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Sample records for link cyp1b1 metabolism

  1. CYP1B1 expression, a potential risk factor for breast cancer

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    Goth-Goldstein, Regine; Erdmann, Christine A.; Russell, Marion

    2001-05-31

    CYP1B1 expression in non-tumor breast tissue from breast cancer patients and cancer-free individuals was determined to test the hypothesis that high CYP1B1 expression is a risk factor for breast cancer. Large interindividual variations in CYP1B1 expression were found with CYP1B1 levels notably higher in breast cancer patients than cancer-free individuals. The results indicate that CYP1B1 might play a role in breast cancer either through increased PAH activation or through metabolism of endogenous estrogen to a carcinogenic derivative.

  2. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  3. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis.

    Science.gov (United States)

    Larsen, Michele Campaigne; Brake, Paul B; Pollenz, Richard S; Jefcoate, Colin R

    2004-11-01

    Cytochrome P4501B1 (CYP1B1), the major constitutively expressed CYP in the rat mammary gland, is induced by Ah-receptor (AhR) ligands, while CYP1A1 is predominantly expressed only after induction. These CYPs contribute to carcinogenic activation of polycyclic aromatic hydrocarbons (PAHs). AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic. RMEC cultured on the extracellular matrix (ECM), Matrigel, or on a floating gel of collagen I demonstrated branching morphogenesis and substantially increased basal CYP1B1 and induced CYP1A1 expression, in parallel with large increases in AhR and ARNT expression. Branching was more pronounced in the Wistar Kyoto than in the Wistar Furth rat strain. Although EGF enhanced branching, neither strain nor growth factor treatment substantially impacted CYP expression. Increased AhR and ARNT expression is observed within 24 h of dispersal on Matrigel, substantially prior to branch formation. Culture on thin layers of collagen I, collagen IV, and laminin, respectively, failed to reproduce the branching morphogenesis or increases in AhR, ARNT, or CYP expression. However, adherent, gelled collagen I recapitulated the increased protein expression, without supporting branching. This increased protein expression was closely paralleled by enhanced expression of beta-catenin and E-cadherin, components of cell-cell adhesion complexes. A synthetic peptide that selectively antagonizes integrin-ECM interactions reduced branch formation, without diminishing AhR, ARNT, and CYP expression. These data demonstrate that early ECM surface adhesion interactions mediate AhR and ARNT expression, which enhances CYP expression, independent of branching morphogenesis.

  4. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    International Nuclear Information System (INIS)

    Trubicka, Joanna; Byrski, Tomasz; Gronwald, Jacek; Złowocka, Elżbieta; Kładny, Józef; Banaszkiewicz, Zbigniew; Wiśniowski, Rafał; Kowalska, Elżbieta; Lubinski, Jan; Scott, Rodney J; Grabowska-Kłujszo, Ewa; Suchy, Janina; Masojć, Bartłomiej; Serrano-Fernandez, Pablo; Kurzawski, Grzegorz; Cybulski, Cezary; Górski, Bohdan; Huzarski, Tomasz

    2010-01-01

    CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility. We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations

  5. CYP1B1 genotype and risk of cardiovascular disease, pulmonary disease, and cancer in 50,000 individuals

    DEFF Research Database (Denmark)

    Kaur-Knudsen, D.; Nordestgaard, B.G.; Tybjaerg-Hansen, A.

    2009-01-01

    OBJECTIVE: Cytochrome P450 (CYP) 1B1 enzymes metabolize tobacco-smoke polycyclic aromatic hydrocarbons and 17beta-estradiol. CYP1B1*3 (rs1056836 = Leu432Val = 4326C>G) and CYP1B1*4 (rs1800440 = Asn453Ser = 4390A>G) influence this metabolism. We, therefore, hypothesized that these two polymorphisms...... associate with risk of myocardial infarction (MI), ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), chronic obstructive pulmonary disease (COPD), cancer overall, tobacco-related cancer, and female cancer, possibly dependent on tobacco exposure. METHOD: We genotyped 10 391 adults from...... the Copenhagen City Heart Study, who had been followed prospectively for more than 30 years. Significant results were retested cross-sectionally in the Copenhagen General Population Study (CGPS) with 37 178 participants, and in the Copenhagen Ischemic Heart Disease Study with 2379 cases and 33 220 controls...

  6. Variant alleles of the CYP1B1 gene are associated with colorectal cancer susceptibility

    Directory of Open Access Journals (Sweden)

    Trubicka Joanna

    2010-08-01

    Full Text Available Abstract Background CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs, it represents an attractive candidate gene for studies into colorectal cancer susceptibility. Methods We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls. Results The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect. Conclusion Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.

  7. Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico.

    Science.gov (United States)

    Zenteno, Juan Carlos; Hernandez-Merino, Elena; Mejia-Lopez, Herlinda; Matías-Florentino, Margarita; Michel, Norma; Elizondo-Olascoaga, Celia; Korder-Ortega, Vincent; Casab-Rueda, Homero; Garcia-Ortiz, Jose Elias

    2008-01-01

    The frequency of primary congenital glaucoma (PCG)-causing CYP1B1 mutations varies importantly among distinct populations, ranging from 20% in Indonesians and Japanese to about 100% among the Saudi Arabians and Slovakian Gypsies. Thus, the molecular characterization of large groups of PCG from different ethnic backgrounds is important to establish the actual CYP1B1 contribution in specific populations. In this work, the molecular analysis of the CYP1B1 gene in a group of Mexican PCG patients is reported. Thirty unrelated Mexican patients fulfilling the clinical criteria for PCG were included. Two cases were familial and with proven consanguinity, originating from distinct regions of the country. Polymerase chain reaction amplification and direct automated sequencing of the CYP1B1 coding region was performed in each participating subject. An identical pathogenic CYP1B1 mutation was demonstrated in 2 unrelated PCG subjects. The mutation consisted of a homozygous G to A transition at nucleotide position 1505 in exon 3, which predicted a substitution of glutamic acid for lysine at residue 387 of the protein (E387K). In the remaining 28 PCG subjects, no deleterious mutations were identified. Both subjects with the E387K mutation shared a same haplotype for 5 CYP1B1 intragenic single nucleotide polymorphisms, indicating a common origin of the allele. Mexican patients with PCG are rarely (less than 10%) due to CYP1B1 mutations. Available data indicate that most of the non-Brazilian Latin American PCG patients investigated to date are not due to CYP1B1 defects. Populations with low incidence of CYP1B1 mutations are appropriate candidates for the identification of novel PCG-causing genes.

  8. CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark

    DEFF Research Database (Denmark)

    Grønskov, Karen; Redó-Riveiro, Alba; Sandfeld, Lisbeth

    2016-01-01

    Primary congenital glaucoma (PCG OMIM 231300) can be caused by pathogenic sequence variations in cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1). The purpose of this study was to investigate the contribution of sequence variations in CYP1B1 in a cohort of individuals with PCG residing...... mutations, 5 of which were novel. The frequency of CYP1B1 mutations in this cohort was comparable with other populations. We also detected an individual heterozygous for p.(Tyr81Asn) mutation, previously suggested to cause autosomal dominant primary open-angle glaucoma....

  9. Polycyclic aromatic hydrocarbon-induced CYP1B1 activity is suppressed by perillyl alcohol in MCF-7 cells

    International Nuclear Information System (INIS)

    Chan, Nelson L.S.; Wang Huan; Wang Yun; Leung, H.Y.; Leung, Lai K.

    2006-01-01

    Perillyl alcohol (POH) is a dietary monoterpene with potential applications in chemoprevention and chemotherapy. Although clinical trials are under way, POH's physiological and pharmacological properties are still unclear. In the present study, the effect of POH on polycyclic aromatic hydrocarbon (PAH)-induced genotoxicity, and the related expression were examined in MCF-7 cells. Exposure to environmental toxicant increases the risk of cancer. Many of these compounds are pro-carcinogens and are biotransformed into their ultimate genotoxic structures by xenobiotic metabolizing enzymes. CYP1A1 and 1B1 are enzymes that catalyze the biotransformation of dimethylbenz[a]anthracene (DMBA). Our data revealed that 0.5 μM of POH was effective in blocking DMBA-DNA binding. Ethoxyresorufin-O-deethylase (EROD) assay indicated that the administration of POH inhibited the DMBA-induced enzyme activity in MCF-7 cells. Enzyme kinetic analysis revealed that POH inhibited CYP1B1 but not CYP1A1 activity. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay also demonstrated that the monoterpene reduced CYP1B1 mRNA abundance induced by DMBA. The present study illustrated that POH might inhibit and downregulate CYP1B1, which could protect against PAH-induced carcinogenesis

  10. CYP1B1 gene polymorphisms correlate with an increased risk of urinary bladder cancer in India.

    Science.gov (United States)

    Sankhwar, Monica; Sankhwar, Satya Narayan; Abhishek, Amar; Gupta, Nishi; Rajender, Singh

    2016-04-01

    The urinary bladder is the target of several toxic compounds, which makes the bladder more prone to cancer. Cytochrome P450 1B1 enzyme is present in tumor tissues and metabolizes the polyaromatic carcinogens and activates several procarcinogens that cause DNA damage. We examined the functional single-nucleotide polymorphisms in the CYP1B1 gene to study their association with the urinary bladder cancer. We recruited 234 cases of pure urothelial and 258 bladder cancer-free control samples from the individuals visiting the clinic for various investigations. We genotyped 4 CYP1B1 single-nucleotide polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism analysis. The genotype data were analyzed by the Chi-square test. Haplotypes were constructed to evaluate the joint effect of the 4 polymorphisms. Overall, 3 polymorphisms-rs10012, rs150799650, and rs1056827 (odds ratio [OR] = 2.34, CI: 1.59-3.45, Pbladder cancer. Haplotype analysis suggested GTTC, GTTG, and ATGC to be the risk factors for bladder cancer. Overall, 3 polymorphisms, rs10012, rs1056827, and rs150799650 in the CYP1B1 gene correlate with urinary bladder cancer significantly in the Indo-European population of Uttar Pradesh, India. Further investigations in other populations are advised. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... Abstract Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood ... Conclusion: The current study further endorses the role of CYP1B1 mutations in the etiology of ..... There is no conflict of interest.

  12. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blindness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a possible ...

