in comparison to more traditional destructive methods such as biochemical and immunochemistry assays and proteomics assessments. Towards this goal, this review will focus on important metabolic functions of adipose tissues and strategies to evaluate them with non-invasive in vitro methods. Current non-invasive methods, such as measuring key metabolic markers and endogenous contrast imaging will be explored.

Differential Gene Expression Patterns in Chicken Cardiomyocytes during Hydrogen Peroxide-Induced Apoptosis.

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Wan, Chunyun; Xiang, Jinmei; Li, Youwen; Guo, Dingzong

2016-01-01

Hydrogen peroxide (H2O2) is both an exogenous and endogenous cytotoxic agent that can reliably induce apoptosis in numerous cell types for studies on apoptosis signaling pathways. However, little is known of these apoptotic processes in myocardial cells of chicken, a species prone to progressive heart failure. Sequencing of mRNA transcripts (RNA-Seq) allows for the identification of differentially expressed genes under various physiological and pathological conditions to elucidate the molecular pathways involved, including cellular responses to exogenous and endogenous toxins. We used RNA-seq to examine genes differentially expressed during H2O2-induced apoptosis in primary cultures of embryonic chicken cardiomyocytes. Following control or H2O2 treatment, RNA was extracted and sequencing performed to identify novel transcripts up- or downregulated in the H2O2 treatment group and construct protein-protein interaction networks. Of the 19,268 known and 2,160 novel transcripts identified in both control and H2O2 treatment groups, 4,650 showed significant differential expression. Among them, 55.63% were upregulated and 44.37% downregulated. Initiation of apoptosis by H2O2 was associated with upregulation of caspase-8, caspase-9, and caspase-3, and downregulation of anti-apoptotic genes API5 and TRIA1. Many other differentially expressed genes were associated with metabolic pathways (including 'Fatty acid metabolism', 'Alanine, aspartate, and glutamate metabolism', and 'Biosynthesis of unsaturated fatty acids') and cell signaling pathways (including 'PPAR signaling pathway', 'Adipocytokine signaling pathway', 'TGF-beta signaling pathway', 'MAPK signaling pathway', and 'p53 signaling pathway'). In chicken cardiomyocytes, H2O2 alters the expression of numerous genes linked to cell signaling and metabolism as well as genes directly associated with apoptosis. In particular, H2O2 also affects the biosynthesis and processing of proteins and unsaturated fatty acids. These

Differential association between sarcopenia and metabolic phenotype in Korean young and older adults with and without obesity.

Science.gov (United States)

Hwang, You-Cheol; Cho, In-Jin; Jeong, In-Kyung; Ahn, Kyu Jeung; Chung, Ho Yeon

2017-01-01

To determine whether sarcopenia was associated with metabolic phenotype in subjects with and without obesity. A total of 6,021 participants (2,592 men, 3,429 women) aged 30 to 93 years were assessed using data from the 2009 Korea National Health and Nutrition Examination Survey. Sarcopenia was defined as appendicular skeletal muscle mass divided by weight (%) that is young adults. Metabolically unhealthy was defined as ≥2 components of metabolic syndrome or the presence of hypertension, diabetes, or cardiovascular disease. Obesity was defined as body mass index ≥25.0 kg/m 2 . Sarcopenia was associated with a metabolically unhealthy phenotype in nonobese men independent of age, smoking, regular physical activity, daily energy intake, total body fat, fasting insulin, non-HDL cholesterol, white blood cell count, ferritin level, and 25(OH) vitamin D level (OR per 1 SD increment (95% CI) 1.88 (1.28-2.75), P obesity. Sarcopenia was independently associated with a metabolically unhealthy phenotype in nonobese men, but this association was not evident in nonobese women or subjects with obesity. © 2016 The Obesity Society.

High-throughput metabolic state analysis: The missing link in integrated functional genomics of yeasts

DEFF Research Database (Denmark)

Villas-Bôas, Silas Granato; Moxley, Joel. F; Åkesson, Mats Fredrik

2005-01-01

that achieve comparable throughput, effort and cost compared with DNA arrays. Our sample workup method enables simultaneous metabolite measurements throughout central carbon metabolism and amino acid biosynthesis, using a standard GC-MS platform that was optimized for this Purpose. As an implementation proof......-of-concept, we assayed metabolite levels in two yeast strains and two different environmental conditions in the context of metabolic pathway reconstruction. We demonstrate that these differential metabolite level data distinguish among sample types, such as typical metabolic fingerprinting or footprinting. More...

Comparative Biochemistry and Metabolism. Part 1. Carcinogenesis

Science.gov (United States)

1982-08-01

1968), Nitrosamine-induced carcino- genesis. The alkylation of nucleic acids of the rat by N-methvl- N- nitrosourea , dimethylnitrosamine...inorganic reducing agent , hydrazine, is toxic and weakly carcinogenic. In earlier studies it was found that oral administration of a toxic dose of...metabolically activated to a methylatinj agent . Liver DNA from mice and hamsters contained considerably more 7-methyl- guanine and 0 6-methylguanine

Fitness attenuates the prevalence of increased coronary artery calcium in individuals with metabolic syndrome.

Science.gov (United States)

Ekblom-Bak, Elin; Ekblom, Örjan; Fagman, Erika; Angerås, Oskar; Schmidt, Caroline; Rosengren, Annika; Börjesson, Mats; Bergström, Göran

2018-02-01

Background The association between cardiorespiratory fitness, physical activity and coronary artery calcium (CAC) is unclear, and whether higher levels of fitness attenuate CAC prevalence in subjects with metabolic syndrome is not fully elucidated. The present study aims to: a) investigate the independent association of fitness on the prevalence of CAC, after adjustment for moderate-to-vigorous physical activity and sedentary time, and b) study the possible attenuation of increased CAC by higher fitness, in participants with metabolic syndrome. Design Cross-sectional. Methods In total 678 participants (52% women), 50-65 years old, from the SCAPIS pilot study were included. Fitness (VO 2 max) was estimated by submaximal cycle ergometer test and moderate-to-vigorous physical activity and sedentary time were assessed using hip-worn accelerometers. CAC score (CACS) was quantified using the Agatston score. Results The odds of having a significant CACS (≥100) was half in participants with moderate/high fitness compared with their low fitness counterparts. Further consideration of moderate-to-vigorous physical activity, sedentary time and number of components of the metabolic syndrome did only slightly alter the effect size. Those with metabolic syndrome had 47% higher odds for significant CAC compared with those without metabolic syndrome. However, moderate/high fitness seems to partially attenuate this risk, as further joint analysis indicated an increased odds for having significant CAC only in the unfit metabolic syndrome participants. Conclusions Being fit is associated with a reduced risk of having significant CAC in individuals with metabolic syndrome. While still very much underutilized, fitness should be taken into consideration in everyday clinical risk prediction in addition to the traditional risk factors of the metabolic syndrome.

Differentiation of human-induced pluripotent stem cell under flow conditions to mature hepatocytes for liver tissue engineering

DEFF Research Database (Denmark)

Starokozhko, Viktoriia; Hemmingsen, Mette; Larsen, Layla

2018-01-01

Hepatic differentiation of human-induced pluripotent stem cells (hiPSCs) under flow conditions in a 3D scaffold is expected to be a major step forward for construction of bioartificial livers. The aims of this study were to induce hepatic differentiation of hiPSCs under perfusion conditions...... and to perform functional comparisons with fresh human precision-cut liver slices (hPCLS), an excellent benchmark for the human liver in vivo. The majority of the mRNA expression of CYP isoenzymes and transporters and the tested CYP activities, Phase II metabolism, and albumin, urea, and bile acid synthesis...... in the hiPSC-derived cells reached values that overlap those of hPCLS, which indicates a higher degree of hepatic differentiation than observed until now. Differentiation under flow compared with static conditions had a strong inducing effect on Phase II metabolism and suppressed AFP expression but resulted...

Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid

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Anna Koczula

2017-02-01

Full Text Available Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq. In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism. In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.

Identification of differentially expressed proteins in response to Pb ...

African Journals Online (AJOL)

In response to Pb, a total of 76 proteins, out of the 95 differentially expressed proteins, were subjected to MALDI-TOF-MS Of these, 46 identities were identified by PMF and 19 identities were identified by microsequencing. Basic metabolisms such as photosynthesis, photorespiration and protein biosynthesis in C. roseus ...

Differential selection on carotenoid biosynthesis genes as a function of gene position in the metabolic pathway: a study on the carrot and dicots.

Directory of Open Access Journals (Sweden)

Jérémy Clotault

Full Text Available Selection of genes involved in metabolic pathways could target them differently depending on the position of genes in the pathway and on their role in controlling metabolic fluxes. This hypothesis was tested in the carotenoid biosynthesis pathway using population genetics and phylogenetics.Evolutionary rates of seven genes distributed along the carotenoid biosynthesis pathway, IPI, PDS, CRTISO, LCYB, LCYE, CHXE and ZEP, were compared in seven dicot taxa. A survey of deviations from neutrality expectations at these genes was also undertaken in cultivated carrot (Daucus carota subsp. sativus, a species that has been intensely bred for carotenoid pattern diversification in its root during its cultivation history. Parts of sequences of these genes were obtained from 46 individuals representing a wide diversity of cultivated carrots. Downstream genes exhibited higher deviations from neutral expectations than upstream genes. Comparisons of synonymous and nonsynonymous substitution rates between genes among dicots revealed greater constraints on upstream genes than on downstream genes. An excess of intermediate frequency polymorphisms, high nucleotide diversity and/or high differentiation of CRTISO, LCYB1 and LCYE in cultivated carrot suggest that balancing selection may have targeted genes acting centrally in the pathway.Our results are consistent with relaxed constraints on downstream genes and selection targeting the central enzymes of the carotenoid biosynthesis pathway during carrot breeding history.

Metabolic fingerprinting of fresh lymphoma samples used to discriminate between follicular and diffuse large B-cell lymphomas.

Science.gov (United States)

Barba, Ignasi; Sanz, Carolina; Barbera, Angels; Tapia, Gustavo; Mate, José-Luis; Garcia-Dorado, David; Ribera, Josep-Maria; Oriol, Albert

2009-11-01

To investigate if proton nuclear magnetic resonance ((1)H NMR) spectroscopy-based metabolic profiling was able to differentiate follicular lymphoma (FL) from diffuse large B-cell lymphoma (DLBCL) and to study which metabolites were responsible for the differences. High-resolution (1)H NMR spectra was obtained from fresh samples of lymph node biopsies obtained consecutively at one center (14 FL and 17 DLBCL). Spectra were processed using pattern-recognition methods. Discriminant models were able to differentiate between the two tumor types with a 86% sensitivity and a 76% specificity; the metabolites that most contributed to the discrimination were a relative increase of alanine in the case of DLBCL and a relative increase of taurine in FL. Metabolic models had a significant but weak correlation with Ki67 expression (r(2)=0.42; p=0.002) We have proved that it is possible to differentiate between FL and DLBCL based on their NMR metabolic profiles. This approach may potentially be applicable as a noninvasive tool for diagnostic and treatment follow-up in the clinical setting using conventional magnetic resonance systems.

Obesity: considerations about etiology, metabolism, and the use of experimental models

Directory of Open Access Journals (Sweden)

Lancha Junior AH

2012-04-01

Full Text Available Luciana O Pereira-Lancha, Patricia L Campos-Ferraz, Antonio H Lancha JuniorSchool of Physical Education and Sport, University of Sao Paulo, Sao Paulo, BrazilAbstract: Studies have been conducted in order to identify the main factors that contribute to the development of obesity. The role of genetics has also been extensively studied. However, the substantial augmentation of obesity prevalence in the last 20 years cannot be justified only by genetic alterations that, theoretically, would have occurred in such a short time. Thus, the difference in obesity prevalence in various population groups is also related to environmental factors, especially diet and the reduction of physical activity. These aspects, interacting or not with genetic factors, could explain the excess of body fat in large proportions worldwide. This article will focus on positive energy balance, high-fat diet, alteration in appetite control hormones, insulin resistance, amino acids metabolism, and the limitation of the experimental models to address this complex issue.Keywords: obesity, diet, leptin, fat, ghrelin, experimental models

Sexual differentiation in fission yeast

DEFF Research Database (Denmark)

Egel, R; Nielsen, O; Weilguny, D

1990-01-01

The regulation of sexual reproduction in yeast constitutes the highest level of differentiation observed in these unicellular organisms. The various ramifications of this system involve DNA rearrangement, transcriptional control, post-translational modification (such as protein phosphorylation) a......) and receptor/signal processing. A few basic similarities are common to both fission and budding yeasts. The wiring of the regulatory circuitry, however, varies considerably between these divergent yeast groups....

Spectrum of metabolic myopathies.

Science.gov (United States)

Angelini, Corrado

2015-04-01

Metabolic myopathies are disorders of utilization of carbohydrates or fat in muscles. The acute nature of energy failure is manifested either by a metabolic crisis with weakness, sometimes associated with respiratory failure, or by myoglobinuria. A typical disorder where permanent weakness occurs is glycogenosis type II (GSDII or Pompe disease) both in infantile and late-onset forms, where respiratory insufficiency is manifested by a large number of cases. In GSDII the pathogenetic mechanism is still poorly understood, and has to be attributed more to structural muscle alterations, possibly in correlation to macro-autophagy, rather than to energetic failure. This review is focused on recent advances about GSDII and its treatment, and the most recent notions about the management and treatment of other metabolic myopathies will be briefly reviewed, including glycogenosis type V (McArdle disease), glycogenosis type III (debrancher enzyme deficiency or Cori disease), CPT-II deficiency, and ETF-dehydrogenase deficiency (also known as riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency or RR-MADD). The discovery of the genetic defect in ETF dehydrogenase confirms the etiology of this syndrome. Other metabolic myopathies with massive lipid storage and weakness are carnitine deficiency, neutral lipid storage-myopathy (NLSD-M), besides RR-MADD. Enzyme replacement therapy is presented with critical consideration and for each of the lipid storage disorders, representative cases and their response to therapy is included. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. Copyright © 2014. Published by Elsevier B.V.

Computational Modeling of Lipid Metabolism in Yeast

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Vera Schützhold

2016-09-01

Full Text Available Lipid metabolism is essential for all major cell functions and has recently gained increasing attention in research and health studies. However, mathematical modeling by means of classical approaches such as stoichiometric networks and ordinary differential equation systems has not yet provided satisfactory insights, due to the complexity of lipid metabolism characterized by many different species with only slight differences and by promiscuous multifunctional enzymes.Here, we present a object-oriented stochastic model approach as a way to cope with the complex lipid metabolic network. While all lipid species are treated objects in the model, they can be modified by the respective converting reactions based on reaction rules, a hybrid method that integrates benefits of agent-based and classical stochastic simulation. This approach allows to follow the dynamics of all lipid species with different fatty acids, different degrees of saturation and different headgroups over time and to analyze the effect of parameter changes, potential mutations in the catalyzing enzymes or provision of different precursors. Applied to yeast metabolism during one cell cycle period, we could analyze the distribution of all lipids to the various membranes in time-dependent manner.The presented approach allows to efficiently treat the complexity of cellular lipid metabolism and to derive conclusions on the time- and location-dependent distributions of lipid species and their properties such as saturation. It is widely applicable, easily extendable and will provide further insights in healthy and diseased states of cell metabolism.

3-Bromopyruvate treatment induces alterations of metabolic and stress-related pathways in glioblastoma cells.

Science.gov (United States)

Chiasserini, Davide; Davidescu, Magdalena; Orvietani, Pier Luigi; Susta, Federica; Macchioni, Lara; Petricciuolo, Maya; Castigli, Emilia; Roberti, Rita; Binaglia, Luciano; Corazzi, Lanfranco

2017-01-30

Glioblastoma (GBM) is the most common and aggressive brain tumour of adults. The metabolic phenotype of GBM cells is highly dependent on glycolysis; therefore, therapeutic strategies aimed at interfering with glycolytic pathways are under consideration. 3-Bromopyruvate (3BP) is a potent antiglycolytic agent, with a variety of targets and possible effects on global cell metabolism. Here we analyzed the changes in protein expression on a GBM cell line (GL15 cells) caused by 3BP treatment using a global proteomic approach. Validation of differential protein expression was performed with immunoblotting and enzyme activity assays in GL15 and U251 cell lines. The results show that treatment of GL15 cells with 3BP leads to extensive changes in the expression of glycolytic enzymes and stress related proteins. Importantly, other metabolisms were also affected, including pentose phosphate pathway, aminoacid synthesis, and glucose derivatives production. 3BP elicited the activation of stress response proteins, as shown by the phosphorylation of HSPB1 at serine 82, caused by the concomitant activation of the p38 pathway. Our results show that inhibition of glycolysis in GL15 cells by 3BP influences different but interconnected pathways. Proteome analysis may help in the molecular characterization of the glioblastoma response induced by pharmacological treatment with antiglycolytic agents. Alteration of the glycolytic pathway characterizes glioblastoma (GBM), one of the most common brain tumours. Metabolic reprogramming with agents able to inhibit carbohydrate metabolism might be a viable strategy to complement the treatment of these tumours. The antiglycolytic agent 3-bromopyruvate (3BP) is able to strongly inhibit glycolysis but it may affect also other cellular pathways and its precise cellular targets are currently unknown. To understand the protein expression changes induced by 3BP, we performed a global proteomic analysis of a GBM cell line (GL15) treated with 3BP. We

Screening newborns for metabolic disorders based on targeted metabolomics using tandem mass spectrometry

OpenAIRE

Yoon, Hye-Ran

2015-01-01

The main purpose of newborn screening is to diagnose genetic, metabolic, and other inherited disorders, at their earliest to start treatment before the clinical manifestations become evident. Understanding and tracing the biochemical data obtained from tandem mass spectrometry is vital for early diagnosis of metabolic diseases associated with such disorders. Accordingly, it is important to focus on the entire diagnostic process, including differential and confirmatory diagnostic options, and ...