  13. CYP1B1 and MYOC Mutations in Vietnamese Primary Congenital Glaucoma Patients.

    Science.gov (United States)

    Do, Tan; Shei, William; Chau, Pham Thi Minh; Trang, Doan Le; Yong, Victor H K; Ng, Xiao Yu; Chen, Yue Ming; Aung, Tin; Vithana, Eranga N

    2016-05-01

    Primary congenital glaucoma (PCG, OMIM 231300), the most common glaucoma in infancy, is caused by developmental defects in the anterior chamber angle. The 3 implicated genes are cytochrome P450 family I subfamily B polypeptide 1 (CYP1B1), latent transforming growth factor β-binding protein 2 (LTBP2), and myocilin (MYOC). In this study, we sought to determine CYP1B1 and MYOC sequence variations in a Vietnamese cohort of index cases with PCG and their families. Thirty Vietnamese subjects with PCG and 120 normal Vietnamese subjects were recruited. PCG was defined by the presence of at least 2 of the following clinical manifestations: increased corneal diameter (>10 mm at birth), corneal edema, Haab's striae, optic disc changes, and absence of other ocular or systemic diseases associated with childhood glaucoma. The coding exons, intron and exon boundaries, and untranslated regions of CYP1B1 and MYOC genes were PCR amplified and subjected to bidirectional sequencing in all subjects. We identified 2 homozygous and 3 heterozygous CYP1B1 sequence alterations in our study subjects. Among the 5 mutations identified, 2 (p.H279L and p.L283F) were novel mutations, whereas 3 (p.A121_S122insDRPAFA, p.L107V, and p.V320L) had been previously reported in PCG cases. None of these mutations was observed in any of the 120 controls. Haplotypes generated with 6 non-disease-causing intragenic single nucleotide polymorphisms detected in CYP1B1 indicated that the most common haplotype in Vietnamese population is similar to that found in Chinese and Japanese. The genotype-phenotype correlation showed no significant difference between mutation and no-mutation groups for quantitative clinical features (presenting intraocular pressure, corneal diameter, number of surgeries performed, the cup-to-disc ratio) as well as for qualitative factors (bilateral cases, phenotype severity, and the prognosis) (P>0.05). Five out of 30 families with PCG (16.7%) had disease attributable to CYP1B1 alterations

  14. Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse

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    Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Bunde, Kristi L. [College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Harper, Tod A. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); McQuistan, Tammie J. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); Löhr, Christiane V. [Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331 (United States); Bramer, Lisa M. [Applied Statistics and Computational Modeling, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Waters, Katrina M. [Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Tilton, Susan C. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Krueger, Sharon K. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331 (United States); Superfund Research Center, Oregon State University, Corvallis, OR 97331 (United States); Linus Pauling Institute, Oregon State University, Corvallis, OR 97331 (United States); and others

    2015-09-01

    FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8 h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8 h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4 h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(±)-11,12-dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8 h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two-stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators. - Highlights: • Cyp1b1 null mice exhibit lower skin cancer sensitivity to DBC but not BaP or CTE. • Cyp1b1 expression impacts expression of other PAH metabolizing enzymes. • cis/trans-DBCDE-dA ratio significantly higher in the skin than the spleen, lung or liver • Potency of DBC and CTE in mouse skin is higher than predicted by RPFs.

  15. Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERα pathway

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    Khanal, Tilak; Kim, Hyung Gyun; Do, Minh Truong; Choi, Jae Ho; Won, Seong Su [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Kang, Wonku [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-05-15

    Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells. - Highlights: • Leptin increased 4-hydroxyoestradiol in MCF-7 breast cancer cells. • Leptin activated ERK and Akt kinases related to ERα phosphorylation. • Leptin induces phosphorylation of ERα at serine residues 118 and 167. • Leptin induces ERE-luciferase activity.

  16. Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels

    Directory of Open Access Journals (Sweden)

    Jacob Aude

    2011-08-01

    Full Text Available Abstract Background AhR activates the transcription of several target genes including CYP1B1. Recently, we showed CYP1B1 as the major cytochrome P450 (CYP enzyme expressed in human brain microvessels. Here, we studied the effect of AhR activation by environmental pollutants on the expression of Cyp1b1 in rat brain microvessels. Methods Expression of AhR and Cyp1b1 was detected in isolated rat brain microvessels. AhR was immunovisualised in brain microvessel endothelial cells. The effect of AhR ligands on Cyp1b1 expression was studied using isolated brain microvessels after ex vivo and/or in vivo exposure to TCDD, heavy hydrocarbons containing diesel exhaust particles (DEP or Δ9-tetrahydrocannabinol (Δ9-THC. Results After ex vivo exposure to TCDD (a highly potent AhR ligand for 3 h, Cyp1b1 expression was significantly increased by 2.3-fold in brain microvessels. A single i.p. dose of TCDD also increased Cyp1b1 transcripts (22-fold and Cyp1b1 protein (2-fold in rat brain microvessels at 72 h after TCDD. Likewise, DEP treatment (in vivo and ex vivo strongly induced Cyp1b1 protein in brain microvessels. DEP-mediated Cyp1b1 induction was inhibited by actinomycin D, cycloheximide, or by an AhR antagonist. In contrast, a sub-chronic in vivo treatment with Δ9-THC once daily for 7 seven days had no effect on Cyp1b1 expression Conclusions Our results show that TCDD and DEP strongly induced Cyp1b1 in rat brain microvessels, likely through AhR activation.

  17. Occurrence of CYP1B1 Mutations in Juvenile Open-Angle Glaucoma With Advanced Visual Field Loss.

    Science.gov (United States)

    Souzeau, Emmanuelle; Hayes, Melanie; Zhou, Tiger; Siggs, Owen M; Ridge, Bronwyn; Awadalla, Mona S; Smith, James E H; Ruddle, Jonathan B; Elder, James E; Mackey, David A; Hewitt, Alex W; Healey, Paul R; Goldberg, Ivan; Morgan, William H; Landers, John; Dubowsky, Andrew; Burdon, Kathryn P; Craig, Jamie E

    2015-07-01

    Juvenile open-angle glaucoma (JOAG) is a severe neurodegenerative eye disorder in which most of the genetic contribution remains unexplained. To assess the prevalence of pathogenic CYP1B1 sequence variants in an Australian cohort of patients with JOAG and severe visual field loss. For this cohort study, we recruited 160 patients with JOAG classified as advanced (n = 118) and nonadvanced (n = 42) through the Australian and New Zealand Registry of Advanced Glaucoma from January 1, 2007, through April 1, 2014. Eighty individuals with no evidence of glaucoma served as a control group. We defined JOAG as diagnosis before age 40 years and advanced JOAG as visual field loss in 2 of the 4 central fixation squares on a reliable visual field test result. We performed direct sequencing of the entire coding region of CYP1B1. Data analysis was performed in October 2014. Identification and characterization of CYP1B1 sequence variants. We identified 7 different pathogenic variants among 8 of 118 patients with advanced JOAG (6.8%) but none among the patients with nonadvanced JOAG. Three patients were homozygous or compound heterozygous for CYP1B1 pathogenic variants, which provided a likely basis for their disease. Five patients were heterozygous. The allele frequency among the patients with advanced JOAG (11 in 236 [4.7%]) was higher than among our controls (1 in 160 [0.6%]; P = .02; odds ratio, 7.8 [95% CI, 0.02-1.0]) or among the control population from the Exome Aggregation Consortium database (2946 of 122 960 [2.4%]; P = .02; odds ratio, 2.0 [95% CI, 0.3-0.9]). Individuals with CYP1B1 pathogenic variants, whether heterozygous or homozygous, had worse mean (SD) deviation on visual fields (-24.5 [5.1] [95% CI, -31.8 to -17.2] vs -15.6 [10.0] [95% CI, -17.1 to -13.6] dB; F1,126 = 5.90; P = .02; partial ηp2 = 0.05) and were younger at diagnosis (mean [SD] age, 23.1 [8.4] [95% CI, 17.2-29.1] vs 31.5 [8.0] [95% CI, 30.1-33.0] years; F1,122 = 7

  18. Genetic heterogeneity and minor CYP1B1 involvement in the molecular basis of primary congenital glaucoma in Gypsies.

    Science.gov (United States)

    Sivadorai, P; Cherninkova, S; Bouwer, S; Kamenarova, K; Angelicheva, D; Seeman, P; Hollingsworth, K; Mihaylova, V; Oscar, A; Dimitrova, G; Kaneva, R; Tournev, I; Kalaydjieva, L

    2008-07-01

    Primary congenital glaucoma (PCG) is a genetically heterogeneous disorder of autosomal recessive inheritance, with mutations in the cytochrome P450 1B1 (CYP1B1) gene detected in an average of approximately 50% of cases worldwide. The Roma/Gypsies are considered to be a rare example of a single founder CYP1B1 mutation, E387K (identified in the Slovak Roma), accounting for 100% of disease alleles. Contrary to this concept, unusual genetic heterogeneity was revealed in this study of 21 Gypsy PCG patients from Bulgaria and 715 controls from the general Gypsy population. In our small sample of affected subjects, we identified five different CYP1B1 mutations - four known (E229K, R368H, E387K and R390C) and one novel and potentially pathogenic (F445I), which together accounted for approximately 30% of disease alleles. E387K was rare in both the patient and the control group, indicating that its high frequency in the Slovak Roma is the product of local founder effect not representative of the overall molecular pattern of PCG in the Gypsy population. Data on other Mendelian disorders and on the population genetics of the Gypsies suggest that a true founder mutation is likely to exist and has remained undetected. Our analysis of another candidate gene, MYOC, and the GLC3B and GLC3C loci did not provide support for their involvement. The molecular basis of PCG in the Gypsies is thus unresolved, and diagnostic analyses should be extended beyond the E387K mutation.