Metabolic pathways for the whole community.

Science.gov (United States)

Hanson, Niels W; Konwar, Kishori M; Hawley, Alyse K; Altman, Tomer; Karp, Peter D; Hallam, Steven J

2014-07-22

A convergence of high-throughput sequencing and computational power is transforming biology into information science. Despite these technological advances, converting bits and bytes of sequence information into meaningful insights remains a challenging enterprise. Biological systems operate on multiple hierarchical levels from genomes to biomes. Holistic understanding of biological systems requires agile software tools that permit comparative analyses across multiple information levels (DNA, RNA, protein, and metabolites) to identify emergent properties, diagnose system states, or predict responses to environmental change. Here we adopt the MetaPathways annotation and analysis pipeline and Pathway Tools to construct environmental pathway/genome databases (ePGDBs) that describe microbial community metabolism using MetaCyc, a highly curated database of metabolic pathways and components covering all domains of life. We evaluate Pathway Tools' performance on three datasets with different complexity and coding potential, including simulated metagenomes, a symbiotic system, and the Hawaii Ocean Time-series. We define accuracy and sensitivity relationships between read length, coverage and pathway recovery and evaluate the impact of taxonomic pruning on ePGDB construction and interpretation. Resulting ePGDBs provide interactive metabolic maps, predict emergent metabolic pathways associated with biosynthesis and energy production and differentiate between genomic potential and phenotypic expression across defined environmental gradients. This multi-tiered analysis provides the user community with specific operating guidelines, performance metrics and prediction hazards for more reliable ePGDB construction and interpretation. Moreover, it demonstrates the power of Pathway Tools in predicting metabolic interactions in natural and engineered ecosystems.

Metabolic alkalosis in children: Study of patients admitted to pediatrics center1

Directory of Open Access Journals (Sweden)

2000-07-01

Full Text Available Metabolic alkalosis is characterized by high HCO3- as it is seen in chronic respiratory acidosis, but PH differentiates the two disorders. There is no characteristic symptom or sign. Orthostatic hypotension may be encountered. Weakness and hyporeflexia occur if serum K+ is markerdly low. Tetany and neuromuscular irritability occur rarely. We report the results of retrospective data analysis of metabolic alkalosis in 15463 patients hospitalized Pediatric Medical Center in Tehran during years 1995-1997. We found 50 cases of metabolic alkalosis (rate of 0.32 percent. 64 precent male and 36 percent female. Most of them had growth failure (40% were bellow 3 percentile of height by age, 44% bellow 5 percentile of weight by height. More than 60 percent had hypokalemia, hypocloremia and hyponatremia. The most common cause of Metabolic alkalosis was cystic fibrosis and pyloric stenosis. Fifty percent of cystic fibrosis patients and Bartter cases had metabolic alkalosis. Metabolic alkalosis should be considered in every pediatric patient presented with projectile vomitting.

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis.

Science.gov (United States)

Bozec, Aline; Hannemann, Nicole

2016-06-03

Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.

Differential programming of p53-deficient embryonic cells during rotenone block

Science.gov (United States)

Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53- efficient embryonic fibroblasts compared to p53-deficient cells. These c...

Proteomic analysis of osteogenic differentiation of dental follicle precursor cells

DEFF Research Database (Denmark)

Morsczeck, Christian; Petersen, Jørgen; Völlner, Florian

2009-01-01

of differentiation. In the present study we applied 2-DE combined with capillary-LC-MS/MS analysis to profile differentially regulated proteins upon differentiation of dental follicle precursor cells (DFPCs). Out of 115 differentially regulated proteins, glutamine synthetase, lysosomal proteinase cathepsin B....... The bioinformatic analyses suggest that proteins associated with cell cycle progression and protein metabolism were down-regulated and proteins involved in catabolism, cell motility and biological quality were up-regulated. These results display the general physiological state of DFPCs before and after osteogenic...... proteins, plastin 3 T-isoform, beta-actin, superoxide dismutases, and transgelin were found to be highly up-regulated, whereas cofilin-1, pro-alpha 1 collagen, destrin, prolyl 4-hydrolase and dihydrolipoamide dehydrogenase were found to be highly down-regulated. The group of up-regulated proteins...

Existence of a coupled system of fractional differential equations

International Nuclear Information System (INIS)

Ibrahim, Rabha W.; Siri, Zailan

2015-01-01

We manage the existence and uniqueness of a fractional coupled system containing Schrödinger equations. Such a system appears in quantum mechanics. We confirm that the fractional system under consideration admits a global solution in appropriate functional spaces. The solution is shown to be unique. The method is based on analytic technique of the fixed point theory. The fractional differential operator is considered from the virtue of the Riemann-Liouville differential operator

Existence of a coupled system of fractional differential equations

Energy Technology Data Exchange (ETDEWEB)

Ibrahim, Rabha W. [Multimedia unit, Department of Computer System and Technology Faculty of Computer Science & IT, University of Malaya, 50603 Kuala Lumpur (Malaysia); Siri, Zailan [Institute of Mathematical Sciences, University of Malaya, 50603 Kuala Lumpur (Malaysia)

2015-10-22

We manage the existence and uniqueness of a fractional coupled system containing Schrödinger equations. Such a system appears in quantum mechanics. We confirm that the fractional system under consideration admits a global solution in appropriate functional spaces. The solution is shown to be unique. The method is based on analytic technique of the fixed point theory. The fractional differential operator is considered from the virtue of the Riemann-Liouville differential operator.

Irisin Enhances Osteoblast Differentiation In Vitro

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Graziana Colaianni

2014-01-01

Full Text Available It has been recently demonstrated that exercise activity increases the expression of the myokine Irisin in skeletal muscle, which is able to drive the transition of white to brown adipocytes, likely following a phenomenon of transdifferentiation. This new evidence supports the idea that muscle can be considered an endocrine organ, given its ability to target adipose tissue by promoting energy expenditure. In accordance with these new findings, we hypothesized that Irisin is directly involved in bone metabolism, demonstrating its ability to increase the differentiation of bone marrow stromal cells into mature osteoblasts. Firstly, we confirmed that myoblasts from mice subjected to 3 weeks of free wheel running increased Irisin expression compared to nonexercised state. The conditioned media (CM collected from myoblasts of exercised mice induced osteoblast differentiation in vitro to a greater extent than those of mice housed in resting conditions. Furthermore, the differentiated osteoblasts increased alkaline phosphatase and collagen I expression by an Irisin-dependent mechanism. Our results show, for the first time, that Irisin directly targets osteoblasts, enhancing their differentiation. This finding advances notable perspectives in future studies which could satisfy the ongoing research of exercise-mimetic therapies with anabolic action on the skeleton.

The metabolism of malate by cultured rat brain astrocytes

Energy Technology Data Exchange (ETDEWEB)

McKenna, M.C.; Tildon, J.T.; Couto, R.; Stevenson, J.H.; Caprio, F.J. (Department of Pediatrics, University of Maryland School of Medicine, Baltimore (USA))

1990-12-01

Since malate is known to play an important role in a variety of functions in the brain including energy metabolism, the transfer of reducing equivalents and possibly metabolic trafficking between different cell types; a series of biochemical determinations were initiated to evaluate the rate of 14CO2 production from L-(U-14C)malate in rat brain astrocytes. The 14CO2 production from labeled malate was almost totally suppressed by the metabolic inhibitors rotenone and antimycin A suggesting that most of malate metabolism was coupled to the electron transport system. A double reciprocal plot of the 14CO2 production from the metabolism of labeled malate revealed biphasic kinetics with two apparent Km and Vmax values suggesting the presence of more than one mechanism of malate metabolism in these cells. Subsequent experiments were carried out using 0.01 mM and 0.5 mM malate to determine whether the addition of effectors would differentially alter the metabolism of high and low concentrations of malate. Effectors studied included compounds which could be endogenous regulators of malate metabolism and metabolic inhibitors which would provide information regarding the mechanisms regulating malate metabolism. Both lactate and aspartate decreased 14CO2 production from malate equally. However, a number of effectors were identified which selectively altered the metabolism of 0.01 mM malate including aminooxyacetate, furosemide, N-acetylaspartate, oxaloacetate, pyruvate and glucose, but had little or no effect on the metabolism of 0.5 mM malate. In addition, alpha-ketoglutarate and succinate decreased 14CO2 production from 0.01 mM malate much more than from 0.5 mM malate. In contrast, a number of effectors altered the metabolism of 0.5 mM malate more than 0.01 mM. These included methionine sulfoximine, glutamate, malonate, alpha-cyano-4-hydroxycinnamate and ouabain.

Forkhead Box C1 Regulates Human Primary Keratinocyte Terminal Differentiation.

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Lianghua Bin

Full Text Available The epidermis serves as a critical protective barrier between the internal and external environment of the human body. Its remarkable barrier function is established through the keratinocyte (KC terminal differentiation program. The transcription factors specifically regulating terminal differentiation remain largely unknown. Using a RNA-sequencing (RNA-seq profiling approach, we found that forkhead box c 1 (FOXC1 was significantly up-regulated in human normal primary KC during the course of differentiation. This observation was validated in human normal primary KC from several different donors and human skin biopsies. Silencing FOXC1 in human normal primary KC undergoing differentiation led to significant down-regulation of late terminal differentiation genes markers including epidermal differentiation complex genes, keratinization genes, sphingolipid/ceramide metabolic process genes and epidermal specific cell-cell adhesion genes. We further demonstrated that FOXC1 works down-stream of ZNF750 and KLF4, and upstream of GRHL3. Thus, this study defines FOXC1 as a regulator specific for KC terminal differentiation and establishes its potential position in the genetic regulatory network.

Neuronal Progenitor Maintenance Requires Lactate Metabolism and PEPCK-M-Directed Cataplerosis.

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Álvarez, Zaida; Hyroššová, Petra; Perales, José Carlos; Alcántara, Soledad

2016-03-01

This study investigated the metabolic requirements for neuronal progenitor maintenance in vitro and in vivo by examining the metabolic adaptations that support neuronal progenitors and neural stem cells (NSCs) in their undifferentiated state. We demonstrate that neuronal progenitors are strictly dependent on lactate metabolism, while glucose induces their neuronal differentiation. Lactate signaling is not by itself capable of maintaining the progenitor phenotype. The consequences of lactate metabolism include increased mitochondrial and oxidative metabolism, with a strict reliance on cataplerosis through the mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) pathway to support anabolic functions, such as the production of extracellular matrix. In vivo, lactate maintains/induces populations of postnatal neuronal progenitors/NSCs in a PEPCK-M-dependent manner. Taken together, our data demonstrate that, lactate alone or together with other physical/biochemical cues maintain NSCs/progenitors with a metabolic signature that is classically found in tissues with high anabolic capacity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Similar post-stress metabolic trajectories in young and old flies.

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Colinet, Hervé; Renault, David

2018-02-01

Homeostenosis (i.e. decline in stress resistance and resilience with age) is a fundamental notion of the biogerontology and physiology of aging. Stressful situations typically challenge metabolic homeostasis and the capacity to recover from a stress-induced metabolic disorder might be particularly compromised in senescent individuals. In the present work, we report the effects of aging on low temperature stress tolerance and metabolic profiles in Drosophila melanogaster females of different ages. Adult flies aged 4, 16, 30 and 44days were subjected to acute and chronic cold stress, and data confirmed a strong decline in cold tolerance and resilience of old flies compared to young counterparts. Using quantitative target GC-MS analysis, we found distinct metabolic phenotypes between young (4day-old) and old (44day-old) flies, with glycolytic pathways being differentially affected between the two age groups. We also compared the robustness of metabolic homeostasis in young vs. old flies when exposed to cold stress using time-series metabolic analysis. In both age groups, we found evidence of strong alteration of metabolic profiles when flies were exposed to low temperature stress. Interestingly, the temporal metabolic trajectories during the recovery period were similar in young and old flies, despite strong differences in thermotolerance. In conclusion, metabolic signatures markedly changed with age and homeostenosis was observed in the phenotypic response to cold stress. However, these changes did not reflect in different temporal homeostatic response at metabolic level. Copyright © 2017 Elsevier Inc. All rights reserved.

Global collective dose commitments from release of long-lived radionuclides. Differential cost-benefit considerations

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Gjoerup, H.L.

1977-01-01

The concept of global collective dose commitment as a measure of total detriment from the release of radioactivity to the environment is outlined. Estimates are given of global collective dose commitments resulting from the release of 14 C and uranium daughter products from the nuclear fuel cycle. Comparisons are made with similar estimates of global collective dose commitments resulting from the use of fossil fuels and certain fertilizers due to their content of uranium and its daughter products. In the case of long-lived radionuclides that remain in circulation in the biosphere, it is shown that the use of global collective dose commitments in differential cost-benefit analysis can lead to questionable results. In differential cost-benefit analysis it is suggested that population exposures should not simply be integrated irrespective of their time of occurrence, but that a certain discount rate should be applied for future doses. This suggestion is examined. (author)

Chronic fluoxetine treatment directs energy metabolism towards the citric acid cycle and oxidative phosphorylation in rat hippocampal nonsynaptic mitochondria.

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Filipović, Dragana; Costina, Victor; Perić, Ivana; Stanisavljević, Andrijana; Findeisen, Peter

2017-03-15

Fluoxetine (Flx) is the principal treatment for depression; however, the precise mechanisms of its actions remain elusive. Our aim was to identify protein expression changes within rat hippocampus regulated by chronic Flx treatment versus vehicle-controls using proteomics. Fluoxetine-hydrohloride (15mg/kg) was administered daily to adult male Wistar rats for 3weeks, and cytosolic and nonsynaptic mitochondrial hippocampal proteomes were analyzed. All differentially expressed proteins were functionally annotated according to biological process and molecular function using Uniprot and Blast2GO. Our comparative study revealed that in cytosolic and nonsynaptic mitochondrial fractions, 60 and 3 proteins respectively, were down-regulated, and 23 and 60 proteins, respectively, were up-regulated. Proteins differentially regulated in cytosolic and nonsynaptic mitochondrial fractions were primarily related to cellular and metabolic processes. Of the identified proteins, the expressions of calretinin and parvalbumine were confirmed. The predominant molecular functions of differentially expressed proteins in both cell hippocampal fractions were binding and catalytic activity. Most differentially expressed proteins in nonsynaptic mitochondria were catalytic enzymes involved in the pyruvate metabolism, citric acid cycle, oxidative phosphorylation, ATP synthesis, ATP transduction and glutamate metabolism. Results indicate that chronic Flx treatment may influence proteins involved in calcium signaling, cytoskeletal structure, chaperone system and stimulates energy metabolism via the upregulation of GAPDH expression in cytoplasm, as well as directing energy metabolism toward the citric acid cycle and oxidative phosphorylation in nonsynaptic mitochondria. This approach provides new insight into the chronic effects of Flx treatment on protein expression in a key brain region associated with stress response and memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Noninfectious differential diagnoses of pneumonia

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Wielandner, A.; Toelly, A.; Agarwal, P.; Bardach, C.

2017-01-01

In patients with a clinical suspicion of pneumonia, typical clinical and laboratory features along with the detection of infiltrates on chest X-ray are as a rule considered diagnostic and therapy is immediately initiated; however, studies have shown that in up to 5% of patients with an initial suspicion of pneumonia, another noninfectious pulmonary disease was the underlying cause. Early recognition and differentiation of diseases mimicking pneumonia are prerequisites for an adequate therapy. The aim of this review is to present the important noninfectious differential diagnoses of pneumonia and to provide the reader with tools for a systematic diagnostic approach. A literature search was carried out. As alterations in the lungs often result in similar imaging appearances and a differentiation between transudates, exsudates, blood and cells is not feasible by chest X-ray or CT, a systematic approach is essential to make an appropriate diagnosis. Hence, consideration of the temporal course, predominant pattern, distribution of findings, additional findings and clinical presentation are indispensable. (orig.) [de

Differential geometry in string models

International Nuclear Information System (INIS)

Alvarez, O.

1986-01-01

In this article the author reviews the differential geometric approach to the quantization of strings. A seminal paper demonstrates the connection between the trace anomaly and the critical dimension. The role played by the Faddeev-Popov ghosts has been instrumental in much of the subsequent work on the quantization of strings. This paper discusses the differential geometry of two dimensional surfaces and its importance in the quantization of strings. The path integral quantization approach to strings will be carefully analyzed to determine the correct effective measure for string theories. The choice of measure for the path integral is determined by differential geometric considerations. Once the measure is determined, the manifest diffeomorphism invariance of the theory will have to be broken by using the Faddeev-Popov ansatz. The gauge fixed theory is studied in detail with emphasis on the role of conformal and gravitational anomalies. In the analysis, the path integral formulation of the gauge fixed theory requires summing over all the distinct complex structures on the manifold

Structural, Functional, and Metabolic Brain Markers Differentiate Collision versus Contact and Non-Contact Athletes.