  19. Furocoumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes.

    Science.gov (United States)

    Girennavar, Basavaraj; Poulose, Shibu M; Jayaprakasha, Guddadarangavvanahally K; Bhat, Narayan G; Patil, Bhimanagouda S

    2006-04-15

    Bioactive compounds present in grapefruit juice are known to increase the bioavailability of certain medications by acting as potent CYP 3A4 inhibitors. An efficient technique has been developed for isolation and purification of three furocoumarins. The isolated compounds have been tested for the inhibition of human CYP 1B1 isoform using specific substrates. Grapefruit juice was extracted with ethyl acetate (EtOAc) and the dried extract was loaded onto silica gel column chromatography. Further, column fractions were subjected to preparative HPLC to obtain three compounds. The purity of these compounds was analyzed by HPLC and structures were determined by NMR studies. The identified compounds, bergamottin, 6',7'-dihydroxybergamottin (DHB), and paradisin-A, were tested for their inhibitory effects on hydroxylase and O-dealkylase activities of human cytochrome P450 isoenzymes CYP 3A4 and CYP 1B1. Paradisin-A was found to be a potent CYP 3A4 inhibitor with an IC50 of 1.2 microM followed by DHB and bergamottin. All three compounds showed a substantial inhibitory effect on CYP 3A4 below 10 microM. Inhibitory effects on CYP 1B1 exhibited a greater variation due to the specificity of substrates. Paradisin A showed an IC50 of 3.56+/-0.12 microM for the ethoxy resorufin O-dealkylase (EROD) activity and 33.56+/-0.72 microM for the benzyloxy resorufin (BROD). DHB and bergamottin showed considerable variations for EROD and BROD activities with an IC50 of 7.17 microM and 13.86 microM, respectively.

  20. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    Energy Technology Data Exchange (ETDEWEB)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Chung, Young Chul [Department of Food Science and Culinary, International University of Korea, Jinju (Korea, Republic of); Jeong, Tae Cheon, E-mail: taecheon@ynu.ac.kr [College of Pharmacy, Yeungnam University, Gyeongsan (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    2014-10-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression.

  1. Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

    International Nuclear Information System (INIS)

    Do, Minh Truong; Kim, Hyung Gyun; Tran, Thi Thu Phuong; Khanal, Tilak; Choi, Jae Ho; Chung, Young Chul; Jeong, Tae Cheon; Jeong, Hye Gwang

    2014-01-01

    Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the anti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down-regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 and CYP1B1 reduction is irrelevant to estrogen receptor α (ERα) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells. The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited endogenous AhR ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor (GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Metformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. - Graphical abstract: Schematic of the CYP1A1 and CYP1B1 gene regulation by metformin. - Highlights: • Metformin inhibits CYP1A1 and CYP1B1 expression. • Metformin down-regulates the AhR signaling. • Metformin reduces Sp1 protein expression. • Metformin suppresses TDO expression

  2. Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans.

    Science.gov (United States)

    Ghisari, Mandana; Long, Manhai; Bonefeld-Jørgensen, Eva C

    2013-01-01

    The Indigenous Arctic population is of Asian descent, and their genetic background is different from the Caucasian populations. Relatively little is known about the specific genetic polymorphisms in genes involved in the activation and detoxification mechanisms of environmental contaminants in Inuit and its relation to health risk. The Greenlandic Inuit are highly exposed to legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), and an elucidation of gene-environment interactions in relation to health risks is needed. The aim of this study was to determine and compare the genotype and allele frequencies of the cytochrome P450 CYP1A1 Ile462Val (rs1048943), CYP1B1 Leu432Val (rs1056836) and catechol-O-methyltransferase COMT Val158Met (rs4680) in Greenlandic Inuit (n=254) and Europeans (n=262) and explore the possible relation between the genotypes and serum levels of POPs. The genotype and allele frequency distributions of the three genetic polymorphisms differed significantly between the Inuit and Europeans. For Inuit, the genotype distribution was more similar to those reported for Asian populations. We observed a significant difference in serum polychlorinated biphenyl (CB-153) and the pesticide 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) levels between Inuit and Europeans, and for Inuit also associations between the POP levels and genotypes for CYP1A1, CYP1B1 and COMT. Our data provide new information on gene polymorphisms in Greenlandic Inuit that might support evaluation of susceptibility to environmental contaminants and warrant further studies.

  3. CYP1A1 and CYP1B1 in human lymphocytes as biomarker of exposure: effect of dioxin exposure and polymorphisms

    Energy Technology Data Exchange (ETDEWEB)

    Duursen, M. van; Sanderson, T.; Berg, M. van den [Inst. for Risk Assessment Sciences, Utrecht (Netherlands)

    2004-09-15

    There are several known genetic polymorphisms of the CYP1A1 and CYP1B1 genes. A polymorphism in the 3'-untranslated region of the CYP1A1 gene (CYP1A1 MspI or CYP1A1 m1) is often studied in relation with breast or lung cancer, but little is known about the functional effect of this polymorphism. An amino acid substitution in codon 432 (Val to Leu) of the CYP1B1 gene is associated with a lower catalytic activity of the enzyme. However, the involvement of these polymorphisms on the inducibility of CYP1A1 and CYP1B1 gene expression is unclear. CYP1A1 and CYP1B1 mRNA expression levels can be determined in peripheral blood lymphocytes. This makes them potential candidates for use as biomarker of exposure to environmental compounds. Interindividual variations in mRNA expression patterns, catalytic activity and polymorphisms are very important factors when CYP1A1 and CYP1B1 expression patterns are used as biomarker of exposure, but little is known about it. Spencer et al. showed a concentration-dependent increase of CYP1B1 mRNA in lymphocytes upon exposure in vitro to 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD), the most potent dioxin. Yet, only a few studies describe the in vivo correlation between polymorphisms, mRNA expression level and exposure to environmental factors. In this study, we wanted to obtain a better insight in the CYP1A1 and CYP1B1 mRNA expression and enzyme activity in human lymphocytes. We determined the constitutive CYP1A1 and CYP1B1 mRNA expression in lymphocytes of ten healthy volunteers and the variability in sensitivity toward enzyme induction by TCDD. Further, the CYP1A1 m1 and CYP1B1 Val432Leu polymorphisms were determined.

  4. Association of CYP1B1 Polymorphisms with Breast Cancer: A Case-Control Study in the Han Population in Ningxia Hui Autonomous Region, P. R. China

    Science.gov (United States)

    Jiao, Haiyan; Liu, Chunlian; Guo, Weidong; Peng, Liang; Chen, Yintao; Martin, Francis L.

    2010-01-01

    Studies investigating possible associations between cytochrome P4501B1 (CYP1B1) polymorphisms and breast cancer risk have been inconsistent. We set out to ascertain whether there might be an association between polymorphisms in exon 2 (codon 119, G→T) and exon 3 (codon 432, G→C) of CYP1B1 and breast cancer in a Chinese Han population in the rural region of Ningxia. Using an allele-specific polymerase chain reaction method and direct DNA sequencing, the presence or absence of the two CYP1B1 polymorphisms was investigated. Genotype and allele frequencies were analyzed in breast cancer cases (n = 152) and healthy age-matched controls (n = 156). The odds ratio (OR) of 119G→T or 432G→C in breast cancer cases and controls was 3.3 (95% CI: 1.28 to 8.28) and 2.8 (95% CI: 1.04 to 7.51), respectively. In addition, the OR for people with both polymorphisms (119T and 432C) was 4.69 (95% CI: 1.97 to 11.19). Our results suggest that certain polymorphisms in the CYP1B1 gene might increase risk for breast cancer among Han Chinese, perhaps because they influence the efficiency of CYP1B1 bio-transformation of oestrogens or pro-carcinogens into DNA-reactive electrophiles that may act as cancer-initiating agents. PMID:20212917

  5. Effect of Ginkgo biloba extract on procarcinogen-bioactivating human CYP1 enzymes: Identification of isorhamnetin, kaempferol, and quercetin as potent inhibitors of CYP1B1

    International Nuclear Information System (INIS)

    Chang, Thomas K.H.; Chen Jie; Yeung, Eugene Y.H.

    2006-01-01

    In the present study, we investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the catalytic activity of human cytochrome P450 enzymes CYP1B1, CYP1A1, and CYP1A2. G. biloba extract of known abundance of terpene trilactones and flavonol glycosides inhibited 7-ethoxyresorufin O-dealkylation catalyzed by human recombinant CYP1B1, CYP1A1, and CYP1A2, and human liver microsomes, with apparent K i values of 2 ± 0.3, 5 ± 0.5, 16 ± 1.4, and 39 ± 1.2 μg/ml (mean ± SE), respectively. In each case, the mode of inhibition was of the mixed type. Bilobalide, ginkgolides A, B, C, and J, quercetin 3-O-rutinoside, kaempferol 3-O-rutinoside, and isorhamentin 3-O-rutinoside were not responsible for the inhibition of CYP1 enzymes by G. biloba extract, as determined by experiments with these individual chemicals at the levels present in the extract. In contrast, the aglycones of quercetin, kaempferol, and isorhamentin inhibited CYP1B1, CYP1A1, and CYP1A2. Among the three flavonol aglycones, isorhamentin was the most potent in inhibiting CYP1B1 (apparent K i = 3 ± 0.1 nM), whereas quercetin was the least potent in inhibiting CYP1A2 (apparent K i 418 ± 50 nM). The mode of inhibition was competitive, noncompetitive, or mixed, depending on the enzyme and the flavonol. G. biloba extract also reduced benzo[a]pyrene hydroxylation, and the effect was greater with CYP1B1 than with CYP1A1 as the catalyst. Overall, our novel findings indicate that G. biloba extract and the flavonol aglycones isorhamnetin, kaempferol, and quercetin preferentially inhibit the in vitro catalytic activity of human CYP1B1

  6. Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women

    DEFF Research Database (Denmark)

    Bräuner, Elvira V; Loft, Steffen; Wellejus, Anja

    2014-01-01

    these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk....... When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29-0.89). We...

  7. Induction of Cyp1a1 and Cyp1b1 and formation of DNA adducts in C57BL/6, Balb/c, and F1 mice following in utero exposure to 3-methylcholanthrene

    International Nuclear Information System (INIS)

    Xu Mian; Nelson, Garret B.; Moore, Joseph E.; McCoy, Thomas P.; Dai, Jian; Manderville, Richard A.; Ross, Jeffrey A.; Miller, Mark Steven

    2005-01-01

    Fetal mice are more sensitive to chemical carcinogens than are adults. Previous studies from our laboratory demonstrated differences in the mutational spectrum induced in the Ki-ras gene from lung tumors isolated from [D2 x B6D2F1]F2 mice and Balb/c mice treated in utero with 3-methylcholanthrene (MC). We thus determined if differences in metabolism, adduct formation, or adduct repair influence strain-specific responses to transplacental MC exposure in C57BL/6 (B6), Balb/c (BC), and reciprocal F1 crosses between these two strains of mice. The induction of Cyp1a1 and Cyp1b1 in fetal lung and liver tissue was determined by quantitative fluorescent real-time PCR. MC treatment caused maximal induction of Cyp1a1 and Cyp1b1 RNA 2-8 h after injection in both organs. RNA levels for both genes then declined in both fetal organs, but a small biphasic, secondary increase in Cyp1a1 was observed specifically in the fetal lung 24-48 h after MC exposure in all four strains. Cyp1a1 induction by MC at 4 h was 2-5 times greater in fetal liver (7000- to 16,000-fold) than fetal lung (2000- to 6000-fold). Cyp1b1 induction in both fetal lung and liver was similar and much lower than that observed for Cyp1a1, with induction ratios of 8- to 18-fold in fetal lung and 10- to 20-fold in fetal liver. The overall kinetics and patterns of induction were thus very similar across the four strains of mice. The only significant strain-specific effect appeared to be the relatively poor induction of Cyp1b1 in the parental strain of B6 mice, especially in fetal lung tissue. We also measured the levels of MC adducts and their disappearance from lung tissue by the P 32 post-labeling assay on gestation days 18 and 19 and postnatal days 1, 4, 11, and 18. Few differences were seen between the different strains of mice; the parental strain of B6 mice had nominally higher levels of DNA adducts 2 (gestation day 19) and 4 (postnatal day 1) days after injection, although this was not statistically significant

  8. Generation of a human iPSC line from a patient with congenital glaucoma caused by mutation in CYP1B1 gene

    Directory of Open Access Journals (Sweden)

    Arantxa Bolinches-Amorós

    2018-04-01

    Full Text Available The human iPSC cell line, GLC-FiPS4F1 (ESi047-A, derived from dermal fibroblast from the patient with congenital glaucoma caused by the mutation of the gene CYP1B1, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors.

  9. Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Larkin, Andrew [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Department of Statistics, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Krueger, Sharon K. [Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Tilton, Susan C.; Waters, Katrina M. [Superfund Research Center, Oregon State University (United States); Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Williams, David E., E-mail: david.williams@oregonstate.edu [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Baird, William M. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States)

    2013-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave-one-out cross-validation. Predictions were within 1 log{sub 2} fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights. - Highlights: ► Tested a model to predict PAH mixture-mediated changes in Cyp1b1 expression ► Quantitative predictions in agreement with microarrays for Cyp1b1 induction ► Unexpected difference in expression between DBC and other treatments predicted ► Model predictions

  10. Role of aryl hydrocarbon receptor polymorphisms on TCDD-mediated CYP1B1 induction and IgM suppression by human B cells

    Energy Technology Data Exchange (ETDEWEB)

    Kovalova, Natalia, E-mail: kovalova@msu.edu [Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824 (United States); Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Manzan, Maria, E-mail: ale.manzan@gmail.com [Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Crawford, Robert, E-mail: crawfo28@msu.edu [Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States); Kaminski, Norbert, E-mail: kamins11@msu.edu [Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI 48824 (United States); Institute for Integrative Toxicology, Michigan State University, Lansing, MI 48824 (United States)

    2016-10-15

    Previous studies have demonstrated that most of the intraspecies variation in sensitivity to the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including suppression of antibody responses, in murine models is due to single nucleotide polymorphisms (SNPs) within the aryl hydrocarbon receptor (AhR) gene. The underlying reason for variation in sensitivity to TCDD-induced suppression of IgM responses among humans is not well understood, but is thought, in part, to be a result of different polymorphic forms of the AhR expressed by different individuals. In this study, the functional properties of six (P517S, R554K, V570I, V570I + P517S, R554K + V570I and P517S + R554K + V570I) human AhR variants were examined in the human B cell line, SKW 6.4. TCDD-induced Cyp1B1 and Cyp1A2 mRNA expression levels and Cyp1B1-regulated reporter gene activity, used for comparative purposes, were markedly lower in SKW cells containing the R554K SNP than in SKW-AHR{sup +} (control AhR) cells. Furthermore, all AhR variants were able to mediate TCDD-induced suppression of the IgM response; however, a combined P517S + R554K + V570I variant partially reduced sensitivity to TCDD-mediated suppression of IgM secretion. Collectively, our findings show that the R554K human AhR SNP alone altered sensitivity of human B cells to TCDD-mediated induction of Cyp1B1 and Cyp1A2. By contrast, attenuation of TCDD-induced IgM suppression required a combination of all three SNPs P517S, R554K, and V570I. - Highlights: • Mouse, rat and SKW-AHR{sup +} B cells have a similar window of sensitivity to TCDD. • R554K AhR SNP alters B cell sensitivity to TCDD-mediated Cyp1B1 and Cyp1A2 induction. • Combination of P517S, R554K, and V570I SNPs attenuates TCDD-induced IgM suppression.

  11. Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population

    Science.gov (United States)

    Millá, Elena; Mañé, Begoña; Duch, Susana; Hernan, Imma; Borràs, Emma; Planas, Ester; Dias, Miguel de Sousa; Carballo, Miguel

    2013-01-01

    Purpose To identify myocilin (MYOC) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in a Spanish population with different clinical forms of familial glaucoma or ocular hypertension (OHT). Methods Index patients from 226 families participated in this study. Patients were diagnosed with familial glaucoma or OHT by complete ophthalmologic examination. Screening for MYOC mutations was performed in 207 index patients: 96 with adult-onset primary open-angle glaucoma (POAG), 21 with primary congenital glaucoma (PCG), 18 with juvenile-onset open-angle glaucoma (JOAG), five with Axenfeld-Rieger syndrome (ARS), and 67 with other types of glaucoma. One hundred two of the families (including all those in whom a MYOC mutation was detected) were also screened for CYP1B1 mutations: 45 POAG, 25 PCG, 21 JOAG, four ARS, and seven others. Results We examined 292 individuals (patients and relatives) with a positive family history of glaucoma or OHT. We identified two novel MYOC variants, p.Lys39Arg and p.Glu218Lys, in two families with POAG, and six previously reported MYOC mutations in seven families with POAG (four), JOAG (one), PCG (one), and normotensive glaucoma (one). CYP1B1 mutations were found in 16 index patients with PCG (nine), POAG (three), JOAG (two), and ARS (two). Conclusions The high percentage (9/25=36%) of mutations in CYP1B1 found in non-consanguineous patients with congenital glaucoma mandates genetic testing. However, the percentage of mutations (9/207=4.4%) in MYOC associated with glaucoma is relatively low in our population. The variable phenotype expression of glaucoma, even in families, cannot be explained with a digenic mechanism between MYOC and CYP1B1. PMID:23922489

  12. Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

    Directory of Open Access Journals (Sweden)

    Withey Laura

    2007-07-01

    Full Text Available Abstract Background Cytochrome P450 (CYP enzymes have the potential to affect colorectal cancer (CRC risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. Methods To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs that have not previously been shown to have functional consequence within these genes. Results There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03–1.80 and OR = 1.34, 95% CI: 1.00–1.79 respectively. Conclusion This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility.

  13. Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic aromatic hydrocarbons in various human tissue-derived cells: chemical-, cytochrome P450 isoform-, and cell-specific differences

    Energy Technology Data Exchange (ETDEWEB)

    Iwanari, M.; Nakajima, M.; Yokoi, T. [Div. of Drug Metabolism, Kanazawa Univ., Kanazawa (Japan); Kizu, R.; Hayakawa, K. [Lab. of Hygienic Chemistry, Kanazawa Univ., Kanazawa (Japan)

    2002-06-01

    Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel exhaust and ambient air. NPAHs as well as polycyclic aromatic hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity, and endocrine-disruptive effects. In the present study, the inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was compared with those produced by their parent PAHs and some reductive metabolites, amino-PAHs. Furthermore, to investigate the differences in the inducibility of the CYP1 family in human tissues, various human tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were determined with reverse transcription-polymerase chain reaction (RT-PCR). The cell lines were classified into two groups: CYP1 inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3 cells, and CYP1 non-inducible cell lines, comprising ACHN, A549, HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction profile of chemical specificity was similar for CYP1A1, CYP1A2, and CYP1B1, although the extent of induction differed among the cell lines and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-, 1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but 1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7 cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger inducibility than fluoranthene in the inducible cell lines. 6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently than chrysene. The induction potencies of 6-nitrobenzo[a]pyrene and 7-nitrobenz[a]anthracene were weaker than those of their parents benzo[a]pyrene and benz[a]anthracene, respectively. This

  14. 2,3,7,8-Tetrachlorodibenzo-p-dioxin modulates estradiol-induced aldehydic DNA lesions in human breast cancer cells through alteration of CYP1A1 and CYP1B1 expression.

    Science.gov (United States)

    Chen, Shou-Tung; Chen, Dar-Ren; Fang, Ju-Pin; Lin, Po-Hsiung

    2015-05-01

    Many genes responsible for the bioactivation of endogenous estrogen to reactive quinonoid metabolites, including cytochrome P450 (CYP) 1A1, 1A2, and 1B1, are well-known target genes of the aryl hydrocarbon receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The purpose of this research was to investigate the roles of TCDD-mediated altered gene expression in the induction of aldehydic DNA lesions (ADLs) by 17β-estradiol (E2) in human MDA-MB-231 and MCF-7 breast cancer cells. We demonstrated that increases in the number of oxidant-mediated ADLs, including abasic sites and aldehydic base/sugar lesions, were detected in MDA-MB-231 cells exposed to E2. The DNA-damaging effects of E2 in MDA-MB-231 cells were prevented by pretreatment of cells with TCDD. In contrast, we did not observe statistically significant increases in the number of ADLs in MCF-7 cells exposed to E2. However, with TCDD pretreatment, an approximately twofold increase in the number of ADLs was detected in MCF-7 cells exposed to E2. TCDD pretreatment induces disparity in the disposition of E2 to reactive quinonoid metabolites and the subsequent formation of oxidative DNA lesions through alteration of CYP1A1 and CYP1B1 expression in human breast cancer cells.