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Churchill, Nathan W; Hutchison, Michael G; Di Battista, Alex P; Graham, Simon J; Schweizer, Tom A

2017-01-01

There is growing concern about how participation in contact sports affects the brain. Retrospective evidence suggests that contact sports are associated with long-term negative health outcomes. However, much of the research to date has focused on former athletes with significant health problems. Less is known about the health of current athletes in contact and collision sports who have not reported significant medical issues. In this cross-sectional study, advanced magnetic resonance imaging (MRI) was used to evaluate multiple aspects of brain physiology in three groups of athletes participating in non-contact sports ( N  = 20), contact sports ( N  = 22), and collision sports ( N  = 23). Diffusion tensor imaging was used to assess white matter microstructure based on measures of fractional anisotropy (FA) and mean diffusivity (MD); resting-state functional MRI was used to evaluate global functional connectivity; single-voxel spectroscopy was used to compare ratios of neural metabolites, including N -acetyl aspartate (NAA), creatine (Cr), choline, and myo-inositol. Multivariate analysis revealed structural, functional, and metabolic measures that reliably differentiated between sport groups. The collision group had significantly elevated FA and reduced MD in white matter, compared to both contact and non-contact groups. In contrast, the collision group showed significant reductions in functional connectivity and the NAA/Cr metabolite ratio, relative to only the non-contact group, while the contact group overlapped with both non-contact and collision groups. For brain regions associated with contact sport participation, athletes with a history of concussion also showed greater alterations in FA and functional connectivity, indicating a potential cumulative effect of both contact exposure and concussion history on brain physiology. These findings indicate persistent differences in brain physiology for athletes participating in contact and collision sports

Telmisartan as metabolic modulator: a new perspective in sports doping?

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Sanchis-Gomar, Fabian; Lippi, Giuseppe

2012-03-01

The World Antidoping Agency (WADA) has introduced some changes in the 2012 prohibited list. Among the leading innovations to the rules are that both 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (peroxisome proliferator-activated receptor-δ [PPAR-δ]-5' adenosine monophosphate-activated protein kinase [AMPK] agonist) and GW1516 (PPAR-δ-agonist) are no longer categorized as gene doping substances in the new 2012 prohibited list but as metabolic modulators in the class "Hormone and metabolic modulators." This may also be valid for the angotensin II receptor blocker telmisartan. It has recently been shown that telmisartan might induce similar biochemical, biological, and metabolic changes (e.g., mitochondrial biogenesis and changes in skeletal muscle fiber type) as those reported for the former call of substances. We suspect that metabolic modulators abuse such as telmisartan might become a tangible threat in sports and should be thereby targeted as an important antidoping issue. The 2012 WADA prohibited list does not provide telmisartan for a potential doping drug, but arguments supporting the consideration to include them among "metabolic modulators" are at hand.

Reconstruction and Analysis of Human Kidney-Specific Metabolic Network Based on Omics Data

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Ai-Di Zhang

2013-01-01

Full Text Available With the advent of the high-throughput data production, recent studies of tissue-specific metabolic networks have largely advanced our understanding of the metabolic basis of various physiological and pathological processes. However, for kidney, which plays an essential role in the body, the available kidney-specific model remains incomplete. This paper reports the reconstruction and characterization of the human kidney metabolic network based on transcriptome and proteome data. In silico simulations revealed that house-keeping genes were more essential than kidney-specific genes in maintaining kidney metabolism. Importantly, a total of 267 potential metabolic biomarkers for kidney-related diseases were successfully explored using this model. Furthermore, we found that the discrepancies in metabolic processes of different tissues are directly corresponding to tissue's functions. Finally, the phenotypes of the differentially expressed genes in diabetic kidney disease were characterized, suggesting that these genes may affect disease development through altering kidney metabolism. Thus, the human kidney-specific model constructed in this study may provide valuable information for the metabolism of kidney and offer excellent insights into complex kidney diseases.

Linking metabolomics data to underlying metabolic regulation

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Thomas eNägele

2014-11-01

Full Text Available The comprehensive experimental analysis of a metabolic constitution plays a central role in approaches of organismal systems biology.Quantifying the impact of a changing environment on the homeostasis of cellular metabolism has been the focus of numerous studies applying various metabolomics techniques. It has been proven that approaches which integrate different analytical techniques, e.g. LC-MS, GC-MS, CE-MS and H-NMR, can provide a comprehensive picture of a certain metabolic homeostasis. Identification of metabolic compounds and quantification of metabolite levels represent the groundwork for the analysis of regulatory strategies in cellular metabolism. This significantly promotes our current understanding of the molecular organization and regulation of cells, tissues and whole organisms.Nevertheless, it is demanding to elicit the pertinent information which is contained in metabolomics data sets.Based on the central dogma of molecular biology, metabolite levels and their fluctuations are the result of a directed flux of information from gene activation over transcription to translation and posttranslational modification.Hence, metabolomics data represent the summed output of a metabolic system comprising various levels of molecular organization.As a consequence, the inverse assignment of metabolomics data to underlying regulatory processes should yield information which-if deciphered correctly-provides comprehensive insight into a metabolic system.Yet, the deduction of regulatory principles is complex not only due to the high number of metabolic compounds, but also because of a high level of cellular compartmentalization and differentiation.Motivated by the question how metabolomics approaches can provide a representative view on regulatory biochemical processes, this article intends to present and discuss current metabolomics applications, strategies of data analysis and their limitations with respect to the interpretability in context of

The depressed central carbon and energy metabolisms is associated to the acquisition of levofloxacin resistance in Vibrio alginolyticus.

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Cheng, Zhi-Xue; Yang, Man-Jun; Peng, Bo; Peng, Xuan-Xian; Lin, Xiang-Min; Li, Hui

2018-06-15

The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. It is especially required to understand for the mechanism of antibiotic resistance to control antibiotic-resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus with the most advanced iTRAQ quantitative proteomics technology. A total of 160 proteins of differential abundance were identified, where 70 were decreased and 90 were increased. Further analysis demonstrated that crucial metabolic pathways like TCA cycle were significantly down-regulated. qRT-PCR analysis demonstrated the decreased gene expression of glycolysis/gluconeogenesis, the TCA cycle, and fatty acid biosynthesis. Moreover, Na(+)-NQR complex gene expression, membrane potential and the adenylate energy charge ratio were decreased, indicating that the decreased central carbon metabolism is associated to the acquisition of levofloxacin resistance. Therefore, the reduced central carbon and energy metabolisms form a characteristic feature as fitness costs of V. alginolyticus in resistance to levofloxacin. The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. Understanding for the antibiotic resistance mechanisms is especially required to control these antibiotic-resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus using the most advanced iTRAQ quantitative proteomics technology. A total of 160 differential abundance of proteins were identified with 70 decreases and 90 increases by liquid chromatography matrix assisted laser desorption ionization mass spectrometry. Most interestingly, crucial metabolic pathways such as the TCA cycle sharply fluctuated. This is the first report that the reduced central carbon and energy metabolisms form a characteristic feature

Positron computed tomography studies of cerebral metabolic responses to complex motor tasks

International Nuclear Information System (INIS)

Phelps, M.E.; Mazziotta, J.C.

1984-01-01

Human motor system organization was explored in 8 right-handed male subjects using /sup 18/F-fluorodeoxyglucose and positron computed tomography to measure cerebral glucose metabolism. Five subjects had triple studies (eyes closed) including: control (hold pen in right hand without moving), normal size writing (subject repeatedly writes name) and large (10-15 X normal) name writing. In these studies normal and large size writing had a similar distribution of metabolic responses when compared to control studies. Activations (percent change from control) were in the range of 12-20% and occurred in the striatum bilaterally > contralateral Rolandic cortex > contralateral thalamus. No significant activations were observed in the ipsilateral thalamus, Rolandic cortex or cerebellum (supplementary motor cortex was not examined). The magnitude of the metabolic response in the striatum was greater with the large versus normal sized writing. This differential response may be due to an increased number and topographic distribution of neurons responding with the same average activity between tasks or an increase in the functional activity of the same neuronal population between the two tasks (present spatial resolution inadequate to differentiate). When subjects (N=3) performed novel sequential finger movements, the maximal metabolic response was in the contralateral Rolandic cortex > striatum. Such studies provide a means of exploring human motor system organization, motor learning and provide a basis for examining patients with motor system disorders

Metabolic cold adaptation of polar fish based on measurements of aerobic oxygen consumption: fact or artefact? Artefact!

DEFF Research Database (Denmark)

Steffensen, John Fleng

2002-01-01

Whether metabolic cold adaptation in polar fish, based on measurements of aerobic standard metabolic rate, is a fact or an artefact has been a dispute since Holeton asked the question in 1974. So far polar fish had been considered to be metabolically cold adapted because they were reported to have...... a considerably elevated resting oxygen consumption, or standard metabolic rate, compared with oxygen consumption values of tropical or temperate fish extrapolated to similar low polar temperatures. Recent experiments on arctic and Antarctic fish, however, do not show elevated resting aerobic oxygen consumption...

Quantitative evaluation of respiration induced metabolic oscillations in erythrocytes

DEFF Research Database (Denmark)

Hald, Bjørn; Madsen, Mads F; Danø, Sune

2009-01-01

The changes in the partial pressures of oxygen and carbon dioxide (P(O(2)) and P(CO(2))) during blood circulation alter erythrocyte metabolism, hereby causing flux changes between oxygenated and deoxygenated blood. In the study we have modeled this effect by extending the comprehensive kinetic...... model by Mulquiney and Kuchel [P.J. Mulquiney, and P.W. Kuchel. Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: equations and parameter refinement, Biochem. J. 1999, 342, 581-596.] with a kinetic model of hemoglobin oxy...... solely by steady state consideration. The metabolic system exhibits a broad distribution of time scales. Relaxations of modes with hemoglobin and Mg(2+) binding reactions are very fast, while modes involving glycolytic, membrane transport and 2,3-BPG shunt reactions are much slower. Incomplete slow mode...

Carcinoid tumors: Challenges and considerations during anesthetic management

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Sukhminder Jit Singh Bajwa

2015-01-01

Full Text Available Carcinoid tumors are rare, slow-growing neoplasms of neuroendocrine tissues from enterochromaffin or kulchitsky cells, which have the potential to metastasize. The mediators released from these tumors when bypass the hepatic metabolism, can lead to the possible development of carcinoid syndrome. This is a life-threatening complication, which can lead to profound hemodynamic instability, especially in a peri-operative period, when the patient is exposed to various types of noxious stimuli. Off late, use of octreotide, a synthetic analog of somatostatin, has significantly reduced the peri-operative morbidity and mortality. The current review discusses the various anesthetic challenges and considerations during peri-operative management of carcinoid tumors.

Differential stimulation of luminol-enhanced chemiluminescence (CL) and arachidonic acid metabolism in rat peritoneal neutrophils

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Sturm, R.J.; Adams, L.M.; Cullinan, C.A.; Berkenkopf, J.W.; Weichman, B.M.

1986-03-05

Phorbol 12-myristate, 13-acetate (PMA) induced the production of radical oxygen species (ROS) from rat peritoneal neutrophils as assessed by CL. ROS generation occurred in a time- (maximum at 13.5 min) and dose- (concentration range of 1.7-498 nM) related fashion. However, 166 nM PMA did not induce either cyclooxygenase (CO) or lipoxygenase (LPO) product formation by 20 min post-stimulation. Conversely, A23187, at concentrations between 0.1 and 10 ..mu..M, stimulated both pathways of arachidonic acid metabolism, but had little or no effect upon ROS production. When suboptimal concentrations of PMA (5.5 nM) and A23187 (0.1-1 ..mu..M) were coincubated with the neutrophils, a synergistic ROS response was elicited. However, arachidonic acid metabolism in the presence of PMA was unchanged relative to A12187 alone. Nordihydroguaiaretic acid (NDGA) inhibited both PMA-induced CL (IC/sub 50/ = 0.9 ..mu..M) and A23187-induced arachidonic acid metabolism (IC/sub 50/ = 1.7 ..mu..M and 6.0 ..mu..M for LPO and CO, respectively). The mixed LPO-CO inhibitor, BW755C, behaved in a qualitatively similar manner to NDGA, whereas the CO inhibitors, indomethacin, piroxicam and naproxen had no inhibitory effect on ROS generation at concentrations as high as 100 ..mu..M. These results suggest that NDGA and BW755C may inhibit CL and arachidonic acid metabolism by distinct mechanisms in rat neutrophils.

Limited brain metabolism changes differentiate between the progression and clearance of rabies virus.

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Keith Schutsky

Full Text Available Central nervous system (CNS metabolic profiles were examined from rabies virus (RABV-infected mice that were either mock-treated or received post-exposure treatment (PET with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality.

Differential regional cerebral glucose metabolism in clinical syndromes of frontotemporal lobar degeneration: a study with FDG PET

International Nuclear Information System (INIS)

Park, J. M.; Cho, S. S.; Na, D. L.; Lee, K. H.; Choi, Y.; Choe, Y. S.; Kim, B. T.; Kim, S. E.

2001-01-01

Frontotemporal lobar degeneration( FTLD) is the third most common dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neurobehavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patient with FTLD presented with four different clinical syndromes. We analysed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral premotor are was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical features of FTLD syndromes. These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLD

Differential regional cerebral glucose metabolism in clinical syndromes of frontotemporal lobar degeneration: a study with FDG PET

Energy Technology Data Exchange (ETDEWEB)

Park, J. M.; Cho, S. S.; Na, D. L.; Lee, K. H.; Choi, Y.; Choe, Y. S.; Kim, B. T.; Kim, S. E. [College of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)

2001-07-01

Frontotemporal lobar degeneration( FTLD) is the third most common dementia, following Alzheimer's disease and Lewy body disease. Four prototypic neurobehavioral syndromes can be produced by FTLD: frontotemporal dementia (FTD), frontotemporal dementia with motor neuron disease (MND), semantic dementia (SD), and progressive aphasia (PA). We investigated patterns of metabolic impairment in patient with FTLD presented with four different clinical syndromes. We analysed glucose metabolic patterns on FDG PET images obtained from 34 patients with a clinical diagnosis of FTLD (19 FTD, 6 MND, 6 SD, and 3 PA, according to a consensus criteria for clinical syndromes associated with FTLD) and 7 age-matched healthy controls using SPM99. Patients with FTD had metabolic deficit in the left frontal cortex and bilateral anterior temporal cortex. Hypometabolism in the bilateral premotor are was shown in patients with MND. Patients with SD had metabolic deficit in the left posterior temporal cortex including Wernicke's area, while hypometabolism in the bilateral inferior frontal gyrus including Broca's area and left angular gyrus was seen in patients with PA. These metabolic patterns were well correlated with clinical features of FTLD syndromes. These data provide a biochemical basis of clinical classification of FTLD. FDG PET may help evaluate and classify patients with FTLD.

PET-imaging of cerebral glucose metabolism during sleep and dreaming

International Nuclear Information System (INIS)

Heiss, W.D.; Pawlik, G.; Herholz, K.; Wagner, R.; Wienhard, K.

1985-01-01

Positron emission tomography (PET) of ( 18 F)-2-fluoro-2-deoxyglucose (FDG) affording non-invasive repeatable quantification of local cerebral glucose utilization was employed to determine possible differential effects of sleep, with and without dreaming, on regional brain metabolism of normal volunteers also measured during wakefulness. (author). 7 refs.; 1 tab

[Metabolic bone disease osteomalacia].

Science.gov (United States)

Reuss-Borst, M A

2014-05-01

Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.

Metabolic pattern analysis of early detection in Alzheimer's disease from other types of dementias and correlated with cognitive function

International Nuclear Information System (INIS)

Ju, R. H.; Lee, C. W.; Jung, Y. A.; Sohn, H. S.; Kim, S. H.; Seo, T. S

2004-01-01

PET/CT studies have demonstrated temporoparietal hypometabolism in probable and definite Alzheimer's disease (AD), a pattern that may help differentiate AD from other types of dementias. Seeking to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Identification of individual differences in patterns of regional cerebral glucose metabolism (rCMRglc) interactions may be important for early detection of AD. We elucidate the relationship between reduced cognitive function and cerebral metabolism. Ten patients with the diagnosis of AD, 3 DLB patients underwent 18F-FDG PET CT. We applied statistical mapping procedure to evaluate the diagnostic power of rCMRglc patterns for differentiation and also correlated with Korean-mini mental status exam (K-MMSE) score include orientation time, place, registration, attention, calculation, recaIl, language and visuospatial function. Glucose metabolic pattern analysis confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortex. DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex. Covariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. AnaIysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled clinical criteria for DLB. occipital hypometabolism is a potential discriminate marker to distinguish DLB versus AD

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions.