  15. Case-only study of interactions between metabolic enzymes and smoking in colorectal cancer

    International Nuclear Information System (INIS)

    Fan, Chunhong; Jin, Mingjuan; Chen, Kun; Zhang, Yongjing; Zhang, Shuangshuang; Liu, Bing

    2007-01-01

    Gene-gene and gene-environment interactions involved in the metabolism of carcinogens may increase the risk of cancer. Our objective was to measure the interactions between common polymorphisms of P450 (CYP1A2, CYP1B1, CYP2E1), GSTM1 and T1, SULT1A1 and cigarette smoking in colorectal cancer (CRC). A case-only design was conducted in a Chinese population including 207 patients with sporadic CRC. Unconditional logistic regression analysis was performed adjusting for age, gender, alcohol consumption, and cigarette smoking. The interaction odds ratio (COR) for the gene-gene interaction between CYP1B1 1294G and SULT1A1 638A allele was 2.68 (95% CI: 1.16–6.26). The results of the gene-environment analyses revealed that an interaction existed between cigarette smoking and the CYP1B1 1294G allele for CRC (COR = 2.62, 95%CI: 1.01–6.72), the COR for the interaction of CYP1B1 1294G and smoking history > 35 pack-years was 3.47 (95%CI: 1.12–10.80). No other significant gene-gene and gene-environment interactions were observed. Our results showed that the interaction between polymorphisms in CYP1B1 1294G and SULT1A1*2 may play a significant role on CRC in the Chinese population. Also, it is suggested that the association between cigarette smoking and CRC could be differentiated by the CYP1B1 1294G allele

  16. Methoxychlor reduces estradiol levels by altering steroidogenesis and metabolism in mouse antral follicles in vitro

    International Nuclear Information System (INIS)

    Basavarajappa, Mallikarjuna S.; Craig, Zelieann R.; Hernandez-Ochoa, Isabel; Paulose, Tessie; Leslie, Traci C.; Flaws, Jodi A.

    2011-01-01

    The organochlorine pesticide methoxychlor (MXC) is a known endocrine disruptor that affects adult rodent females by causing reduced fertility, persistent estrus, and ovarian atrophy. Since MXC is also known to target antral follicles, the major producer of sex steroids in the ovary, the present study was designed to test the hypothesis that MXC decreases estradiol (E 2 ) levels by altering steroidogenic and metabolic enzymes in the antral follicles. To test this hypothesis, antral follicles were isolated from CD-1 mouse ovaries and cultured with either dimethylsulfoxide (DMSO) or MXC. Follicle growth was measured every 24 h for 96 h. In addition, sex steroid hormone levels were measured using enzyme-linked immunosorbent assays (ELISA) and mRNA expression levels of steroidogenic enzymes as well as the E 2 metabolic enzyme Cyp1b1 were measured using qPCR. The results indicate that MXC decreased E 2 , testosterone, androstenedione, and progesterone (P 4 ) levels compared to DMSO. In addition, MXC decreased expression of aromatase (Cyp19a1), 17β-hydroxysteroid dehydrogenase 1 (Hsd17b1), 17α-hydroxylase/17,20-lyase (Cyp17a1), 3β hydroxysteroid dehydrogenase 1 (Hsd3b1), cholesterol side-chain cleavage (Cyp11a1), steroid acute regulatory protein (Star), and increased expression of Cyp1b1 enzyme levels. Thus, these data suggest that MXC decreases steroidogenic enzyme levels, increases metabolic enzyme expression and this in turn leads to decreased sex steroid hormone levels. - Highlights: → MXC inhibits steroidogenesis → MXC inhibits steroidogenic enzymes → MXC induces metabolic enzymes

  17. kpath: integration of metabolic pathway linked data.

    Science.gov (United States)

    Navas-Delgado, Ismael; García-Godoy, María Jesús; López-Camacho, Esteban; Rybinski, Maciej; Reyes-Palomares, Armando; Medina, Miguel Ángel; Aldana-Montes, José F

    2015-01-01

    In the last few years, the Life Sciences domain has experienced a rapid growth in the amount of available biological databases. The heterogeneity of these databases makes data integration a challenging issue. Some integration challenges are locating resources, relationships, data formats, synonyms or ambiguity. The Linked Data approach partially solves the heterogeneity problems by introducing a uniform data representation model. Linked Data refers to a set of best practices for publishing and connecting structured data on the Web. This article introduces kpath, a database that integrates information related to metabolic pathways. kpath also provides a navigational interface that enables not only the browsing, but also the deep use of the integrated data to build metabolic networks based on existing disperse knowledge. This user interface has been used to showcase relationships that can be inferred from the information available in several public databases. © The Author(s) 2015. Published by Oxford University Press.

  18. Complex genetics of glaucoma: defects in CYP1B1, and not MYOC ...

    Indian Academy of Sciences (India)

    wide, affecting almost 60 million people (Quigley and Bro- man 2006). Defects ... Analysis of the family mem- ... both parents of the proband do not show any symptom of. POAG ... †These authors contributed equally to the work. .... stage of life.

  19. Lactate: link between glycolytic and oxidative metabolism.

    Science.gov (United States)

    Brooks, George A

    2007-01-01

    Once thought to be the consequence of oxygen lack in contracting skeletal muscle, the glycolytic product lactate is formed and utilised continuously under fully aerobic conditions. 'Cell-cell' and 'intracellular lactate shuttle' concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signalling. Examples of cell-cell shuttles include lactate exchanges (i) between white-glycolytic and red-oxidative fibres within a working muscle bed; (ii) between working skeletal muscle and heart; and (iii) between tissues of net lactate release and gluconeogenesis. Lactate shuttles exist in diverse tissues including in the brain, where a shuttle between astrocytes and neurons is linked to glutamatergic signalling. Because lactate, the product of glycogenolysis and glycolysis, is disposed of by oxidative metabolism, lactate shuttling unites the two major processes of cellular energy transduction. Lactate disposal is mainly through oxidation, especially during exercise when oxidation accounts for 70-75% of removal and gluconeogenesis the remainder. Lactate flux occurs down proton and concentration gradients that are established by the mitochondrial lactate oxidation complex. Marathon running is a power activity requiring high glycolytic and oxidative fluxes; such activities require lactate shuttling. Knowledge of the lactate shuttle is yet to be imparted to the sport.

  20. Linking neuronal brain activity to the glucose metabolism

    OpenAIRE

    Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regul...

  1. Linking metabolomics data to underlying metabolic regulation

    Directory of Open Access Journals (Sweden)

    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

  2. Linking Arsenic Metabolism and Toxic Effects

    Science.gov (United States)

    Although arsenic has been long recognized as a toxicant and a carcinogen, the molecular basis for few of its adverse effects are well understood. Like other metalloids, arsenic undergoes extensive metabolism involving oxidation state changes and formation of methyl-arsenic bonds ...

  3. A metabolic link to skeletal muscle wasting and regeneration

    Directory of Open Access Journals (Sweden)

    René eKoopman

    2014-02-01

    Full Text Available Due to its essential role in movement, insulating the internal organs, generating heat to maintain core body temperature, and acting as a major energy storage depot, any impairment to skeletal muscle structure and function may lead to an increase in both morbidity and mortality. In the context of skeletal muscle, altered metabolism is directly associated with numerous pathologies and disorders, including diabetes, and obesity, while many skeletal muscle pathologies have secondary changes in metabolism, including cancer cachexia, sarcopenia and the muscular dystrophies. Furthermore, the importance of cellular metabolism in the regulation of skeletal muscle stem cells is beginning to receive significant attention. Thus, it is clear that skeletal muscle metabolism is intricately linked to the regulation of skeletal muscle mass and regeneration. The aim of this review is to discuss some of the recent findings linking a change in metabolism to changes in skeletal muscle mass, as well as describing some of the recent studies in developmental, cancer and stem-cell biology that have identified a role for cellular metabolism in the regulation of stem cell function, a process termed ‘metabolic reprogramming’.

  4. Linking neuronal brain activity to the glucose metabolism.

    Science.gov (United States)

    Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

    2013-08-29

    Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

  5. Stress transgenerationally programs metabolic pathways linked to altered mental health.

    Science.gov (United States)

    Kiss, Douglas; Ambeskovic, Mirela; Montina, Tony; Metz, Gerlinde A S

    2016-12-01

    Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Down-stream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-great-grandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

  6. Effects of sexually dimorphic growth hormone secretory patterns on arachidonic acid metabolizing enzymes in rodent heart

    International Nuclear Information System (INIS)

    Zhang, Furong; Yu, Xuming; He, Chunyan; Ouyang, Xiufang; Wu, Jinhua; Li, Jie; Zhang, Junjie; Duan, Xuejiao; Wan, Yu; Yue, Jiang

    2015-01-01

    The arachidonic acid (AA) metabolizing enzymes are the potential therapeutic targets of cardiovascular diseases (CVDs). As sex differences have been shown in the risk and outcome of CVDs, we investigated the regulation of heart AA metabolizing enzymes (COXs, LOXs, and CYPs) by sex-dependent growth hormone (GH) secretory patterns. The pulsatile (masculine) GH secretion at a physiological concentration decreased CYP1A1 and CYP2J3 mRNA levels more efficiently in the H9c2 cells compared with the constant (feminine) GH secretion; however, CYP1B1 mRNA levels were higher following the pulsatile GH secretion. Sex differences in CYP1A1, CYP1B1, and CYP2J11 mRNA levels were observed in both the wild-type and GHR deficient mice. No sex differences in the mRNA levels of COXs, LOXs, or CYP2E1 were observed in the wild-type mice. The constant GH infusion induced heart CYP1A1 and CYP2J11, and decreased CYP1B1 in the male C57/B6 mice constantly infused with GH (0.4 μg/h, 7 days). The activity of rat Cyp2j3 promoter was inhibited by the STAT5B protein, but was activated by C/EBPα (CEBPA). Compared with the constant GH administration, the levels of the nuclear phosphorylated STAT5B protein and its binding to the rat Cyp2j3 promoter were higher following the pulsatile GH administration. The constant GH infusion decreased the binding of the nuclear phosphorylated STAT5B protein to the mouse Cyp2j11 promoter. The data suggest the sexually dimorphic transcription of heart AA metabolizing enzymes, which might alter the risk and outcome of CVDs. GHR-STAT5B signal transduction pathway may be involved in the sex difference in heart CYP2J levels. - Highlights: • The transcription of heart Cyp1a1, Cyp1b1 and Cyp2j genes is sexually dimorphic. • There are no sex differences in the mRNA levels of heart COXs, LOXs, or CYP2E1. • GHR-STAT5B pathway is involved in sexually dimorphic transcription of heart Cpy2j genes. • Heart CYPs-mediated metabolism pathway of arachidonic acid may be sex

  7. Effects of sexually dimorphic growth hormone secretory patterns on arachidonic acid metabolizing enzymes in rodent heart

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Furong; Yu, Xuming [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); He, Chunyan [Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Ouyang, Xiufang; Wu, Jinhua; Li, Jie; Zhang, Junjie; Duan, Xuejiao [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Wan, Yu [Department of Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China); Yue, Jiang, E-mail: yuejiang@whu.edu.cn [Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071 (China)

    2015-12-15

    The arachidonic acid (AA) metabolizing enzymes are the potential therapeutic targets of cardiovascular diseases (CVDs). As sex differences have been shown in the risk and outcome of CVDs, we investigated the regulation of heart AA metabolizing enzymes (COXs, LOXs, and CYPs) by sex-dependent growth hormone (GH) secretory patterns. The pulsatile (masculine) GH secretion at a physiological concentration decreased CYP1A1 and CYP2J3 mRNA levels more efficiently in the H9c2 cells compared with the constant (feminine) GH secretion; however, CYP1B1 mRNA levels were higher following the pulsatile GH secretion. Sex differences in CYP1A1, CYP1B1, and CYP2J11 mRNA levels were observed in both the wild-type and GHR deficient mice. No sex differences in the mRNA levels of COXs, LOXs, or CYP2E1 were observed in the wild-type mice. The constant GH infusion induced heart CYP1A1 and CYP2J11, and decreased CYP1B1 in the male C57/B6 mice constantly infused with GH (0.4 μg/h, 7 days). The activity of rat Cyp2j3 promoter was inhibited by the STAT5B protein, but was activated by C/EBPα (CEBPA). Compared with the constant GH administration, the levels of the nuclear phosphorylated STAT5B protein and its binding to the rat Cyp2j3 promoter were higher following the pulsatile GH administration. The constant GH infusion decreased the binding of the nuclear phosphorylated STAT5B protein to the mouse Cyp2j11 promoter. The data suggest the sexually dimorphic transcription of heart AA metabolizing enzymes, which might alter the risk and outcome of CVDs. GHR-STAT5B signal transduction pathway may be involved in the sex difference in heart CYP2J levels. - Highlights: • The transcription of heart Cyp1a1, Cyp1b1 and Cyp2j genes is sexually dimorphic. • There are no sex differences in the mRNA levels of heart COXs, LOXs, or CYP2E1. • GHR-STAT5B pathway is involved in sexually dimorphic transcription of heart Cpy2j genes. • Heart CYPs-mediated metabolism pathway of arachidonic acid may be sex

  8. Carotid body, insulin and metabolic diseases: unravelling the links

    Directory of Open Access Journals (Sweden)

    Silvia V Conde

    2014-10-01

    Full Text Available The carotid bodies (CB are peripheral chemoreceptors that sense changes in arterial blood O2, CO2 and pH levels. Hypoxia, hypercapnia and acidosis activate the CB, which respond by increasing the action potential frequency in their sensory nerve, the carotid sinus nerve (CSN. CSN activity is integrated in the brain stem to induce a panoply of cardiorespiratory reflexes aimed, primarily, to normalize the altered blood gases, via hyperventilation, and to regulate blood pressure and cardiac performance, via sympathetic nervous system (SNS activation. Besides its role in the cardiorespiratory control the CB has been proposed as a metabolic sensor implicated in the control of energy homeostasis and, more recently, in the regulation of whole body insulin sensitivity. Hypercaloric diets cause CB overactivation in rats, which seems to be at the origin of the development of insulin resistance and hypertension, core features of metabolic syndrome and type 2 diabetes. Consistent with this notion, CB sensory denervation prevents metabolic and hemodynamic alterations in hypercaloric feed animal. Obstructive sleep apnoea (OSA is another chronic disorder characterized by increased CB activity and intimately related with several metabolic and cardiovascular abnormalities. In this manuscript we review in a concise manner the putative pathways linking CB chemoreceptors deregulation with the pathogenesis of insulin resistance and arterial hypertension. Also, the link between chronic intermittent hypoxia (CIH and insulin resistance is discussed. Then, a final section is devoted to debate strategies to reduce CB activity and its use for prevention and therapeutics of metabolic diseases with an emphasis on new exciting research in the modulation of bioelectronic signals, likely to be central in the future.

  9. Genetic polymorphisms in catalase and CYP1B1 determine DNA adduct formation by bento(a)pyrene ex vivo

    NARCIS (Netherlands)

    Schults, Marten A.; Chiu, Roland K.; Nagle, Peter; Kleinjans, J C; van Schooten, Frederik Jan; Godschalk, Roger W.

    Genetic polymorphisms can partially explain the large inter-individual variation in DNA adduct levels following exposure to polycyclic aromatic hydrocarbons. Effects of genetic polymorphisms on DNA adduct formation are difficult to assess in human studies because exposure misclassification

  10. Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease

    International Nuclear Information System (INIS)

    Gallicchio, Lisa; Berndt, Sonja I; McSorley, Meghan A; Newschaffer, Craig J; Thuita, Lucy W; Argani, Pedram; Hoffman, Sandra C; Helzlsouer, Kathy J

    2006-01-01

    A cohort study was conducted to examine the role of genetic polymorphisms in three estrogen metabolizing enzymes (COMT, CYP1A1, CYP1B1) and the two estrogen receptors (ESR1, ESR2) in the progression of benign breast disease (BBD) to breast cancer. Among participants in an ongoing cohort study, 1438 Caucasian women had a breast biopsy for BBD and were successfully genotyped for at least one of the polymorphisms examined in this study. Genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer occurring subsequent to BBD diagnosis up to 2003 were identified through cancer registries. Among all participants, the ESR2 *5772G allele was associated with a significant decrease in the risk of breast cancer among women with BBD (Odds Ratio (OR) 0.38; 95% Confidence Interval (CI) 0.15, 0.96). Compared to the reference wild-type genotypes, marginally significant associations with the development of breast cancer were observed between carriers of the variant ESR1 – 104062T allele (OR 0.70, 95% CI 0.45, 1.09), the variant ESR2 *38A allele (OR 1.40; 95% CI 0.88, 2.25), and the variant CYP1B1 453Ser allele (OR 1.48, 95% CI 0.95, 2.32). The results indicate that specific polymorphisms in the CYP1B1, ESR1, and ESR2 genes may play a role in progression of BBD to breast cancer among Caucasian women. Although additional studies are needed to confirm or refute our findings, these results suggest that genetic markers may aid in the identification of women who are at risk for progression of BBD to cancer

  11. DMPD: Nuclear receptors in macrophages: a link between metabolism and inflammation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18022390 Nuclear receptors in macrophages: a link between metabolism and inflammati...on. Szanto A, Roszer T. FEBS Lett. 2008 Jan 9;582(1):106-16. Epub 2007 Nov 20. (.png) (.svg) (.html) (.csml) Show Nuclear... receptors in macrophages: a link between metabolism and inflammation. PubmedID 18022390 Title Nuclear

  12. Fluorescence in situ hybridization mapping of six loci containing genes involved in the dioxin metabolism of domestic bovids.

    Science.gov (United States)

    Genualdo, Viviana; Spalenza, Veronica; Perucatti, Angela; Iannuzzi, Alessandra; Di Meo, Giulia Pia; Caputi-Jambrenghi, Annamaria; Vonghia, Gino; Rasero, Roberto; Nebbia, Carlo; Sacchi, Paola; Iannuzzi, Leopoldo

    2011-05-01

    Six loci containing genes involved in the dioxin metabolism (ARNT, AHR, CYP1A1, CYP1A2, CYP1B1 and AHRR) were assigned, for the first time, to cattle (Bos taurus, 2n = 60, BTA), river buffalo (Bubalus bubalis, 2n = 50, BBU), sheep (Ovis aries, 2n = 54, OAR) and goat (Capra hircus, 2n = 60, CHI) chromosomes by comparative FISH-mapping and R-banding using bovine BAC-clones. The following chromosome locations were found: ARNT to BTA3q21, BBU6q21, OAR1p21 and CHI3q21, AHR to BTA4q15, BBU8q15, OAR4q15 and CHI4q15; CYP1A1 and CYP1A2 to BTA21q17, BBU20q17, OAR18q17 and CHI21q17; CYP1B1 to BTA11q16, BBU12q22, OAR3p16 and CHI11q16, AHRR to BTA20q24, BBU19q24, OAR16q24 and CHI20q24. All loci were mapped at the same homoeologous chromosomes and chromosome bands of the four bovid species. Comparisons with corresponding human locations were also reported.

  13. Branch-point stoichiometry can generate weak links in metabolism ...

    Indian Academy of Sciences (India)

    PRAKASH KUMAR

    glycine is partitioned between the synthesis of collagen and other metabolic functions when .... reaction that converts arginine into ornithine and urea, and, in the reverse ..... synthesis and causes increased excretion of 5-oxoproline in the urine.

  14. Kidney cancer progression linked to shifts in tumor metabolism

    Science.gov (United States)

    Investigators in The Cancer Genome Atlas Research Network have uncovered a connection between how tumor cells use energy from metabolic processes and the aggressiveness of the most common form of kidney cancer, clear cell renal cell carcinoma.

  15. A link between sleep loss, glucose metabolism and adipokines

    Directory of Open Access Journals (Sweden)

    H.G. Padilha

    2011-10-01

    Full Text Available The present review evaluates the role of sleep and its alteration in triggering problems of glucose metabolism and the possible involvement of adipokines in this process. A reduction in the amount of time spent sleeping has become an endemic condition in modern society, and a search of the current literature has found important associations between sleep loss and alterations of nutritional and metabolic contexts. Studies suggest that sleep loss is associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and type 2 diabetes mellitus. The mechanism involved may be associated with the decreased efficacy of regulation of the hypothalamus-pituitary-adrenal axis by negative feedback mechanisms in sleep-deprivation conditions. In addition, changes in the circadian pattern of growth hormone (GH secretion might also contribute to the alterations in glucose regulation observed during sleep loss. On the other hand, sleep deprivation stress affects adipokines - increasing tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6 and decreasing leptin and adiponectin -, thus establishing a possible association between sleep-debt, adipokines and glucose metabolism. Thus, a modified release of adipokines resulting from sleep deprivation could lead to a chronic sub-inflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes mellitus. Further studies are necessary to investigate the role of sleep loss in adipokine release and its relationship with glucose metabolism.

  16. The growing landscape of lysine acetylation links metabolism and cell signalling

    DEFF Research Database (Denmark)

    Choudhary, Chuna Ram; Weinert, Brian Tate; Nishida, Yuya

    2014-01-01

    Lysine acetylation is a conserved protein post-translational modification that links acetyl-coenzyme A metabolism and cellular signalling. Recent advances in the identification and quantification of lysine acetylation by mass spectrometry have increased our understanding of lysine acetylation...