Science.gov (United States)

Karigane, Daiki; Takubo, Keiyo

2017-07-01

Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

SU-E-J-102: Separation of Metabolic Supply and Demand: From Power Grid Economics to Cancer Metabolism

Energy Technology Data Exchange (ETDEWEB)

Epstein, T; Xu, L; Gillies, R; Gatenby, R [Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

2014-06-01

Purpose: To study a new model of glucose metabolism which is primarily governed by the timescale of the energetic demand and not by the oxygen level, and its implication on cancer metabolism (Warburg effect) Methods: 1) Metabolic profiling of membrane transporters activity in several cell lines, which represent the spectrum from normal breast epithelium to aggressive, metastatic cancer, using Seahorse XF reader.2) Spatial localization of oxidative and non-oxidative metabolic components using immunocytochemical imaging of the glycolytic ATP-producing enzyme, pyruvate kinase and mitochondria. 3) Finite element simulations of coupled partial differential equations using COMSOL and MATLAB. Results: Inhibition or activation of pumps on the cell membrane led to reduction or increase in aerobic glycolysis, respectively, while oxidative phosphorylation remained unchanged. These results were consistent with computational simulations of changes in short-timescale demand for energy by cell membrane processes. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. These predictions were confirmed experimentally. Conclusion: The results in this work support a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Similar to power grid economics, optimal metabolic control requires the two pathways, even in normoxic conditions, to match two different types of energy demands. Cells use aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism to meet short-timescale energy demands, mainly from membrane transport activities, even in the presence of oxygen. This model provides a mechanism for the origin of the Warburg effect in cancer cells. Here, the Warburg effect emerges during carcinogenesis is a physiological

SU-E-J-102: Separation of Metabolic Supply and Demand: From Power Grid Economics to Cancer Metabolism

International Nuclear Information System (INIS)

Epstein, T; Xu, L; Gillies, R; Gatenby, R

2014-01-01

Purpose: To study a new model of glucose metabolism which is primarily governed by the timescale of the energetic demand and not by the oxygen level, and its implication on cancer metabolism (Warburg effect) Methods: 1) Metabolic profiling of membrane transporters activity in several cell lines, which represent the spectrum from normal breast epithelium to aggressive, metastatic cancer, using Seahorse XF reader.2) Spatial localization of oxidative and non-oxidative metabolic components using immunocytochemical imaging of the glycolytic ATP-producing enzyme, pyruvate kinase and mitochondria. 3) Finite element simulations of coupled partial differential equations using COMSOL and MATLAB. Results: Inhibition or activation of pumps on the cell membrane led to reduction or increase in aerobic glycolysis, respectively, while oxidative phosphorylation remained unchanged. These results were consistent with computational simulations of changes in short-timescale demand for energy by cell membrane processes. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. These predictions were confirmed experimentally. Conclusion: The results in this work support a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Similar to power grid economics, optimal metabolic control requires the two pathways, even in normoxic conditions, to match two different types of energy demands. Cells use aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism to meet short-timescale energy demands, mainly from membrane transport activities, even in the presence of oxygen. This model provides a mechanism for the origin of the Warburg effect in cancer cells. Here, the Warburg effect emerges during carcinogenesis is a physiological

Lactate induces osteoblast differentiation by stabilization of HIF1α.

Science.gov (United States)

Wu, Yu; Wang, Miaomiao; Feng, Haihua; Peng, Ying; Sun, Jieyun; Qu, Xiuxia; Li, Chunping

2017-09-05

Aerobic glycolysis is involved in osteoblast differentiation induced by Wnt signaling or PTH treatment. However, it is still unclear whether lactate, the end product of aerobic glycolysis, plays any role in osteoblast differentiation. Herein we report that in cultures of osteoblast-lineage cells, lactate promoted alkaline phosphatase-positive cell formation, increased the activity of alkaline phosphatase, and induced the expression of osteocalcin. This osteoblast differentiation-inducing effect of lactate can be inhibited by blocking its entry into cells with MCT1 siRNA or inhibitors, and by interfering with its metabolism by using specific siRNAs for LDHB and PDH. Moreover, lactate stabilized HIF1α expression and inhibited HIF1α activity, with BAY87-2243 lowering the osteoblast differentiation-inducing effect of lactate. Thus, these findings reveal an unrecognized role for aerobic glycolysis in osteoblast differentiation via its end product, lactate. Copyright © 2017 Elsevier B.V. All rights reserved.

The Mechanism of White and Brown Adipocyte Differentiation

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Hironori Nakagami

2013-04-01

Full Text Available Obesity gives vent to many diseases such as type 2 diabetes, hypertension, and hyperlipidemia, being considered as the main causes of mortality and morbidity worldwide. The pathogenesis and pathophysiology of metabolic syndrome can well be understood by studying the molecular mechanisms that control the development and function of adipose tissue. In human body, exist two types of adipose tissue, the white and the brown one, which are reported to play various roles in energy homeostasis. The major and most efficient storage of energy occurs in the form of triglycerides in white adipose tissue while brown adipose tissue actively participates in both basal and inducible energy consumption in the form of thermogenesis. Recent years have observed a rapid and greater interest towards developmental plasticity and therapeutic potential of stromal cells those isolated from adipose tissue. The adipocyte differentiation involves a couple of regulators in the white or brown adipogenesis. Peroxisome proliferators-activated receptor-γ actively participates in regulating carbohydrate and lipid metabolism, and also acts as main regulator of both white and brown adipogenesis. This review based on our recent research, seeks to highlight the adipocyte differentiation.

Genetic control of differential acetylation in diabetic rats.

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Pamela J Kaisaki

Full Text Available Post-translational protein modifications such as acetylation have significant regulatory roles in metabolic processes, but their relationship to both variation in gene expression and DNA sequence is unclear. We address this question in the Goto-Kakizaki (GK rat inbred strain, a model of polygenic type 2 diabetes. Expression of the NAD-dependent deacetylase Sirtuin-3 is down-regulated in GK rats compared to normoglycemic Brown Norway (BN rats. We show first that a promoter SNP causes down-regulation of Sirtuin-3 expression in GK rats. We then use mass-spectrometry to identify proteome-wide differential lysine acetylation of putative Sirtuin-3 protein targets in livers of GK and BN rats. These include many proteins in pathways connected to diabetes and metabolic syndrome. We finally sequence GK and BN liver transcriptomes and find that mRNA expression of these targets does not differ significantly between GK and BN rats, in contrast to other components of the same pathways. We conclude that physiological differences between GK and BN rats are mediated by a combination of differential protein acetylation and gene transcription and that genetic variation can modulate acetylation independently of expression.

Respiration and nitrogen assimilation: targeting mitochondria-associated metabolism as a means to enhance nitrogen use efficiency.

Science.gov (United States)

Foyer, Christine H; Noctor, Graham; Hodges, Michael

2011-02-01

Considerable advances in our understanding of the control of mitochondrial metabolism and its interactions with nitrogen metabolism and associated carbon/nitrogen interactions have occurred in recent years, particularly highlighting important roles in cellular redox homeostasis. The tricarboxylic acid (TCA) cycle is a central metabolic hub for the interacting pathways of respiration, nitrogen assimilation, and photorespiration, with components that show considerable flexibility in relation to adaptations to the different functions of mitochondria in photosynthetic and non-photosynthetic cells. By comparison, the operation of the oxidative pentose phosphate pathway appears to represent a significant limitation to nitrogen assimilation in non-photosynthetic tissues. Valuable new insights have been gained concerning the roles of the different enzymes involved in the production of 2-oxoglutarate (2-OG) for ammonia assimilation, yielding an improved understanding of the crucial role of cellular energy balance as a broker of co-ordinate regulation. Taken together with new information on the mechanisms that co-ordinate the expression of genes involved in organellar functions, including energy metabolism, and the potential for exploiting the existing flexibility for NAD(P)H utilization in the respiratory electron transport chain to drive nitrogen assimilation, the evidence that mitochondrial metabolism and machinery are potential novel targets for the enhancement of nitrogen use efficiency (NUE) is explored.

Diversity of sharp-wave–ripple LFP signatures reveals differentiated brain-wide dynamical events

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Ramirez-Villegas, Juan F.; Logothetis, Nikos K.; Besserve, Michel

2015-01-01

Sharp-wave–ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R–triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions. PMID:26540729

Diversity of sharp-wave-ripple LFP signatures reveals differentiated brain-wide dynamical events.

Science.gov (United States)

Ramirez-Villegas, Juan F; Logothetis, Nikos K; Besserve, Michel

2015-11-17

Sharp-wave-ripple (SPW-R) complexes are believed to mediate memory reactivation, transfer, and consolidation. However, their underlying neuronal dynamics at multiple scales remains poorly understood. Using concurrent hippocampal local field potential (LFP) recordings and functional MRI (fMRI), we study local changes in neuronal activity during SPW-R episodes and their brain-wide correlates. Analysis of the temporal alignment between SPW and ripple components reveals well-differentiated SPW-R subtypes in the CA1 LFP. SPW-R-triggered fMRI maps show that ripples aligned to the positive peak of their SPWs have enhanced neocortical metabolic up-regulation. In contrast, ripples occurring at the trough of their SPWs relate to weaker neocortical up-regulation and absent subcortical down-regulation, indicating differentiated involvement of neuromodulatory pathways in the ripple phenomenon mediated by long-range interactions. To our knowledge, this study provides the first evidence for the existence of SPW-R subtypes with differentiated CA1 activity and metabolic correlates in related brain areas, possibly serving different memory functions.

Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia.

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Xin Fang

Full Text Available The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB, to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to

Transcriptomic and proteomic approach to identify differentially expressed genes and proteins in Arabidopsis thaliana mutants lacking chloroplastic 1 and cytosolic FBPases reveals several levels of metabolic regulation.

Science.gov (United States)

Soto-Suárez, Mauricio; Serrato, Antonio J; Rojas-González, José A; Bautista, Rocío; Sahrawy, Mariam

2016-12-01

During the photosynthesis, two isoforms of the fructose-1,6-bisphosphatase (FBPase), the chloroplastidial (cFBP1) and the cytosolic (cyFBP), catalyse the first irreversible step during the conversion of triose phosphates (TP) to starch or sucrose, respectively. Deficiency in cyFBP and cFBP1 isoforms provokes an imbalance of the starch/sucrose ratio, causing a dramatic effect on plant development when the plastidial enzyme is lacking. We study the correlation between the transcriptome and proteome profile in rosettes and roots when cFBP1 or cyFBP genes are disrupted in Arabidopsis thaliana knock-out mutants. By using a 70-mer oligonucleotide microarray representing the genome of Arabidopsis we were able to identify 1067 and 1243 genes whose expressions are altered in the rosettes and roots of the cfbp1 mutant respectively; whilst in rosettes and roots of cyfbp mutant 1068 and 1079 genes are being up- or down-regulated respectively. Quantitative real-time PCR validated 100% of a set of 14 selected genes differentially expressed according to our microarray analysis. Two-dimensional (2-D) gel electrophoresis-based proteomic analysis revealed quantitative differences in 36 and 26 proteins regulated in rosettes and roots of cfbp1, respectively, whereas the 18 and 48 others were regulated in rosettes and roots of cyfbp mutant, respectively. The genes differentially expressed and the proteins more or less abundant revealed changes in protein metabolism, RNA regulation, cell signalling and organization, carbon metabolism, redox regulation, and transport together with biotic and abiotic stress. Notably, a significant set (25%) of the proteins identified were also found to be regulated at a transcriptional level. This transcriptomic and proteomic analysis is the first comprehensive and comparative study of the gene/protein re-adjustment that occurs in photosynthetic and non-photosynthetic organs of Arabidopsis mutants lacking FBPase isoforms.

Legal considerations for urban underground space development in Malaysia

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F. Zaini

2017-12-01

Full Text Available In 2008, the Malaysia land code, named the National Land Code 1965 (NLC 1965, was amended to add Part Five (A to deal with the disposal of underground space. In addition, the Circular of the Director General of Lands and Mines No. 1/2008 was issued to assist the application of Part Five (A of the NLC 1965. However, the legislation is still questionable and has instigated many arguments among numerous actors. Therefore, this research was undertaken to examine legal considerations for the development of underground space. The focus is on four legal considerations, namely underground space ownership, the bundle of rights, depth, and underground space utilization. Rooted in qualitative methods, interviews were conducted with respondents involved in the development of underground space in Malaysia. The obtained data were then analyzed descriptively. The findings differentiated the rights of landowners for surface land and underground space, and their liability for damages and the depth. It was indicated that the current legislation in Malaysia, namely Part Five (A of the NLC 1965 and the Circular of the Director General of Lands and Mines No. 1/2008, is adequate to facilitate the development of underground space in terms of legal considerations. However, to further facilitate the development of underground land in the future, based on the research, four enhancements are recommended for legal considerations pertaining to the development of underground space in Malaysia. Keywords: Underground space, Legal consideration, Land right, Urban development

Consequences of C4 differentiation for chloroplast membrane proteomes in maize mesophyll and bundle sheath cells.

Science.gov (United States)

Majeran, Wojciech; Zybailov, Boris; Ytterberg, A Jimmy; Dunsmore, Jason; Sun, Qi; van Wijk, Klaas J

2008-09-01

Chloroplasts of maize leaves differentiate into specific bundle sheath (BS) and mesophyll (M) types to accommodate C(4) photosynthesis. Chloroplasts contain thylakoid and envelope membranes that contain the photosynthetic machineries and transporters but also proteins involved in e.g. protein homeostasis. These chloroplast membranes must be specialized within each cell type to accommodate C(4) photosynthesis and regulate metabolic fluxes and activities. This quantitative study determined the differentiated state of BS and M chloroplast thylakoid and envelope membrane proteomes and their oligomeric states using innovative gel-based and mass spectrometry-based protein quantifications. This included native gels, iTRAQ, and label-free quantification using an LTQ-Orbitrap. Subunits of Photosystems I and II, the cytochrome b(6)f, and ATP synthase complexes showed average BS/M accumulation ratios of 1.6, 0.45, 1.0, and 1.33, respectively, whereas ratios for the light-harvesting complex I and II families were 1.72 and 0.68, respectively. A 1000-kDa BS-specific NAD(P)H dehydrogenase complex with associated proteins of unknown function containing more than 15 proteins was observed; we speculate that this novel complex possibly functions in inorganic carbon concentration when carboxylation rates by ribulose-bisphosphate carboxylase/oxygenase are lower than decarboxylation rates by malic enzyme. Differential accumulation of thylakoid proteases (Egy and DegP), state transition kinases (STN7,8), and Photosystem I and II assembly factors was observed, suggesting that cell-specific photosynthetic electron transport depends on post-translational regulatory mechanisms. BS/M ratios for inner envelope transporters phosphoenolpyruvate/P(i) translocator, Dit1, Dit2, and Mex1 were determined and reflect metabolic fluxes in carbon metabolism. A wide variety of hundreds of other proteins showed differential BS/M accumulation. Mass spectral information and functional annotations are

Genetic variability and cadmium metabolism and toxicity

OpenAIRE

Rentschler, Gerda

2014-01-01

Abstract: Cadmium (Cd) is ubiquitous in the environment. Human exposure in non-smokers occurs mainly via intake of healthy food like vegetables, cereals, and shellfish. Adverse health effects on kidney and bone at low-level environmental Cd exposure are well-documented in adults. There is considerable inter-individual variation in both metabolism (toxicokinetics) and toxicity (toxicodynamics) of Cd. This may be due to genetic factors. The aim of this thesis was to identify genetic fact...

Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2.

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Jian-Guo Ren

2010-09-01

Full Text Available Malic enzyme 2 (ME2 is a mitochondrial enzyme that catalyzes the conversion of malate to pyruvate and CO2 and uses NAD as a cofactor. Higher expression of this enzyme correlates with the degree of cell de-differentiation. We found that ME2 is expressed in K562 erythroleukemia cells, in which a number of agents have been found to induce differentiation either along the erythroid or the myeloid lineage. We found that knockdown of ME2 led to diminished proliferation of tumor cells and increased apoptosis in vitro. These findings were accompanied by differentiation of K562 cells along the erythroid lineage, as confirmed by staining for glycophorin A and hemoglobin production. ME2 knockdown also totally abolished growth of K562 cells in nude mice. Increased ROS levels, likely reflecting increased mitochondrial production, and a decreased NADPH/NADP+ ratio were noted but use of a free radical scavenger to decrease inhibition of ROS levels did not reverse the differentiation or apoptotic phenotype, suggesting that ROS production is not causally involved in the resultant phenotype. As might be expected, depletion of ME2 induced an increase in the NAD+/NADH ratio and ATP levels fell significantly. Inhibition of the malate-aspartate shuttle was insufficient to induce K562 differentiation. We also examined several intracellular signaling pathways and expression of transcription factors and intermediate filament proteins whose expression is known to be modulated during erythroid differentiation in K562 cells. We found that silencing of ME2 leads to phospho-ERK1/2 inhibition, phospho-AKT activation, increased GATA-1 expression and diminished vimentin expression. Metabolomic analysis, conducted to gain insight into intermediary metabolic pathways that ME2 knockdown might affect, showed that ME2 depletion resulted in high orotate levels, suggesting potential impairment of pyrimidine metabolism. Collectively our data point to ME2 as a potentially novel

Elevated host lipid metabolism revealed by iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients

Energy Technology Data Exchange (ETDEWEB)

Mu, Jun [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Yang, Yongtao [Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing (China); Chen, Jin; Cheng, Ke; Li, Qi; Wei, Yongdong; Zhu, Dan; Shao, Weihua; Zheng, Peng [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Xie, Peng, E-mail: xiepeng@cqmu.edu.cn [Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing (China); Chongqing Key Laboratory of Neurobiology, Chongqing (China); Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing (China)

2015-10-30

Purpose: Tuberculous meningitis (TBM) remains to be one of the most deadly infectious diseases. The pathogen interacts with the host immune system, the process of which is largely unknown. Various cellular processes of Mycobacterium tuberculosis (MTB) centers around lipid metabolism. To determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (CSF) obtained from TBM patients (n = 12) and healthy controls (n = 12). Methods: CSF samples were desalted, concentrated, labelled with isobaric tags for relative and absolute quantitation (iTRAQ™), and analyzed by multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene ontology and proteomic phenotyping analysis of the differential proteins were conducted using Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. ApoE and ApoB were selected for validation by ELISA. Results: Proteomic phenotyping of the 4 differential proteins was invloved in the lipid metabolism. ELISA showed significantly increased ApoB levels in TBM subjects compared to healthy controls. Area under the receiver operating characteristic curve analysis demonstrated ApoB levels could distinguish TBM subjects from healthy controls and viral meningitis subjects with 89.3% sensitivity and 92% specificity. Conclusions: CSF lipid metabolism disregulation, especially elevated expression of ApoB, gives insights into the pathogenesis of TBM. Further evaluation of these findings in larger studies including anti-tuberculosis medicated and unmedicated patient cohorts with other center nervous system infectious diseases is required for successful clinical translation. - Highlights: • The first proteomic study on the cerebrospinal fluid of tuberculous meningitis patients using iTRAQ. • Identify 4 differential proteins invloved in the lipid metabolism. • Elevated expression of ApoB gives

Elevated host lipid metabolism revealed by iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid of tuberculous meningitis patients

International Nuclear Information System (INIS)

Mu, Jun; Yang, Yongtao; Chen, Jin; Cheng, Ke; Li, Qi; Wei, Yongdong; Zhu, Dan; Shao, Weihua; Zheng, Peng; Xie, Peng

2015-01-01

Purpose: Tuberculous meningitis (TBM) remains to be one of the most deadly infectious diseases. The pathogen interacts with the host immune system, the process of which is largely unknown. Various cellular processes of Mycobacterium tuberculosis (MTB) centers around lipid metabolism. To determine the lipid metabolism related proteins, a quantitative proteomic study was performed here to identify differential proteins in the cerebrospinal fluid (CSF) obtained from TBM patients (n = 12) and healthy controls (n = 12). Methods: CSF samples were desalted, concentrated, labelled with isobaric tags for relative and absolute quantitation (iTRAQ™), and analyzed by multi-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene ontology and proteomic phenotyping analysis of the differential proteins were conducted using Database for Annotation, Visualization, and Integrated Discovery (DAVID) Bioinformatics Resources. ApoE and ApoB were selected for validation by ELISA. Results: Proteomic phenotyping of the 4 differential proteins was invloved in the lipid metabolism. ELISA showed significantly increased ApoB levels in TBM subjects compared to healthy controls. Area under the receiver operating characteristic curve analysis demonstrated ApoB levels could distinguish TBM subjects from healthy controls and viral meningitis subjects with 89.3% sensitivity and 92% specificity. Conclusions: CSF lipid metabolism disregulation, especially elevated expression of ApoB, gives insights into the pathogenesis of TBM. Further evaluation of these findings in larger studies including anti-tuberculosis medicated and unmedicated patient cohorts with other center nervous system infectious diseases is required for successful clinical translation. - Highlights: • The first proteomic study on the cerebrospinal fluid of tuberculous meningitis patients using iTRAQ. • Identify 4 differential proteins invloved in the lipid metabolism. • Elevated expression of ApoB gives

Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells

DEFF Research Database (Denmark)

Prawitt, Janne; Niemeier, Andreas; Kassem, Moustapha

2008-01-01

There is a great demand for cell models to study human adipocyte function. Here we describe the adipogenic differentiation of a telomerase-immortalized human mesenchymal stem cell line (hMSC-Tert) that maintains numerous features of terminally differentiated adipocytes even after prolonged...

JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes

Energy Technology Data Exchange (ETDEWEB)

Ming, Guang-feng [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Xiao, Di; Gong, Wei-jing [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Hui-xia; Liu, Jun [Department of Geriatrics, Xiangya Hospital, Central South University, Changsha 410008, Hunan (China); Zhou, Hong-hao [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China); Liu, Zhao-qian, E-mail: liuzhaoqian63@126.com [Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, Hunan (China)

2014-03-14

Highlights: • JAZF1 was significantly upregulated during the differentiation of 3T3-L1 preadipocytes. • JAZF1 overexpression inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes. • JAZF1 overexpression inhibited the expression of SREBP1, ACC, and FAS. • JAZF1 overexpression upregulated the expression of HSL and ATGL. • SREBP1 and JAZF1 could regulate each other in adipocytes. - Abstract: JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders.

JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes

International Nuclear Information System (INIS)

Ming, Guang-feng; Xiao, Di; Gong, Wei-jing; Liu, Hui-xia; Liu, Jun; Zhou, Hong-hao; Liu, Zhao-qian

2014-01-01

Highlights: • JAZF1 was significantly upregulated during the differentiation of 3T3-L1 preadipocytes. • JAZF1 overexpression inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes. • JAZF1 overexpression inhibited the expression of SREBP1, ACC, and FAS. • JAZF1 overexpression upregulated the expression of HSL and ATGL. • SREBP1 and JAZF1 could regulate each other in adipocytes. - Abstract: JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders

Different level of population differentiation among human genes.

Science.gov (United States)

Wu, Dong-Dong; Zhang, Ya-Ping

2011-01-14

During the colonization of the world, after dispersal out of African, modern humans encountered changeable environments and substantial phenotypic variations that involve diverse behaviors, lifestyles and cultures, were generated among the different modern human populations. Here, we study the level of population differentiation among different populations of human genes. Intriguingly, genes involved in osteoblast development were identified as being enriched with higher FST SNPs, a result consistent with the proposed role of the skeletal system in accounting for variation among human populations. Genes involved in the development of hair follicles, where hair is produced, were also found to have higher levels of population differentiation, consistent with hair morphology being a distinctive trait among human populations. Other genes that showed higher levels of population differentiation include those involved in pigmentation, spermatid, nervous system and organ development, and some metabolic pathways, but few involved with the immune system. Disease-related genes demonstrate excessive SNPs with lower levels of population differentiation, probably due to purifying selection. Surprisingly, we find that Mendelian-disease genes appear to have a significant excessive of SNPs with high levels of population differentiation, possibly because the incidence and susceptibility of these diseases show differences among populations. As expected, microRNA regulated genes show lower levels of population differentiation due to purifying selection. Our analysis demonstrates different level of population differentiation among human populations for different gene groups.

Obestatin as a regulator of adipocyte metabolism and adipogenesis

Science.gov (United States)

Gurriarán-Rodríguez, Uxía; Al-Massadi, Omar; Roca-Rivada, Arturo; Crujeiras, Ana Belén; Gallego, Rosalía; Pardo, Maria; Seoane, Luisa Maria; Pazos, Yolanda; Casanueva, Felipe F; Camiña, Jesús P

2011-01-01

Abstract The role of obestatin, a 23-amino-acid peptide encoded by the ghrelin gene, on the control of the metabolism of pre-adipocyte and adipocytes as well as on adipogenesis was determined. For in vitro assays, pre-adipocyte and adipocyte 3T3-L1 cells were used to assess the obestatin effect on cell metabolism and adipogenesis based on the regulation of the key enzymatic nodes, Akt and AMPK and their downstream targets. For in vivo assays, white adipose tissue (WAT) was obtained from male rats under continuous subcutaneous infusion of obestatin. Obestatin activated Akt and its downstream targets, GSK3α/β, mTOR and S6K1, in 3T3-L1 adipocyte cells. Simultaneously, obestatin inactivated AMPK in this cell model. In keeping with this, ACC phosphorylation was also decreased. This fact was confirmed in vivo in white adipose tissue (omental, subcutaneous and gonadal) obtained from male rats under continuous sc infusion of obestatin (24 and 72 hrs). The relevance of obestatin as regulator of adipocyte metabolism was supported by AS160 phosphorylation, GLUT4 translocation and augment of glucose uptake in 3T3-L1 adipocyte cells. In contrast, obestatin failed to modify translocation of fatty acid transporters, FATP1, FATP4 and FAT/CD36, to plasma membrane. Obestatin treatment in combination with IBMX and DEX showed to regulate the expression of C/EBPα, C/EBPβ, C/EBPδ and PPARγ promoting adipogenesis. Remarkable, preproghrelin expression, and thus obestatin expression, increased during adipogenesis being sustained throughout terminal differentiation. Neutralization of endogenous obestatin secreted by 3T3-L1 cells by anti-obestatin antibody decreased adipocyte differentiation. Furthermore, knockdown experiments by preproghrelin siRNA supported that obestatin contributes to adipogenesis. In summary, obestatin promotes adipogenesis in an autocrine/paracrine manner, being a regulator of adipocyte metabolism. These data point to a putative role in the pathogenesis of

The Role of Nrf2: Adipocyte Differentiation, Obesity, and Insulin Resistance

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Hyun-Ae Seo

2013-01-01

Full Text Available Metabolic diseases, such as type 2 diabetes and obesity, are increasing globally, and much work has been performed to elucidate the regulatory mechanisms of these diseases. Nuclear factor E2-related factor 2 (Nrf2 is a basic leucine zipper transcription factor that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Recent studies have proposed a close relationship between oxidative stress and energy metabolism-associated disease. The Nrf2 pathway, as a master regulator of cellular defense against oxidative stress, has emerged as a critical target of energy metabolism; however, its effects are controversial. This review examines the current state of research on the role of Nrf2 on energy metabolism, specifically with respect to its participation in adipocyte differentiation, obesity, and insulin resistance, and discusses the possibility of using Nrf2 as a therapeutic target in the clinic.

C1 metabolism plays an important role during formaldehyde metabolism and detoxification in petunia under liquid HCHO stress.

Science.gov (United States)

Zhang, Wei; Tang, Lijuan; Sun, Huiqun; Han, Shuang; Wang, Xinjia; Zhou, Shengen; Li, Kunzhi; Chen, Limei

2014-10-01

Petunia hybrida is a model ornamental plant grown worldwide. To understand the HCHO-uptake efficiency and metabolic mechanism of petunia, the aseptic petunia plants were treated in HCHO solutions. An analysis of HCHO-uptake showed that petunia plants effectively removed HCHO from 2, 4 and 6 mM HCHO solutions. The (13)C NMR analyses indicated that H(13)CHO was primarily used to synthesize [5-(13)C]methionine (Met) via C1 metabolism in petunia plants treated with 2 mM H(13)CHO. Pretreatment with cyclosporin A (CSA) or l-carnitine (LC), the inhibitors of mitochondrial permeability transition pores, did not affect the synthesis of [5-(13)C]Met in petunia plants under 2 mM H(13)CHO stress, indicating that the Met-generated pathway may function in the cytoplasm. Under 4 or 6 mM liquid H(13)CHO stress, H(13)CHO metabolism in petunia plants produced considerable amount of H(13)COOH and [2-(13)C]glycine (Gly) through C1 metabolism and a small amount of [U-(13)C]Gluc via the Calvin Cycle. Pretreatment with CSA or LC significantly inhibited the production of [2-(13)C]Gly in 6 mM H(13)CHO-treated petunia plants, which suggests that chloroplasts and peroxisomes might be involved in the generation of [2-(13)C]Gly. These results revealed that the C1 metabolism played an important role, whereas the Calvin Cycle had only a small contribution during HCHO metabolism and detoxification in petunia under liquid HCHO stress. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Differential content of glyphosate and its metabolites in Digitaria insularis biotypes

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Leonardo Bianco de Carvalho

2013-07-01

Full Text Available Experiments were carried out in controlled conditions to analyze the role of metabolism of glyphosate in Digitaria insularis (sourgrass biotypes with differential response to the herbicide. Contents of glyphosate, aminomethylphosphonic acid (AMPA, glyoxylate, and sarcosine was detected in leaf tissues by using reversed-polarity capillarity electrophoresis. Glyphosate content in the A biotype increased from 19.7 up to 65.5 µg g fresh weight-1, whereas decreasing from 19.9 down to 5.0 µg g fresh weight-1 in the B biotype, from 48 up to 168 hours after treatment. At 168 hours after treatment, percentage of the sum of AMPA, glyoxylate, and sarcosine was > 56% in the B biotype, whereas a small percentage of metabolites (< 10% was found in the A biotype. Thus, the faster herbicide degradation in the B biotype is evidence that a differential metabolism of glyphosate can be conferring its lesser susceptibility to the herbicide.

Effects of hypo- und hyperthyroidism on skeletal muscle metabolism

International Nuclear Information System (INIS)

Moka, D.; Theissen, P.; Linden, A.; Waters, W.; Schicha, H.

1991-01-01

31 P magnetic resonance spectroscopy allows non-invasive evaluation of phosphorus metabolism in man. The purpose of the present study was to assess the influence of hyper- and hypothyroidism on the metabolism of resting human skeletal muscle. The present data show that quantitative measurement of phosphate metabolism by NMR is possible as also demonstrated by other studies. Using a quantitative evaluation method with an external standard, significant differences in the levels of phosphocreatine, adenosintriphosphate, and phosphodiesters were found. In hypothyroid patients a TSH-dependent increase in phosphodiesters and a decrease in adenosintriphosphate and phosphocreatine was observed. In hyperthyroidism a similar decrease in adenosintriphosphate but a considerably higher decrease in phosphocreatine occurred. In the light of the results of other studies of muscle matabolism, these changes appear to be non-specific so that further studies are required to assess the clinical value of such measurements. (orig.) [de

Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis

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Boix Loreto

2006-11-01

Full Text Available Abstract Background Little is known at the molecular level concerning the differences and/or similarities between alcohol and hepatitis C virus induced liver disease. Global transcriptional profiling using oligonucleotide microarrays was therefore performed on liver biopsies from patients with cirrhosis caused by either chronic alcohol consumption or chronic hepatitis C virus (HCV. Results Global gene expression patterns varied significantly depending upon etiology of liver disease, with a greater number of differentially regulated genes seen in HCV-infected patients. Many of the gene expression changes specifically observed in HCV-infected cirrhotic livers were expectedly associated with activation of the innate antiviral immune response. We also compared severity (CTP class of cirrhosis for each etiology and identified gene expression patterns that differentiated ethanol-induced cirrhosis by class. CTP class A ethanol-cirrhotic livers showed unique expression patterns for genes implicated in the inflammatory response, including those related to macrophage activation and migration, as well as lipid metabolism and oxidative stress genes. Conclusion Stages of liver cirrhosis could be differentiated based on gene expression patterns in ethanol-induced, but not HCV-induced, disease. In addition to genes specifically regulating the innate antiviral immune response, mechanisms responsible for differentiating chronic liver damage due to HCV or ethanol may be closely related to regulation of lipid metabolism and to effects of macrophage activation on deposition of extracellular matrix components.

Differential mobility in plasm

International Nuclear Information System (INIS)

Jewur, S.S.

1983-01-01

Theoretical considerations about the technique based on differential plasma mobility are made for the analysis of trace amounts of chemical products. The mechanisms for the formation of reagent-ion, reaction between ion and molecule, separation of ions and molecules and production of plasmogram, are explained. Despite being a very modern technique and the equipment has not yet been put in the market, it is already confirmed that the structural sensitivity of the fluctuation time in DPM is greater than the retention time in chromatographic techniques. (CLB) [pt

The metabolic response of Candida albicans to farnesol under hyphae-inducing conditions.

Science.gov (United States)

Han, Ting-Li; Cannon, Richard D; Villas-Bôas, Silas G

2012-12-01

Farnesol is a quorum-sensing molecule (QSM) produced, and sensed, by the polymorphic fungus, Candida albicans. This cell-to-cell communication molecule is known to suppress the hyphal formation of C. albicans at high cell density. Despite many studies investigating the signalling mechanisms by which QSMs influence the morphogenesis of C. albicans, the downstream metabolic effect of these signalling pathways in response to farnesol-mediated morphogenesis remains obscure. Here, we have used metabolomics to investigate the metabolic response of C. albicans upon exposure to farnesol under hyphae-inducing conditions. We have found a general up-regulation of central carbon metabolic pathways when hyphal formation was suppressed by farnesol evidenced by a considerably larger number of central carbon metabolic intermediates detected under this condition at an overall lower intracellular level. By combining the metabolic profiles from farnesol-exposed cells with previous metabolomics data for C. albicans undergoing morphogenesis, we have identified several metabolic pathways that are likely to be associated with the morphogenetic process of C. albicans, as well as metabolic pathways such as those involved in lipid metabolism that appeared to be specifically affected by farnesol. Therefore, our results provide important new insights into the metabolic role of farnesol in C. albicans metabolism. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Series: Utilization of Differential Equations and Methods for Solving Them in Medical Physics (3).

Science.gov (United States)

Murase, Kenya

2016-01-01

In this issue, simultaneous differential equations were introduced. These differential equations are often used in the field of medical physics. The methods for solving them were also introduced, which include Laplace transform and matrix methods. Some examples were also introduced, in which Laplace transform and matrix methods were applied to solving simultaneous differential equations derived from a three-compartment kinetic model for analyzing the glucose metabolism in tissues and Bloch equations for describing the behavior of the macroscopic magnetization in magnetic resonance imaging.In the next (final) issue, partial differential equations and various methods for solving them will be introduced together with some examples in medical physics.

A Natural Light/Dark Cycle Regulation of Carbon-Nitrogen Metabolism and Gene Expression in Rice Shoots.