  17. [Chronic mild inflammation links obesity, metabolic syndrome, atherosclerosis and diabetes].

    Science.gov (United States)

    Andel, M; Polák, J; Kraml, P; Dlouhý, P; Stich, V

    2009-01-01

    Chronic low grade inflammation is relatively new concept in metabolic medicine. This concept describes the relations between the inflammation and adipose tissue, insulin resistence, atherosclerosis and type 2 diabetes mellitus. Macrophages and lymphocytes deposed in adipose tissue produce proinflammatory cytokines which directly or through the CRP liver secretion are targeting endothelial cells, hepatocytes and beta cells of Langerhans islets of pancreas. The dysfunction of these cells follows often further disturbances and in case of beta cells - the cell death. The connection between the adipose tissue insulin resistence, atherosclerosis and type 2 diabetes was earlier described with endocrine and metabolic descriptors. The concept of chronic low grade inflammation creates also another description of multilateral connections in metabolic syndome. The salicylates and the drugs related to them seem to have some glucose lowering properties. The recent development in the field ofchronic low grade inflammation represents also certain therapeutic hope for antiinflammatory intervention in type 2 diabetes.

  18. The role of IL6 in liver cancer linked to metabolic liver disease ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    The role of IL6 in liver cancer linked to metabolic liver disease. Liver cancer is highly fatal, it has very few treatment options, and it is one of the few cancers whose incidence is rising worldwide. One poorly understood risk factor for liver cancer is obesity/metabolic disease (such as diabetes and fatty liver disease).

  19. Citrate Defines a Regulatory Link Between Energy Metabolism and the Liver Hormone Hepcidin

    OpenAIRE

    Ladeira Courelas da Silva, Ana Rita

    2017-01-01

    Iron plays a critical role as an oxygen carrier in hemoglobin as well as a constituent of iron-sulfur clusters. Increasing evidence suggests that mechanisms maintaining iron homeostasis cross-talk to intermediary metabolism. The liver hormone hepcidin is the key regulator of systemic iron metabolism. Hepcidin transcriptional control is linked to the nutrient-sensing mTOR pathway, proliferative signals, gluconeogenic responses during starvation and hormones that modulate energy metabolism. The...

  20. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders

    NARCIS (Netherlands)

    Stoyanova, Irina

    2014-01-01

    Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics:

  1. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro.

    Science.gov (United States)

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotra-nsformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two‑dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases.

  2. A tryptophan derivative, ITE, enhances liver cell metabolic functions in vitro

    Science.gov (United States)

    Zhang, Xiaoqian; Lu, Juan; He, Bin; Tang, Lingling; Liu, Xiaoli; Zhu, Danhua; Cao, Hongcui; Wang, Yingjie; Li, Lanjuan

    2017-01-01

    Cell encapsulation provides a three-dimensional support by incorporating isolated cells into microcapsules with the goal of simultaneously maintaining cell survival and function, as well as providing active transport for a bioreactor in vitro similarly to that observed in vivo. However, the biotransformation and metabolic functions of the encapsulated cells are not satisfactory for clinical applications. For this purpose, in this study, hepatoma-derived Huh7 cells/C3A cells were treated with 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), an endogenous non-toxic ligand for aryl hydrocarbon receptor, in monolayer cultures and on microspheres. The mRNA and protein levels, as well as the metabolic activities of drug metabolizing enzymes, albumin secretion and urea synthesis were determined. When the Huh7 and C3A cells cultured in a monolayer on two-dimensional surfaces, ITE enhanced the protein levels and the metabolic activities of the major cytochrome P450 (CYP450) enzymes, CYP1A1, CYP1A2, CYP3A4 and CYP1B1, and slightly increased albumin secretion and urea synthesis. Moreover, when cultured on microspheres, ITE also substantially increased the protein levels and metabolic activities of CYP1A1, CYP1A2, CYP3A4 and CYP1B1 in both liver cell lines. On the whole, our findings indicate that ITE enhances the enzymatic activities of major CYP450 enzymes and the metabolic functions of liver cells cultured in monolayer or on microspheres, indicating that it may be utilized to improve the functions of hepatocytes. Thus, it may be used in the future for the treatment of liver diseases. PMID:27959388

  3. Metabolic link between phosphatidylethanolamine and triacylglycerol metabolism in the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Horvath, Susanne E; Wagner, Andrea; Steyrer, Ernst; Daum, Günther

    2011-12-01

    In the yeast Saccharomyces cerevisiae triacylglycerols (TAG) are synthesized by the acyl-CoA dependent acyltransferases Dga1p, Are1p, Are2p and the acyl-CoA independent phospholipid:diacylglycerol acyltransferase (PDAT) Lro1p which uses phosphatidylethanolamine (PE) as a preferred acyl donor. In the present study we investigated a possible link between TAG and PE metabolism by analyzing the contribution of the four different PE biosynthetic pathways to TAG formation, namely de novo PE synthesis via Psd1p and Psd2p, the CDP-ethanolamine (CDP-Etn) pathway and lyso-PE acylation by Ale1p. In cells grown on the non-fermentable carbon source lactate supplemented with 5mM ethanolamine (Etn) the CDP-Etn pathway contributed most to the cellular TAG level, whereas mutations in the other pathways displayed only minor effects. In cki1∆dpl1∆eki1∆ mutants bearing defects in the CDP-Etn pathway both the cellular and the microsomal levels of PE were markedly decreased, whereas in other mutants of PE biosynthetic routes depletion of this aminoglycerophospholipid was less pronounced in microsomes. This observation is important because Lro1p similar to the enzymes of the CDP-Etn pathway is a component of the ER. We conclude from these results that in cki1∆dpl1∆eki1∆ insufficient supply of PE to the PDAT Lro1p was a major reason for the strongly reduced TAG level. Moreover, we found that Lro1p activity was markedly decreased in cki1∆dpl1∆eki1∆, although transcription of LRO1 was not affected. Our findings imply that (i) TAG and PE syntheses in the yeast are tightly linked; and (ii) TAG formation by the PDAT Lro1p strongly depends on PE synthesis through the CDP-Etn pathway. Moreover, it is very likely that local availability of PE in microsomes is crucial for TAG synthesis through the Lro1p reaction. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Dietary fatty acids linking postprandial metabolic response and chronic diseases.

    Science.gov (United States)

    Ortega, Almudena; Varela, Lourdes M; Bermudez, Beatriz; Lopez, Sergio; Abia, Rocio; Muriana, Francisco J G

    2012-01-01

    Chronic diseases are by far one of the main causes of mortality in the world. One of the current global recommendations to counteract disability and premature death resulting from chronic diseases is to decrease the consumption of energy-dense high-fat diets, particularly those rich in saturated fatty acids (SFA). The most effective replacement for SFA in terms of risk factor outcomes for chronic disease are polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA). The biochemical basis for healthy benefits of such a dietary pattern has been widely evaluated under fasting conditions. However, the increasing amount of data available from multiple studies suggest that the postprandial state, i.e., "the period that comprises and follows a meal", plays an important, yet underappreciated, role in the genesis of numerous pathological conditions. In this review, the potential of MUFA, PUFA, and SFA to postprandially affect selected metabolic abnormalities related to chronic diseases is discussed.

  5. Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation

    Energy Technology Data Exchange (ETDEWEB)

    Noecker, Cecilia; Eng, Alexander; Srinivasan, Sujatha; Theriot, Casey M.; Young, Vincent B.; Jansson, Janet K.; Fredricks, David N.; Borenstein, Elhanan; Sanchez, Laura M.

    2015-12-22

    ABSTRACT

    Multiple molecular assays now enable high-throughput profiling of the ecology, metabolic capacity, and activity of the human microbiome. However, to date, analyses of such multi-omic data typically focus on statistical associations, often ignoring extensive prior knowledge of the mechanisms linking these various facets of the microbiome. Here, we introduce a comprehensive framework to systematically link variation in metabolomic data with community composition by utilizing taxonomic, genomic, and metabolic information. Specifically, we integrate available and inferred genomic data, metabolic network modeling, and a method for predicting community-wide metabolite turnover to estimate the biosynthetic and degradation potential of a given community. Our framework then compares variation in predicted metabolic potential with variation in measured metabolites’ abundances to evaluate whether community composition can explain observed shifts in the community metabolome, and to identify key taxa and genes contributing to the shifts. Focusing on two independent vaginal microbiome data sets, each pairing 16S community profiling with large-scale metabolomics, we demonstrate that our framework successfully recapitulates observed variation in 37% of metabolites. Well-predicted metabolite variation tends to result from disease-associated metabolism. We further identify several disease-enriched species that contribute significantly to these predictions. Interestingly, our analysis also detects metabolites for which the predicted variation negatively correlates with the measured variation, suggesting environmental control points of community metabolism. Applying this framework to gut microbiome data sets reveals similar trends, including prediction of bile acid metabolite shifts. This framework is an important first step toward a system-level multi-omic integration and an improved mechanistic understanding of the microbiome activity and dynamics in

  6. Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle

    OpenAIRE

    Chao, Lily C.; Zhang, Zidong; Pei, Liming; Saito, Tsugumichi; Tontonoz, Peter; Pilch, Paul F.

    2007-01-01

    Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from the neuromuscular junction to the nucleus and affect changes in metabolic gene expression are not well defined. We demonstrate here that the orphan nuclear receptor Nur77 is a regulator of gene expression linked to glucose utilization in muscle. In vivo, Nur77 is preferentially expressed in glycolytic compared to oxidativ...