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Li, Haixing; Liang, Zhijun; Ding, Guangda; Shi, Lei; Xu, Fangsen; Cai, Hongmei

2016-01-01

Light and temperature are two particularly important environmental cues for plant survival. Carbon and nitrogen are two essential macronutrients required for plant growth and development, and cellular carbon and nitrogen metabolism must be tightly coordinated. In order to understand how the natural light/dark cycle regulates carbon and nitrogen metabolism in rice plants, we analyzed the photosynthesis, key carbon-nitrogen metabolites, and enzyme activities, and differentially expressed genes and miRNAs involved in the carbon and nitrogen metabolic pathway in rice shoots at the following times: 2:00, 6:00, 10:00, 14:00, 18:00, and 22:00. Our results indicated that more CO2 was fixed into carbohydrates by a high net photosynthetic rate, respiratory rate, and stomatal conductance in the daytime. Although high levels of the nitrate reductase activity, free ammonium and carbohydrates were exhibited in the daytime, the protein synthesis was not significantly facilitated by the light and temperature. In mRNA sequencing, the carbon and nitrogen metabolism-related differentially expressed genes were obtained, which could be divided into eight groups: photosynthesis, TCA cycle, sugar transport, sugar metabolism, nitrogen transport, nitrogen reduction, amino acid metabolism, and nitrogen regulation. Additionally, a total of 78,306 alternative splicing events have been identified, which primarily belong to alternative 5' donor sites, alternative 3' acceptor sites, intron retention, and exon skipping. In sRNA sequencing, four carbon and nitrogen metabolism-related miRNAs (osa-miR1440b, osa-miR2876-5p, osa-miR1877 and osa-miR5799) were determined to be regulated by natural light/dark cycle. The expression level analysis showed that the four carbon and nitrogen metabolism-related miRNAs negatively regulated their target genes. These results may provide a good strategy to study how natural light/dark cycle regulates carbon and nitrogen metabolism to ensure plant growth and

A natural light/dark cycle regulation of carbon-nitrogen metabolism and gene expression in rice shoots

Directory of Open Access Journals (Sweden)

Haixing Li

2016-08-01

Full Text Available Light and temperature are two particularly important environmental cues for plant survival. Carbon and nitrogen are two essential macronutrients required for plant growth and development, and cellular carbon and nitrogen metabolism must be tightly coordinated. In order to understand how the natural light/dark cycle regulates carbon and nitrogen metabolism in rice plants, we analyzed the photosynthesis, key carbon-nitrogen metabolites and enzyme activities, and differentially expressed genes and miRNAs involved in the carbon and nitrogen metabolic pathway in rice shoots at the following times: 2:00, 6:00, 10:00, 14:00, 18:00 and 22:00. Our results indicated that more CO2 was fixed into carbohydrates by a high net photosynthetic rate, respiratory rate and stomatal conductance in the daytime. Although high levels of the nitrate reductase activity, free ammonium and carbohydrates were exhibited in the daytime, the protein synthesis was not significantly facilitated by the light and temperature. In mRNA sequencing, the carbon and nitrogen metabolism-related differentially expressed genes were obtained, which could be divided into eight groups: photosynthesis, TCA cycle, sugar transport, sugar metabolism, nitrogen transport, nitrogen reduction, amino acid metabolism and nitrogen regulation. Additionally, a total of 78,306 alternative splicing events have been identified, which primarily belong to alternative 5' donor sites, alternative 3' acceptor sites, intron retention and exon skipping. In sRNA sequencing, four carbon and nitrogen metabolism-related miRNAs (osa-miR1440b, osa-miR2876-5p, osa-miR1877 and osa-miR5799 were determined to be regulated by natural light/dark cycle. The expression level analysis showed that the four carbon and nitrogen metabolism-related miRNAs negatively regulated their target genes. These results may provide a good strategy to study how natural light/dark cycle regulates carbon and nitrogen metabolism to ensure plant

Non-photosynthetic plastids as hosts for metabolic engineering

DEFF Research Database (Denmark)

Mellor, Silas Busck; Behrendorff, James Bruce Yarnton H; Nielsen, Agnieszka Janina Zygadlo

2018-01-01

Using plants as hosts for production of complex, high-value compounds and therapeutic proteins has gained increasing momentum over the past decade. Recent advances in metabolic engineering techniques using synthetic biology have set the stage for production yields to become economically attractive......, but more refined design strategies are required to increase product yields without compromising development and growth of the host system. The ability of plant cells to differentiate into various tissues in combination with a high level of cellular compartmentalization represents so far the most...... in green tissues, have proven to be suitable for high yield protein and bio-compound production. Unfortunately, chloroplast manipulation often affects photosynthetic efficiency and therefore plant fitness. In this respect, plastids of non-photosynthetic tissues, which have focused metabolisms for synthesis...

Body Temperature Measurements for Metabolic Phenotyping in Mice

Science.gov (United States)

Meyer, Carola W.; Ootsuka, Youichirou; Romanovsky, Andrej A.

2017-01-01

Endothermic organisms rely on tightly balanced energy budgets to maintain a regulated body temperature and body mass. Metabolic phenotyping of mice, therefore, often includes the recording of body temperature. Thermometry in mice is conducted at various sites, using various devices and measurement practices, ranging from single-time probing to continuous temperature imaging. Whilst there is broad agreement that body temperature data is of value, procedural considerations of body temperature measurements in the context of metabolic phenotyping are missing. Here, we provide an overview of the various methods currently available for gathering body temperature data from mice. We explore the scope and limitations of thermometry in mice, with the hope of assisting researchers in the selection of appropriate approaches, and conditions, for comprehensive mouse phenotypic analyses. PMID:28824441

The Central Nervous System and Bone Metabolism: An Evolving Story.

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Dimitri, Paul; Rosen, Cliff

2017-05-01

Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

Cytochrome P450-mediated metabolic engineering

DEFF Research Database (Denmark)

Renault, Hugues; Bassard, Jean-Étienne André; Hamberger, Björn Robert

2014-01-01

for the engineered bioproduction of such compounds. Two ground-breaking developments of commercial products driven by the engineering of P450s are the antimalarial drug precursor artemisinic acid and blue roses or carnations. Tedious optimizations were required to generate marketable products. Hurdles encountered...... in P450 engineering and their potential solutions are summarized here. Together with recent technical developments and novel approaches to metabolic engineering, the lessons from this pioneering work should considerably boost exploitation of the amazing P450 toolkit emerging from accelerated sequencing...

Is anatomical distribution helpful for differentiating TB spondylitis ...

African Journals Online (AJOL)

Background. Extradural spinal cord compression in children may be the result of infection/inflammation or neoplasia. It is vital to differentiate between the two as there is considerable difference in the management of these entities. Objective. The aim of this paper is to determine whether there are significant differences ...

Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.

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Louise von Stechow

Full Text Available The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.

Interdisciplinary Pathways for Urban Metabolism Research

Science.gov (United States)

Newell, J. P.

2011-12-01

urban metabolism, which adds spatial differentiation to materials flows and form, as well as a focus on equity, access, and governance dimensions of the urban metabolism.

A review of metabolic and enzymatic engineering strategies for designing and optimizing performance of microbial cell factories

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Amanda K. Fisher

2014-08-01

Full Text Available Microbial cell factories (MCFs are of considerable interest to convert low value renewable substrates to biofuels and high value chemicals. This review highlights the progress of computational models for the rational design of an MCF to produce a target bio-commodity. In particular, the rational design of an MCF involves: (i product selection, (ii de novo biosynthetic pathway identification (i.e., rational, heterologous, or artificial, (iii MCF chassis selection, (iv enzyme engineering of promiscuity to enable the formation of new products, and (v metabolic engineering to ensure optimal use of the pathway by the MCF host. Computational tools such as (i de novo biosynthetic pathway builders, (ii docking, (iii molecular dynamics (MD and steered MD (SMD, and (iv genome-scale metabolic flux modeling all play critical roles in the rational design of an MCF. Genome-scale metabolic flux models are of considerable use to the design process since they can reveal metabolic capabilities of MCF hosts. These can be used for host selection as well as optimizing precursors and cofactors of artificial de novo biosynthetic pathways. In addition, recent advances in genome-scale modeling have enabled the derivation of metabolic engineering strategies, which can be implemented using the genomic tools reviewed here as well.

iTRAQ Protein Profile Differential Analysis of Dormant and Germinated Grassbur Twin Seeds Reveals that Ribosomal Synthesis and Carbohydrate Metabolism Promote Germination Possibly Through the PI3K Pathway.

Science.gov (United States)

Zhang, Guo-Liang; Zhu, Yue; Fu, Wei-Dong; Wang, Peng; Zhang, Rui-Hai; Zhang, Yan-Lei; Song, Zhen; Xia, Gui-Xian; Wu, Jia-He

2016-06-01

Grassbur is a destructive and invasive weed in pastures, and its burs can cause gastric damage to animals. The strong adaptability and reproductive potential of grassbur are partly due to a unique germination mechanism whereby twin seeds develop in a single bur: one seed germinates, but the other remains dormant. To investigate the molecular mechanism of seed germination in twin seeds, we used isobaric tags for relative and absolute quantitation (iTRAQ) to perform a dynamic proteomic analysis of germination and dormancy. A total of 1,984 proteins were identified, 161 of which were considered to be differentially accumulated. The differentially accumulated proteins comprised 102 up-regulated and 59 down-regulated proteins. These proteins were grouped into seven functional categories, ribosomal proteins being the predominant group. The authenticity and accuracy of the results were confirmed by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time reverse transcription-PCR (qPCR). A dynamic proteomic analysis revealed that ribosome synthesis and carbohydrate metabolism affect seed germination possibly through the phosphoinositide 3-kinase (PI3K) pathway. As the PI3K pathway is generally activated by insulin, analyses of seeds treated with exogenous insulin by qPCR, ELISA and iTRAQ confirmed that the PI3K pathway can be activated, which suppresses dormancy and promotes germination in twin grassbur seeds. Together, these results show that the PI3K pathway may play roles in stimulating seed germination in grassbur by modulating ribosomal synthesis and carbohydrate metabolism. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Benign bone-forming lesions: osteoma, osteoid osteoma, and osteoblastoma; Clinical, imaging, pathologic, and differential considerations

Energy Technology Data Exchange (ETDEWEB)

Greenspan, A. (Depts. of Radiology and Orthopedic Surgery, California Univ., Davis School of Medicine, Sacramento, CA (United States) Section of Musculoskeletal Radiology, UC Davis Medical Center, Sacramento, CA (United States))

1993-10-01

The benign bone lesions - osteoma, osteoid osteoma, and osteoblastoma - are characterized as bone-forming because tumor cells produce osteoid or mature bone. Osteoma is a slow-growing lesion most commonly seen in the paranasal sinuses and in the calvaria. When it occurs in the long bones, it is invariably juxtacortical and may need to be differentiated from, among others, parosteal osteosarcoma, sessile osteochondroma, and a matured juxtacortical focus of myositis ossificans. Osteoid osteoma and osteoblastoma appear histologically very similar. Their clinical presentations and distribution in the skeleton, however, are distinct: osteoid osteoma is usually accompanied by nocturnal pain promptly relieved by salicylates; osteoblastoma arises predominantly in the axial skeleton, spinal lesions constituting one-third of reported cases. This review focuses on the application of the various imaging modalities in the diagnosis, differential diagnosis, and evaluation of these lesions. Their histopathology also is discussed, and their treatment briefly outlined. (orig.)

Tensor and vector analysis with applications to differential geometry

CERN Document Server

Springer, C E

2012-01-01

Concise and user-friendly, this college-level text assumes only a knowledge of basic calculus in its elementary and gradual development of tensor theory. The introductory approach bridges the gap between mere manipulation and a genuine understanding of an important aspect of both pure and applied mathematics.Beginning with a consideration of coordinate transformations and mappings, the treatment examines loci in three-space, transformation of coordinates in space and differentiation, tensor algebra and analysis, and vector analysis and algebra. Additional topics include differentiation of vect

Pediatric gliosarcoma with fibrosarcomatous differentiation: Report of a rare case

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Shantha Ravisankar

2012-01-01

Full Text Available Gliosarcoma is a rare variant of glioblastoma with a biphasic pattern showing glial and mesenchymal differentiation. It is seen in adults during their fifth to sixth decades of life and is extremely rare in children. We report a case of primary gliosarcoma with fibrosarcomatous differentiation in an 11-year-old boy presenting with headache and vomiting. Imaging showed a contrast-enhancing isodense space-occupying lesion with areas of calcification in the right temporoparietal cortex. A total excision was done and, on histopathologic examination, a differential diagnostic consideration of gliosarcoma and teratoma with malignant transformation was made. After immunohistochemical analysis, a final diagnosis of gliosarcoma with fibrosarcomatous differentiation was then made. Primary gliosarcoma is a very rare tumor in children with a poor prognosis.

CCAAT/Enhancer Binding Protein β in relation to ER Stress, Inflammation, and Metabolic Disturbances

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Sophie E. van der Krieken

2015-01-01

Full Text Available The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-β in these metabolic disturbances. C/EBP-β deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of β-oxidation genes in brown adipose tissue. Furthermore, C/EBP-β is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-β is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-β at molecular and physiological level in humans.

Cellular Glycolysis and The Differential Survival of Lung Fibroblast and Lung Carcinoma Cell Lines.

Science.gov (United States)

Farah, Ibrahim O

2016-04-01

Tumor growth and abnormal cell survival were shown to be associated with a number of cellular metabolic abnormalities revealed by impaired oral glucose tolerance, depressed lipoprotein lipase activity leading to hypertriglyceridemia, and changes in amino acid profile as evidenced by increased plasma free tryptophan levels in patients with breast, lung, colon, stomach, and other cancers from various origins. The above findings seem to relate to or indicate a shift to non-oxidative metabolic pathways in cancer. In contrast to normal cells, cancer cells may lose the ability to utilize aerobic respiration due to either defective mitochondria or hypoxia within the tumor microenvironments. Glucose was shown to be the major energy source in cancer cells where it utilizes aerobic /anaerobic glycolysis with the resultant lactic acid formation. The role of energetic modulations and use of glycolytic inhibitors on cancer/normal cell survival is not clearly established in the literature. We hypothesize that natural intermediates of glycolysis and the citric acid cycle will differentially and negatively impact the cancer phenotype in contrast to their no effects on the normal cell phenotype. Therefore, the purpose of this study was to evaluate six potential glycolytic modulators namely, Pyruvic acid, oxalic acid, Zn acetate, sodium citrate, fructose diphosphate (FDP) and sodium bicarbonate at μM concentrations on growing A549 (lung cancer) and MRC-5 (normal; human lung fibroblast) cell lines with the objective of determining their influence on visual impact, cell metabolic activity, cell viability and end-point cell survival. Exposed and non-exposed cells were tested with phase-contrast micro-scanning, survival/death and metabolic activity trends through MTT-assays, as well as death end-point determinations by testing re-growth on complete media and T4 cellometer counts. Results showed that oxalic acid and Zn acetate both influenced the pH of the medium and resulted in

Optimization of a blueprint for in vitro glycolysis by metabolic real-time analysis

NARCIS (Netherlands)

Bujara, Matthias; Schümperli, Michael; Pellaux, René; Heinemann, Matthias; Panke, Sven

Recruiting complex metabolic reaction networks for chemical synthesis has attracted considerable attention but frequently requires optimization of network composition and dynamics to reach sufficient productivity. As a design framework to predict optimal levels for all enzymes in the network is

Differential Protein Expressions in Virus-Infected and Uninfected Trichomonas vaginalis.

Science.gov (United States)

He, Ding; Pengtao, Gong; Ju, Yang; Jianhua, Li; He, Li; Guocai, Zhang; Xichen, Zhang

2017-04-01

Protozoan viruses may influence the function and pathogenicity of the protozoa. Trichomonas vaginalis is a parasitic protozoan that could contain a double stranded RNA (dsRNA) virus, T. vaginalis virus (TVV). However, there are few reports on the properties of the virus. To further determine variations in protein expression of T. vaginalis , we detected 2 strains of T. vaginalis ; the virus-infected (V + ) and uninfected (V - ) isolates to examine differentially expressed proteins upon TVV infection. Using a stable isotope N-terminal labeling strategy (iTRAQ) on soluble fractions to analyze proteomes, we identified 293 proteins, of which 50 were altered in V + compared with V - isolates. The results showed that the expression of 29 proteins was increased, and 21 proteins decreased in V + isolates. These differentially expressed proteins can be classified into 4 categories: ribosomal proteins, metabolic enzymes, heat shock proteins, and putative uncharacterized proteins. Quantitative PCR was used to detect 4 metabolic processes proteins: glycogen phosphorylase, malate dehydrogenase, triosephosphate isomerase, and glucose-6-phosphate isomerase, which were differentially expressed in V + and V - isolates. Our findings suggest that mRNA levels of these genes were consistent with protein expression levels. This study was the first which analyzed protein expression variations upon TVV infection. These observations will provide a basis for future studies concerning the possible roles of these proteins in host-parasite interactions.

β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling.

Science.gov (United States)

Engskog, Mikael K R; Ersson, Lisa; Haglöf, Jakob; Arvidsson, Torbjörn; Pettersson, Curt; Brittebo, Eva

2017-05-01

β-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that induces long-term cognitive deficits, as well as an increased neurodegeneration and intracellular fibril formation in the hippocampus of adult rodents following short-time neonatal exposure and in vervet monkey brain following long-term exposure. It has also been proposed to be involved in the etiology of neurodegenerative disease in humans. The aim of this study was to identify metabolic effects not related to excitotoxicity or oxidative stress in human neuroblastoma SH-SY5Y cells. The effects of BMAA (50, 250, 1000 µM) for 24 h on cells differentiated with retinoic acid were studied. Samples were analyzed using LC-MS and NMR spectroscopy to detect altered intracellular polar metabolites. The analysis performed, followed by multivariate pattern recognition techniques, revealed significant perturbations in protein biosynthesis, amino acid metabolism pathways and citrate cycle. Of specific interest were the BMAA-induced alterations in alanine, aspartate and glutamate metabolism and as well as alterations in various neurotransmitters/neuromodulators such as GABA and taurine. The results indicate that BMAA can interfere with metabolic pathways involved in neurotransmission in human neuroblastoma cells.

Metabolic Imaging in Parkinson Disease.

Science.gov (United States)

Meles, Sanne K; Teune, Laura K; de Jong, Bauke M; Dierckx, Rudi A; Leenders, Klaus L

2017-01-01

This review focuses on recent human 18 F-FDG PET studies in Parkinson disease. First, an overview is given of the current analytic approaches to metabolic brain imaging data. Next, we discuss how 18 F-FDG PET studies have advanced understanding of the relation between distinct brain regions and associated symptoms in Parkinson disease, including cognitive decline. In addition, the value of 18 F-FDG PET studies in differential diagnosis, identifying prodromal patients, and the evaluation of treatment effects are reviewed. Finally, anticipated developments in the field are addressed. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Cold-hearted bats: uncoupling of heart rate and metabolism during torpor at sub-zero temperatures.

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Currie, Shannon E; Stawski, Clare; Geiser, Fritz

2018-01-04

Many hibernating animals thermoregulate during torpor and defend their body temperature ( T b ) near 0°C by an increase in metabolic rate. Above a critical temperature ( T crit ), animals usually thermoconform. We investigated the physiological responses above and below T crit for a small tree-dwelling bat ( Chalinolobus gouldii , ∼14 g) that is often exposed to sub-zero temperatures during winter. Through simultaneous measurement of heart rate ( f H ) and oxygen consumption ( V̇ O 2 ), we show that the relationship between oxygen transport and cardiac function is substantially altered in thermoregulating torpid bats between 1 and -2°C, compared with thermoconforming torpid bats at mild ambient temperatures ( T a 5-20°C). T crit for this species was at a T a of 0.7±0.4°C, with a corresponding T b of 1.8±1.2°C. Below T crit , animals began to thermoregulate, as indicated by a considerable but disproportionate increase in both f H and V̇ O 2 The maximum increase in f H was only 4-fold greater than the average thermoconforming minimum, compared with a 46-fold increase in V̇ O 2 The differential response of f H and V̇ O 2  to low T a was reflected in a 15-fold increase in oxygen delivery per heart beat (cardiac oxygen pulse). During torpor at low T a , thermoregulating bats maintained a relatively slow f H and compensated for increased metabolic demands by significantly increasing stroke volume and tissue oxygen extraction. Our study provides new information on the relationship between metabolism and f H in an unstudied physiological state that may occur frequently in the wild and can be extremely costly for heterothermic animals. © 2018. Published by The Company of Biologists Ltd.

Differentially expressed genes distributed over chromosomes and implicated in certain biological processes for site insertion genetically modified rice Kemingdao.

Science.gov (United States)

Liu, Zhi; Li, Yunhe; Zhao, Jie; Chen, Xiuping; Jian, Guiliang; Peng, Yufa; Qi, Fangjun

2012-01-01

Release of genetically modified (GM) plants has sparked off intensive debates worldwide partly because of concerns about potential adverse unintended effects of GM plants to the agro system and the safety of foods. In this study, with the aim of revealing the molecular basis for unintended effects of a single site insertion GM Kemingdao (KMD) rice transformed with a synthetic cry1Ab gene, and bridging unintended effects of KMD rice through clues of differentially expressed genes, comparative transcriptome analyses were performed for GM KMD rice and its parent rice of Xiushui11 (XS11). The results showed that 680 differentially expressed transcripts were identified from 30-day old seedlings of GM KMD rice. The absolute majority of these changed expression transcripts dispersed and located over all rice chromosomes, and existed physical distance on chromosome from the insertion site, while only two transcripts were found to be differentially expressed within the 21 genes located within 100 kb up and down-stream of the insertion site. Pathway and biology function analyses further revealed that differentially expressed transcripts of KMD rice were involved in certain biological processes, and mainly implicated in two types of pathways. One type was pathways implicated in plant stress/defense responses, which were considerably in coordination with the reported unintended effects of KMD rice, which were more susceptible to rice diseases compared to its parent rice XS11; the other type was pathways associated with amino acids metabolism. With this clue, new unintended effects for changes in amino acids synthesis of KMD rice leaves were successfully revealed. Such that an actual case was firstly provided for identification of unintended effects in GM plants by comparative transciptome analysis.

Generalized ordinary differential equations not absolutely continuous solutions

CERN Document Server

Kurzweil, Jaroslav

2012-01-01

This book provides a systematic treatment of the Volterra integral equation by means of a modern integration theory which extends considerably the field of differential equations. It contains many new concepts and results in the framework of a unifying theory. In particular, this new approach is suitable in situations where fast oscillations occur.

Differential proteomics reveals novel insights into Nosema-honey bee interactions

DEFF Research Database (Denmark)

Kurze, Christoph; Dosselli, Ryan; Grassl, Julia

2016-01-01

. In general, infections of Nosema resulted in an up-regulation of the bee's energy metabolism. Additionally, we identified 8 proteins that were differentially abundant between tolerant and sensitive honey bees regardless of the Nosema infection. Those proteins were linked to metabolism, response to oxidative...... stress and apoptosis. In addition to bee proteins, we also identified 3 Nosema ceranae proteins. Interestingly, abundance of two of these Nosema proteins were significantly higher in infected Nosema-sensitive honeybees relative to the infected Nosema-tolerant lineage. This may provide a novel candidate...

Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway.

Science.gov (United States)

Hatori, Yuta; Yan, Ye; Schmidt, Katharina; Furukawa, Eri; Hasan, Nesrin M; Yang, Nan; Liu, Chin-Nung; Sockanathan, Shanthini; Lutsenko, Svetlana

2016-02-16

Brain development requires a fine-tuned copper homoeostasis. Copper deficiency or excess results in severe neuro-pathologies. We demonstrate that upon neuronal differentiation, cellular demand for copper increases, especially within the secretory pathway. Copper flow to this compartment is facilitated through transcriptional and metabolic regulation. Quantitative real-time imaging revealed a gradual change in the oxidation state of cytosolic glutathione upon neuronal differentiation. Transition from a broad range of redox states to a uniformly reducing cytosol facilitates reduction of the copper chaperone Atox1, liberating its metal-binding site. Concomitantly, expression of Atox1 and its partner, a copper transporter ATP7A, is upregulated. These events produce a higher flux of copper through the secretory pathway that balances copper in the cytosol and increases supply of the cofactor to copper-dependent enzymes, expression of which is elevated in differentiated neurons. Direct link between glutathione oxidation and copper compartmentalization allows for rapid metabolic adjustments essential for normal neuronal function.

Differential toxicity of heterocyclic aromatic amines and their mixture in metabolically competent HepaRG cells

International Nuclear Information System (INIS)

Dumont, Julie; Josse, Rozenn; Lambert, Carine; Antherieu, Sebastien; Le Hegarat, Ludovic; Aninat, Caroline; Robin, Marie-Anne; Guguen-Guillouzo, Christiane

2010-01-01

Human exposure to heterocyclic aromatic amines (HAA) usually occurs through mixtures rather than individual compounds. However, the toxic effects and related mechanisms of co-exposure to HAA in humans remain unknown. We compared the effects of two of the most common HAA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), individually or in combination, in the metabolically competent human hepatoma HepaRG cells. Various endpoints were measured including cytotoxicity, apoptosis, oxidative stress and DNA damage by the comet assay. Moreover, the effects of PhIP and/or MeIQx on mRNA expression and activities of enzymes involved in their activation and detoxification pathways were evaluated. After a 24 h treatment, PhIP and MeIQx, individually and in combination, exerted differential effects on apoptosis, oxidative stress, DNA damage and cytochrome P450 (CYP) activities. Only PhIP induced DNA damage. It was also a stronger inducer of CYP1A1 and CYP1B1 expression and activity than MeIQx. In contrast, only MeIQx exposure resulted in a significant induction of CYP1A2 activity. The combination of PhIP with MeIQx induced an oxidative stress and showed synergistic effects on apoptosis. However, PhIP-induced genotoxicity was abolished by a co-exposure with MeIQx. Such an inhibitory effect could be explained by a significant decrease in CYP1A2 activity which is responsible for PhIP genotoxicity. Our findings highlight the need to investigate interactions between HAA when assessing risks for human health and provide new insights in the mechanisms of interaction between PhIP and MeIQx.

Activities of xenobiotic metabolizing enzymes in rat placenta and liver in vitro

NARCIS (Netherlands)

Fabian, Eric; Wang, Xinyi; Engel, Franziska; Li, Hequn; Landsiedel, Robert; Ravenzwaay, van Bennard

2016-01-01

In order to assess whether the placental metabolism of xenobiotic compounds should be taken into consideration for physiologically-based toxicokinetic (PBTK) modelling, the activities of seven phase I and phase II enzymes have been quantified in the 18-day placenta of untreated Wistar rats. To

The association between self-reported sleep quality and metabolic syndrome.

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Hao-Chang Hung

Full Text Available OBJECTIVES: Short and long sleep duration are associated with metabolic syndrome. However, there is limited research on the association between sleep quality and metabolic syndrome, and thus the aim of this study is to investigate this relationship. MATERIALS AND METHODS: The cross-sectional baseline data were collected from the decoded database of the Prevention Health Center of National Cheng Kung University Hospital from 2002 to 2006. The diagnosis of metabolic syndrome was according to the statement of the American Heart Association/National Heart, Lung, and Blood Institute. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI. A higher global PSQI score indicates poorer sleep quality, and a global PSQI score greater than five differentiates poor from good sleepers. RESULTS: Of the 3,435 subjects recruited, 899 (26.2% had metabolic syndrome. Subjects with metabolic syndrome had higher PSQI and prevalence of poor sleepers than those without metabolic syndrome. The multivariate lineal regression analysis showed that female gender, metabolic syndrome, sleep duration, snoring, alcohol drinking, and habitual exercise were independent predictors of PSQI. When substituting metabolic syndrome with the five components, hyperglycemia and low high-density lipoprotein cholesterol (HDL-C were positively associated with PSQI. The multivariate logistic regression analyses showed that female gender, metabolic syndrome, sleep duration, and snoring were independently associated with being poor sleepers. Of the five components, only low HDL-C was an independent predictor of being poor sleepers. CONCLUSIONS: Subjects with metabolic syndrome have higher global PSQI scores and a higher risk of being poor sleepers. Of the five components of metabolic syndrome, hyperglycemia and low HDL-C are independently associated with the global PSQI scores, while low HDL-C is an independent predictor of being poor sleepers.

Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet.

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Kerley-Hamilton, Joanna S; Trask, Heidi W; Ridley, Christian J A; Dufour, Eric; Ringelberg, Carol S; Nurinova, Nilufer; Wong, Diandra; Moodie, Karen L; Shipman, Samantha L; Moore, Jason H; Korc, Murray; Shworak, Nicholas W; Tomlinson, Craig R

2012-09-01

Obesity is a growing worldwide problem with genetic and environmental causes, and it is an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic-metabolizing genes. The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants. We used two congenic mouse models that differ at the Ahr gene and encode AHRs with a 10-fold difference in signaling activity. The two mouse strains were fed either a low-fat (regular) diet or a high-fat (Western) diet. The Western diet differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. The regular diet had no significant differential effects. The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model.

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Lucie Šedová

Full Text Available Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16 and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx into the genomic background of the spontaneously hypertensive rat (SHR strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference and diastolic (10-15 mmHg difference blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001. The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1. Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic

Different level of population differentiation among human genes

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Zhang Ya-Ping

2011-01-01

Full Text Available Abstract Background During the colonization of the world, after dispersal out of African, modern humans encountered changeable environments and substantial phenotypic variations that involve diverse behaviors, lifestyles and cultures, were generated among the different modern human populations. Results Here, we study the level of population differentiation among different populations of human genes. Intriguingly, genes involved in osteoblast development were identified as being enriched with higher FST SNPs, a result consistent with the proposed role of the skeletal system in accounting for variation among human populations. Genes involved in the development of hair follicles, where hair is produced, were also found to have higher levels of population differentiation, consistent with hair morphology being a distinctive trait among human populations. Other genes that showed higher levels of population differentiation include those involved in pigmentation, spermatid, nervous system and organ development, and some metabolic pathways, but few involved with the immune system. Disease-related genes demonstrate excessive SNPs with lower levels of population differentiation, probably due to purifying selection. Surprisingly, we find that Mendelian-disease genes appear to have a significant excessive of SNPs with high levels of population differentiation, possibly because the incidence and susceptibility of these diseases show differences among populations. As expected, microRNA regulated genes show lower levels of population differentiation due to purifying selection. Conclusion Our analysis demonstrates different level of population differentiation among human populations for different gene groups.

Differential metabolic effects of casein and soy protein meals on skeletal muscle in healthy volunteers.

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Luiking, Yvette C; Engelen, Mariëlle P K J; Soeters, Peter B; Boirie, Yves; Deutz, Nicolaas E P

2011-02-01

Dietary protein intake is known to affect whole body and interorgan protein turnover. We examined if moderate-nitrogen and carbohydrate casein and soy meals have a different effect on skeletal muscle protein and amino acid kinetics in healthy young subjects. Muscle protein and amino acid kinetics were measured in the postabsorptive state and during 4-h enteral intake of isonitrogenous [0.21 g protein/(kg body weight. 4 h)] protein-based test meals, which contained either casein (CAPM; n = 12) or soy protein (SOPM; n = 10) in 2 separate groups. Stable isotope and muscle biopsy techniques were used to study metabolic effects. The net uptake of glutamate, serine, histidine, and lysine across the leg was larger during CAPM than during SOPM intake. Muscle concentrations of glutamate, serine, histidine, glutamine, isoleucine and BCAA changed differently after CAPM and SOPM (P CAPM and SOPM, but differences in their (net) breakdown rates were not significant. Muscle protein synthesis was not different between CAPM and SOPM. Moderate-nitrogen casein and soy protein meals differently alter leg amino acid uptake without a significant difference in influencing acute muscle protein metabolism. Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Identification of microRNAs controlling hepatic mRNA levels for metabolic genes during the metabolic transition from embryonic to posthatch development in the chicken.

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Hicks, Julie A; Porter, Tom E; Liu, Hsiao-Ching

2017-09-05

The transition from embryonic to posthatch development in the chicken represents a massive metabolic switch from primarily lipolytic to primarily lipogenic metabolism. This metabolic switch is essential for the chick to successfully transition from the metabolism of stored egg yolk to the utilization of carbohydrate-based feed. However, regulation of this metabolic switch is not well understood. We hypothesized that microRNAs (miRNAs) play an important role in the metabolic switch that is essential to efficient growth of chickens. We used high-throughput RNA sequencing to characterize expression profiles of mRNA and miRNA in liver during late embryonic and early posthatch development of the chicken. This extensive data set was used to define the contributions of microRNAs to the metabolic switch during development that is critical to growth and nutrient utilization in chickens. We found that expression of over 800 mRNAs and 30 miRNAs was altered in the embryonic liver between embryonic day 18 and posthatch day 3, and many of these differentially expressed mRNAs and miRNAs are associated with metabolic processes. We confirmed the regulation of some of these mRNAs by miRNAs expressed in a reciprocal pattern using luciferase reporter assays. Finally, through the use of yeast one-hybrid screens, we identified several proteins that likely regulate expression of one of these important miRNAs. Integration of the upstream regulatory mechanisms governing miRNA expression along with monitoring the downstream effects of this expression will ultimately allow for the construction of complete miRNA regulatory networks associated with the hepatic metabolic switch in chickens. Our findings support a key role for miRNAs in controlling the metabolic switch that occurs between embryonic and posthatch development in the chicken.

Decoding cell signalling and regulation of oligodendrocyte differentiation.

Science.gov (United States)

Santos, A K; Vieira, M S; Vasconcellos, R; Goulart, V A M; Kihara, A H; Resende, R R

2018-05-22

Oligodendrocytes are fundamental for the functioning of the nervous system; they participate in several cellular processes, including axonal myelination and metabolic maintenance for astrocytes and neurons. In the mammalian nervous system, they are produced through waves of proliferation and differentiation, which occur during embryogenesis. However, oligodendrocytes and their precursors continue to be generated during adulthood from specific niches of stem cells that were not recruited during development. Deficiencies in the formation and maturation of these cells can generate pathologies mainly related to myelination. Understanding the mechanisms involved in oligodendrocyte development, from the precursor to mature cell level, will allow inferring therapies and treatments for associated pathologies and disorders. Such mechanisms include cell signalling pathways that involve many growth factors, small metabolic molecules, non-coding RNAs, and transcription factors, as well as specific elements of the extracellular matrix, which act in a coordinated temporal and spatial manner according to a given stimulus. Deciphering those aspects will allow researchers to replicate them in vitro in a controlled environment and thus mimic oligodendrocyte maturation to understand the role of oligodendrocytes in myelination in pathologies and normal conditions. In this study, we review these aspects, based on the most recent in vivo and in vitro data on oligodendrocyte generation and differentiation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quantitative Rates of Brain Glucose Metabolism Distinguish Minimally Conscious from Vegetative State Patients

DEFF Research Database (Denmark)

Stender, Johan; Kupers, Ron; Rodell, Anders

2015-01-01

of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n=14), MCS (n=21) or emergence from MCS (EMCS, n=6), and healthy volunteers (n=29). Global......The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function...... these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 October 2014; doi:10...

Inhibition of mitogen-activated protein kinase kinase, DNA methyltransferase, and transforming growth factor-β promotes differentiation of human induced pluripotent stem cells into enterocytes.

Science.gov (United States)

Kodama, Nao; Iwao, Takahiro; Kabeya, Tomoki; Horikawa, Takashi; Niwa, Takuro; Kondo, Yuki; Nakamura, Katsunori; Matsunaga, Tamihide

2016-06-01

We previously reported that small-molecule compounds were effective in generating pharmacokinetically functional enterocytes from human induced pluripotent stem (iPS) cells. In this study, to determine whether the compounds promote the differentiation of human iPS cells into enterocytes, we investigated the effects of a combination of mitogen-activated protein kinase kinase (MEK), DNA methyltransferase (DNMT), and transforming growth factor (TGF)-β inhibitors on intestinal differentiation. Human iPS cells cultured on feeder cells were differentiated into endodermal cells by activin A. These endodermal-like cells were then differentiated into intestinal stem cells by fibroblast growth factor 2. Finally, the cells were differentiated into enterocyte cells by epidermal growth factor and small-molecule compounds. After differentiation, mRNA expression levels and drug-metabolizing enzyme activities were measured. The mRNA expression levels of the enterocyte marker sucrase-isomaltase and the major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 were increased by a combination of MEK, DNMT, and TGF-β inhibitors. The mRNA expression of CYP3A4 was markedly induced by 1α,25-dihydroxyvitamin D3. Metabolic activities of CYP1A1/2, CYP2B6, CYP2C9, CYP2C19, CYP3A4/5, UDP-glucuronosyltransferase, and sulfotransferase were also observed in the differentiated cells. In conclusion, MEK, DNMT, and TGF-β inhibitors can be used to promote the differentiation of human iPS cells into pharmacokinetically functional enterocytes. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

LGR4 and its role in intestinal protection and energy metabolism

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Ziru eLi

2015-08-01

Full Text Available Leucine-rich repeat-containing G protein-coupled receptors (LGRs were identified by the unique nature of their long leucine-rich repeat extracellular domains. Distinct from classical G protein-coupled receptors which act via G proteins, LGR4 functions mainly through Wnt/β-catenin signaling to regulate cell proliferation, differentiation, and adult stem cell homeostasis. LGR4 is widely expressed in tissues ranging from the reproductive system, urinary system, sensory organs, digestive system, and the central nervous system, indicating LGR4 may have multiple functions in development. Here we focus on the digestive system by reviewing its effects on crypt cells differentiation and stem cells maintenance, which are important for cell regeneration after injury. Through effects on Wnt/β-catenin signaling and cell proliferation, LGR4 and its endogenous ligands, R-spondins, are involved in colon tumorigenesis. LGR4 also contributes to regulation of energy metabolism, including food intake, energy expenditure and lipid metabolism, as well as pancreatic β-cell proliferation and insulin secretion. This review summarizes the identification of LGR4, its endogenous ligand, ligand-receptor binding and intracellular signaling. Physiological functions include intestinal development and energy metabolism. The potential effects of LGR4 and its ligand in the treatment of inflammatory bowel disease, chemoradiotherapy induced gut damage, colorectal cancer and diabetes are also discussed.

GC-MS-Based metabolomics discovers a shared serum metabolic characteristic among three types of epileptic seizures.

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Wang, Dian; Wang, Xingxing; Kong, Jing; Wu, Jiayan; Lai, Minchao

2016-10-01

Understanding the overall and common metabolic changes of seizures can provide novel clues for their control and prevention. Here, we aim to investigate the global metabolic feature of serum for three types of seizures. We recruited 27 patients who had experienced a seizure within 48h (including 11 who had a generalized seizure, nine who had a generalized seizure secondary to partial seizure and seven who had a partial seizure) and 23 healthy controls. We analyzed the global metabolic changes of serum after seizures using gas chromatography-mass spectrometry-based metabolomics. Based on differential metabolites, the metabolic pathways and their potential to diagnose seizures were analyzed, and metabolic differences among three types of seizures were compared. The metabolic profiles of serum were distinctive between the seizure group and the controls but were not different among the three types of seizures. Compared to the controls, patients with seizures had higher levels of lactate, butanoic acid, proline and glutamate and lower levels of palmitic acid, linoleic acid, elaidic acid, trans-13-octadecenoic acid, stearic acid, citrate, cysteine, glutamine, asparagine, and glyceraldehyde in the serum. Furthermore, these differential metabolites had common change trends among the three types of seizures. Related pathophysiological processes reflected by these metabolites are energy deficit, inflammation, nervous excitation and neurotoxicity. Importantly, transamination inhibition is suspected to occur in seizures. Lactate, glyceraldehyde and trans-13-octadecenoic acid in serum jointly enabled a precision of 92.9% for diagnosing seizures. There is a common metabolic feature in three types of seizures. Lactate, glyceraldehyde and trans-13-octadecenoic acid levels jointly enable high-precision seizure diagnosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Outline of metabolic diseases in adult neurology.

Science.gov (United States)

Mochel, F

2015-01-01

Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available. Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises - acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided - GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases - ornithine transcarbamylase deficiency and adrenoleukodystrophy - and recommended in maternally inherited mitochondrial diseases - mutations of mitochondrial DNA. Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Identifying genes and gene networks involved in chromium metabolism and detoxification in Crambe abyssinica

International Nuclear Information System (INIS)

Zulfiqar, Asma; Paulose, Bibin; Chhikara, Sudesh; Dhankher, Om Parkash

2011-01-01

Chromium pollution is a serious environmental problem with few cost-effective remediation strategies available. Crambe abyssinica (a member of Brassicaseae), a non-food, fast growing high biomass crop, is an ideal candidate for phytoremediation of heavy metals contaminated soils. The present study used a PCR-Select Suppression Subtraction Hybridization approach in C. abyssinica to isolate differentially expressed genes in response to Cr exposure. A total of 72 differentially expressed subtracted cDNAs were sequenced and found to represent 43 genes. The subtracted cDNAs suggest that Cr stress significantly affects pathways related to stress/defense, ion transporters, sulfur assimilation, cell signaling, protein degradation, photosynthesis and cell metabolism. The regulation of these genes in response to Cr exposure was further confirmed by semi-quantitative RT-PCR. Characterization of these differentially expressed genes may enable the engineering of non-food, high-biomass plants, including C. abyssinica, for phytoremediation of Cr-contaminated soils and sediments. - Highlights: → Molecular mechanism of Cr uptake and detoxification in plants is not well known. → We identified differentially regulated genes upon Cr exposure in Crambe abyssinica. → 72 Cr-induced subtracted cDNAs were sequenced and found to represent 43 genes. → Pathways linked to stress, ion transport, and sulfur assimilation were affected. → This is the first Cr transcriptome study in a crop with phytoremediation potential. - This study describes the identification and isolation of differentially expressed genes involved in chromium metabolism and detoxification in a non-food industrial oil crop Crambe abyssinica.

Identifying genes and gene networks involved in chromium metabolism and detoxification in Crambe abyssinica

Energy Technology Data Exchange (ETDEWEB)

Zulfiqar, Asma, E-mail: asmazulfiqar08@yahoo.com [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Paulose, Bibin, E-mail: bpaulose@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Chhikara, Sudesh, E-mail: sudesh@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States); Dhankher, Om Parkash, E-mail: parkash@psis.umass.edu [Department of Plant, Soil, and Insect Sciences, 270 Stockbridge Road, University of Massachusetts Amherst, MA 01003 (United States)

2011-10-15

Chromium pollution is a serious environmental problem with few cost-effective remediation strategies available. Crambe abyssinica (a member of Brassicaseae), a non-food, fast growing high biomass crop, is an ideal candidate for phytoremediation of heavy metals contaminated soils. The present study used a PCR-Select Suppression Subtraction Hybridization approach in C. abyssinica to isolate differentially expressed genes in response to Cr exposure. A total of 72 differentially expressed subtracted cDNAs were sequenced and found to represent 43 genes. The subtracted cDNAs suggest that Cr stress significantly affects pathways related to stress/defense, ion transporters, sulfur assimilation, cell signaling, protein degradation, photosynthesis and cell metabolism. The regulation of these genes in response to Cr exposure was further confirmed by semi-quantitative RT-PCR. Characterization of these differentially expressed genes may enable the engineering of non-food, high-biomass plants, including C. abyssinica, for phytoremediation of Cr-contaminated soils and sediments. - Highlights: > Molecular mechanism of Cr uptake and detoxification in plants is not well known. > We identified differentially regulated genes upon Cr exposure in Crambe abyssinica. > 72 Cr-induced subtracted cDNAs were sequenced and found to represent 43 genes. > Pathways linked to stress, ion transport, and sulfur assimilation were affected. > This is the first Cr transcriptome study in a crop with phytoremediation potential. - This study describes the identification and isolation of differentially expressed genes involved in chromium metabolism and detoxification in a non-food industrial oil crop Crambe abyssinica.

Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study.

Directory of Open Access Journals (Sweden)

Obiamaka Obianyo

Full Text Available An alcohol use disorder (AUD is associated with an increased susceptibility to respiratory infection and injury and, upon hospitalization, higher mortality rates. Studies in model systems show effects of alcohol on mitochondrial function, lipid metabolism and antioxidant systems. The present study applied high-resolution metabolomics to test for these changes in bronchoalveolar lavage fluid (BALF of subjects with an AUD. Smokers were excluded to avoid confounding effects and compliance was verified by cotinine measurements. Statistically significant metabolic features, differentially expressed by control and AUD subjects, were identified by statistical and bioinformatic methods. The results show that fatty acid and acylcarnitine concentrations were increased in AUD subjects, consistent with perturbed mitochondrial and lipid metabolism. Decreased concentrations of methyl-donor compounds suggest altered one-carbon metabolism and oxidative stress. An accumulation of peptides suggests proteolytic activity, which could reflect altered epithelial barrier function. Two metabolites of possible microbial origin suggest subclinical bacterial infection. Furthermore, increased diacetylspermine suggests additional metabolic perturbations, which could contribute to dysregulated alveolar macrophage function and vulnerability to infection. Together, the results show an extended metabolic consequence of AUD in the bronchoalveolar space.

Nucleons II: cryopreservation and metabolic activity.

Science.gov (United States)

Reyes, R; Flores-Alonso, J C; Rodríguez-Hernández, H M; Merchant-Larios, H M; Delgado, N M

2001-01-01

The establishment of intracytoplasmatic sperm injection (ICSI) as a routine procedure in assisted fertilization has been used in the treatment of male infertility. The major technical problem that has arisen with the use of immotile sperm for ICSI has been differentiating between live and dead cells. Nucleons from human, pig, hamster, mouse, rat, and bull have been able to induce their chromatin decondensation by the action of heparin/GSH. Cryopreservation is deleterious to sperm function, killing more than 50% of the spermatozoa during the process. Nucleon cryostorage was performed at 5 and -5 degrees C and analyzed for total area (mu2), perimeter (mu), width (mu), and length (mu), using Metamorph Imaging System software. On the other hand, fluorescein diacetate (FDA) is hydrolyzed by intracellular estereases to produce fluorescein, which exhibits green fluorescence when excited by blue light. This fact is a striking result since the presence of this metabolic activity opens the possibility to select the nucleons for ICSI. In the present study, the authors decided to search for a suitable metabolic test, which might reflect the metabolism and viability of these chromatin structures. This is a simple cryostorage technique that after months of cryopreservation, allow the use of nucleons for ICSI with suitable fertilization and pregnancies rates.

Obesity and Metabolic Comorbidities: Environmental Diseases?

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Carla Lubrano

2013-01-01

Full Text Available Obesity and metabolic comorbidities represent increasing health problems. Endocrine disrupting compounds (EDCs are exogenous agents that change endocrine function and cause adverse health effects. Most EDCs are synthetic chemicals; some are natural food components as phytoestrogens. People are exposed to complex mixtures of chemicals throughout their lives. EDCs impact hormone-dependent metabolic systems and brain function. Laboratory and human studies provide compelling evidence that human chemical contamination can play a role in obesity epidemic. Chemical exposures may increase the risk of obesity by altering the differentiation of adipocytes. EDCs can alter methylation patterns and normal epigenetic programming in cells. Oxidative stress may be induced by many of these chemicals, and accumulating evidence indicates that it plays important roles in the etiology of chronic diseases. The individual sensitivity to chemicals is variable, depending on environment and ability to metabolize hazardous chemicals. A number of genes, especially those representing antioxidant and detoxification pathways, have potential application as biomarkers of risk assessment. The potential health effects of combined exposures make the risk assessment process more complex compared to the assessment of single chemicals. Techniques and methods need to be further developed to fill data gaps and increase the knowledge on harmful exposure combinations.

Sex steroids and glucose metabolism

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Carolyn A Allan

2014-04-01

Full Text Available Testosterone levels are lower in men with metabolic syndrome and type 2 diabetes mellitus (T2DM and also predict the onset of these adverse metabolic states. Body composition (body mass index, waist circumference is an important mediator of this relationship. Sex hormone binding globulin is also inversely associated with insulin resistance and T2DM but the data regarding estrogen are inconsistent. Clinical models of androgen deficiency including Klinefelter's syndrome and androgen deprivation therapy in the treatment of advanced prostate cancer confirm the association between androgens and glucose status. Experimental manipulation of the insulin/glucose milieu and suppression of endogenous testicular function suggests the relationship between androgens and insulin sensitivity is bidirectional. Androgen therapy in men without diabetes is not able to differentiate the effect on insulin resistance from that on fat mass, in particular visceral adiposity. Similarly, several small clinical studies have examined the efficacy of exogenous testosterone in men with T2DM, however, the role of androgens, independent of body composition, in modifying insulin resistance is uncertain.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis.

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Johannes J Kovarik

Full Text Available A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR, is responsible for controlling the balance between pro-inflammatory interleukin (IL-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR-activation and glucose-deprivation or co-treatment with 5'-adenosine monophosphate (AMP-activated protein kinase (AMPK activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation.

Fasting metabolism modulates the interleukin-12/interleukin-10 cytokine axis

Science.gov (United States)

Kernbauer, Elisabeth; Hölzl, Markus A.; Hofer, Johannes; Gualdoni, Guido A.; Schmetterer, Klaus G.; Miftari, Fitore; Sobanov, Yury; Meshcheryakova, Anastasia; Mechtcheriakova, Diana; Witzeneder, Nadine; Greiner, Georg; Ohradanova-Repic, Anna; Waidhofer-Söllner, Petra; Säemann, Marcus D.; Decker, Thomas

2017-01-01

A crucial role of cell metabolism in immune cell differentiation and function has been recently established. Growing evidence indicates that metabolic processes impact both, innate and adaptive immunity. Since a down-stream integrator of metabolic alterations, mammalian target of rapamycin (mTOR), is responsible for controlling the balance between pro-inflammatory interleukin (IL)-12 and anti-inflammatory IL-10, we investigated the effect of upstream interference using metabolic modulators on the production of pro- and anti-inflammatory cytokines. Cytokine release and protein expression in human and murine myeloid cells was assessed after toll-like receptor (TLR)-activation and glucose-deprivation or co-treatment with 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) activators. Additionally, the impact of metabolic interference was analysed in an in-vivo mouse model. Glucose-deprivation by 2-deoxy-D-glucose (2-DG) increased the production of IL-12p40 and IL-23p19 in monocytes, but dose-dependently inhibited the release of anti-inflammatory IL-10. Similar effects have been observed using pharmacological AMPK activation. Consistently, an inhibition of the tuberous sclerosis complex-mTOR pathway was observed. In line with our in vitro observations, glycolysis inhibition with 2-DG showed significantly reduced bacterial burden in a Th2-prone Listeria monocytogenes mouse infection model. In conclusion, we showed that fasting metabolism modulates the IL-12/IL-10 cytokine balance, establishing novel targets for metabolism-based immune-modulation. PMID:28742108

Bone mineral density and metabolic indices in hyperthyroidism.

Science.gov (United States)

Al-Nuaim, A; El-Desouki, M; Sulimani, R; Mohammadiah, M

1991-09-01

Hyperthyroidism can alter bone metabolism by increasing both bone resorption and formation. The increase in bone resorption predominates, leading to a decrease in bone mass. To assess the effect of hyperthyroidism on bone and mineral metabolism, we measured bone density using single photon absorptiometry in 30 untreated hyperthyroid patients. Patients were categorized into three groups based on sex and alkaline phosphatase levels: 44 sex- and age-matched subjects were used as controls. Bone densities were significanlty lower in all patient groups compared with controls. Alkaline phosphatase was found to be a useful marker for assessing severity of bone disease in hyperthyroid patients as there is significant bone density among patients with higher alkaline phosphatase value. Hyperthyroidism should be considered in the differential diagnosis of unexplained alkaline phophatase activity.

Dynamic optimization and differential games

CERN Document Server

Friesz, Terry L

2010-01-01

Dynamic Optimization and Differential Games has been written to address the increasing number of Operations Research and Management Science problems that involve the explicit consideration of time and of gaming among multiple agents. With end-of-chapter exercises throughout, it is a book that can be used both as a reference and as a textbook. It will be useful as a guide to engineers, operations researchers, applied mathematicians and social scientists whose work involves both the theoretical and computational aspects of dynamic optimization and differential games. Included throughout the text are detailed explanations of several original dynamic and game-theoretic mathematical models which are of particular relevance in today's technologically-driven-global economy: revenue management, oligopoly pricing, production planning, supply chain management, dynamic traffic assignment and dynamic congestion pricing. The book emphasizes deterministic theory, computational tools and applications associated with the stu...

A model for allometric scaling of mammalian metabolism with ambient heat loss

KAUST Repository

Kwak, Ho Sang; Im, Hong G.; Shim, Eun Bo

2016-01-01

The finding that additional radiative heat loss and the consideration of an outer insulation fur layer attenuate these deviation effects and render the scaling law closer to 2/3 provides in silico evidence for a functional impact of heat transfer mode on the allometric scaling law in mammalian metabolism.

Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography

Energy Technology Data Exchange (ETDEWEB)

Rumsey, J.M.; Duara, R.; Grady, C.; Rapoport, J.L.; Margolin, R.A.; Rapoport, S.I.; Cutler, N.R.

1985-05-01

The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic rates (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.