  7. Expression Profile of Genes Related to Drug Metabolism in Human Brain Tumors.

    Directory of Open Access Journals (Sweden)

    Pantelis Stavrinou

    Full Text Available Endogenous and exogenous compounds as well as carcinogens are metabolized and detoxified by phase I and II enzymes, the activity of which could be crucial to the inactivation and hence susceptibility to carcinogenic factors. The expression of these enzymes in human brain tumor tissue has not been investigated sufficiently. We studied the association between tumor pathology and the expression profile of seven phase I and II drug metabolizing genes (CYP1A1, CYP1B1, ALDH3A1, AOX1, GSTP1, GSTT1 and GSTM3 and some of their proteins.Using qRT-PCR and western blotting analysis the gene and protein expression in a cohort of 77 tumors were investigated. The major tumor subtypes were meningioma, astrocytoma and brain metastases, -the later all adenocarcinomas from a lung primary.Meningeal tumors showed higher expression levels for AOX1, CYP1B1, GSTM3 and GSTP1. For AOX1, GSTM and GSTP1 this could be verified on a protein level as well. A negative correlation between the WHO degree of malignancy and the strength of expression was identified on both transcriptional and translational level for AOX1, GSTM3 and GSTP1, although the results could have been biased by the prevalence of meningiomas and glioblastomas in the inevitably bipolar distribution of the WHO grades. A correlation between the gene expression and the protein product was observed for AOX1, GSTP1 and GSTM3 in astrocytomas.The various CNS tumors show different patterns of drug metabolizing gene expression. Our results suggest that the most important factor governing the expression of these enzymes is the histological subtype and to a far lesser extent the degree of malignancy itself.

  8. PPARs Link Early Life Nutritional Insults to Later Programmed Hypertension and Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    You-Lin Tain

    2015-12-01

    Full Text Available Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three members of PPARs, PPARα, PPARβ/δ, and PPARγ, are expressed in the kidney and involved in blood pressure control. This review provides an overview of potential clinical applications of targeting on the PPARs in the kidney to prevent programmed hypertension and metabolic syndrome, with an emphasis on the following areas: mechanistic insights to interpret programmed hypertension; the link between the PPARs, nutritional insults, and programmed hypertension and metabolic syndrome; the impact of PPAR signaling pathway in a maternal high-fructose model; and current experimental studies on early intervention by PPAR modulators to prevent programmed hypertension and metabolic syndrome. Animal studies employing a reprogramming strategy via targeting PPARs to prevent hypertension have demonstrated interesting results. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies, to halt the globally-growing epidemic of metabolic syndrome-related diseases.

  9. Seasonal changes in mood and behavior are linked to metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Reeta Rintamäki

    Full Text Available BACKGROUND: Obesity is a major public health problem worldwide. Metabolic syndrome is a risk factor to the cardiovascular diseases. It has been reported that disruptions of the circadian clockwork are associated with and may predispose to metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS: 8028 individuals attended a nationwide health examination survey in Finland. Data were collected with a face-to-face interview at home and during an individual health status examination. The waist circumference, height, weight and blood pressure were measured and samples were taken for laboratory tests. Participants were assessed using the ATP-III criteria for metabolic syndrome and with the Seasonal Pattern Assessment Questionnaire for their seasonal changes in mood and behavior. Seasonal changes in weight in particular were a risk factor of metabolic syndrome, after controlling for a number of known risk and potential confounding factors. CONCLUSIONS AND SIGNIFICANCE: Metabolic syndrome is associated with high global scores on the seasonal changes in mood and behavior, and with those in weight in particular. Assessment of these changes may serve as a useful indicator of metabolic syndrome, because of easy assessment. Abnormalities in the circadian clockwork which links seasonal fluctuations to metabolic cycles may predispose to seasonal changes in weight and to metabolic syndrome.

  10. CYP1B1, Oxidative Stress, and Inflammation in the Etiology of Ovarian Epithelial Cancer Using an Avian Model of Ovarian Carcinoma

    National Research Council Canada - National Science Library

    Hales, Dale B

    2007-01-01

    .... Research in ovarian cancer has been hampered by a lack of suitable animal models. With the exception of the laying hen, no other animal gets ovarian epithelial cancer analogous to the human disease...

  11. CYP1B1, Oxidative Stress, and Inflammation in the Etiology of Ovarian Epithelial Cancer Using an Avian Model of Ovarian Carcinoma

    Science.gov (United States)

    2007-11-01

    fibrovascular cores lined by atypical epithelial cells. Tumors 7 resembling human endometrioid carcinomas were generally characterized by a complex 8...presence of focal lesions, glandular structures, cells with pleomorphic nucleus with mitotic bodies and hyperplastic surface or stromal hyperplasia ...Non-tumor pathologies included increased atresia of developing stromal follicles, cystic structures, hyperplasia without any focal lesion or malignant

  12. Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle.

    Science.gov (United States)

    Chao, Lily C; Zhang, Zidong; Pei, Liming; Saito, Tsugumichi; Tontonoz, Peter; Pilch, Paul F

    2007-09-01

    Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from the neuromuscular junction to the nucleus and affect changes in metabolic gene expression are not well defined. We demonstrate here that the orphan nuclear receptor Nur77 is a regulator of gene expression linked to glucose utilization in muscle. In vivo, Nur77 is preferentially expressed in glycolytic compared with oxidative muscle and is responsive to beta-adrenergic stimulation. Denervation of rat muscle compromises expression of Nur77 in parallel with that of numerous genes linked to glucose metabolism, including glucose transporter 4 and genes involved in glycolysis, glycogenolysis, and the glycerophosphate shuttle. Ectopic expression of Nur77, either in rat muscle or in C2C12 muscle cells, induces expression of a highly overlapping set of genes, including glucose transporter 4, muscle phosphofructokinase, and glycogen phosphorylase. Furthermore, selective knockdown of Nur77 in rat muscle by small hairpin RNA or genetic deletion of Nur77 in mice reduces the expression of a battery of genes involved in skeletal muscle glucose utilization in vivo. Finally, we show that Nur77 binds the promoter regions of multiple genes involved in glucose metabolism in muscle. These results identify Nur77 as a potential mediator of neuromuscular signaling in the control of metabolic gene expression.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  14. 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.

  15. All in the family: Clueing into the link between metabolic syndrome and hematologic malignancies.

    Science.gov (United States)

    Karmali, Reem; Dalovisio, Andrew; Borgia, Jeffrey A; Venugopal, Parameswaran; Kim, Brian W; Grant-Szymanski, Kelly; Hari, Parameswaran; Lazarus, Hillard

    2015-03-01

    Metabolic syndrome constitutes a constellation of findings including central obesity, insulin resistance/type 2 diabetes mellitus (DM), dyslipidemia and hypertension. Metabolic syndrome affects 1 in 4 adults in the United States and is rapidly rising in prevalence, largely driven by the dramatic rise in obesity and insulin resistance/DM. Being central to the development of metabolic syndrome and its other related diseases, much focus has been placed on identifying the mitogenic effects of obesity and insulin resistance/DM as mechanistic clues of the link between metabolic syndrome and cancer. Pertinent mechanisms identified include altered lipid signaling, adipokine and inflammatory cytokine effects, and activation of PI3K/Akt/mTOR and RAS/RAF/MAPK/ERK pathways via dysregulated insulin/insulin-like growth factor-1 (IGF-1) signaling. Through variable activation of these multiple pathways, obesity and insulin resistance/DM pre-dispose to hematologic malignancies, imposing the aggressive and chemo-resistant phenotypes typically seen in cancer patients with underlying metabolic syndrome. Growing understanding of these pathways has identified druggable cancer targets, rationalizing the development and testing of agents like PI3K inhibitor idelalisib, mTOR inhibitors everolimus and temsirolimus, and IGF-1 receptor inhibitor linsitinib. It has also led to exploration of obesity and diabetes-directed therapies including statins and oral hypoglycemic for the management of metabolic syndrome-related hematologic neoplasms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. NPAS2 and PER2 are linked to risk factors of the metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Aromaa Arpo

    2009-05-01

    Full Text Available Abstract Background Mammalian circadian clocks control multiple physiological events. The principal circadian clock generates seasonal variations in behavior as well. Seasonality elevates the risk for metabolic syndrome, and evidence suggests that disruption of the clockwork can lead to alterations in metabolism. Our aim was to analyze whether circadian clock polymorphisms contribute to seasonal variations in behavior and to the metabolic syndrome. Methods We genotyped 39 single-nucleotide polymorphisms (SNP from 19 genes which were either canonical circadian clock genes or genes related to the circadian clockwork from 517 individuals drawn from a nationwide population-based sample. Associations between these SNPs and seasonality, metabolic syndrome and its risk factors were analyzed using regression analysis. The p-values were corrected for multiple testing. Results Our findings link circadian gene variants to the risk factors of the metabolic syndrome, since Npas2 was associated with hypertension (P-value corrected for multiple testing = 0.0024 and Per2 was associated with high fasting blood glucose (P-value corrected for multiple testing = 0.049. Conclusion Our findings support the view that relevant relationships between circadian clocks and the metabolic syndrome in humans exist.

  17. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

    Directory of Open Access Journals (Sweden)

    Mei-Fei Yueh

    Full Text Available Triclocarban (3,4,4'-trichlorocarbanilide, TCC is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs. To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR and estrogen receptor alpha (ERα activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR because no induction occurred in hUGT1Car(-/- mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for

  18. Does circadian disruption play a role in the metabolic-hormonal link to delayed lactogenesis II?

    Directory of Open Access Journals (Sweden)

    Manjie eFu

    2015-02-01

    Full Text Available Breastfeeding improves maternal and child health. The American Academy of Pediatrics recommends exclusive breastfeeding for six months, with continued breastfeeding for at least one year. However, in the US, only 18.8% of infants are exclusively breastfed until six months of age. For mothers who initiate breastfeeding, the early postpartum period sets the stage for sustained breastfeeding. Mothers who experience breastfeeding problems in the early postpartum period are more likely to discontinue breastfeeding within two weeks. A major risk factor for shorter breastfeeding duration is delayed lactogenesis II (i.e. onset of milk coming in more than 72 h postpartum. Recent studies report a metabolic-hormonal link to delayed lactogenesis II. This is not surprising because around the time of birth the mother’s entire metabolism changes to direct nutrients to mammary glands. Circadian and metabolic systems are closely linked, and our rodent studies suggest circadian clocks coordinate hormonal and metabolic changes to support lactation. Molecular and environmental disruption of the circadian system decreases a dam’s ability to initiate lactation and negatively impacts milk production. Circadian and metabolic systems evolved to be functional and adaptive when lifestyles and environmental exposures were quite different from modern times. We now have artificial lights, longer work days, and increases in shift work. Disruption in the circadian system due to shift work, jet lag, sleep disorders and other modern life style choices are associated with metabolic disorders, obesity, and impaired reproduction. We hypothesize delayed lactogenesis II is related to disruption of the mother’s circadian system. Here we review literature that supports this hypothesis, and describe interventions that may help to increase breastfeeding success.

  19. Diurnal variation of the human adipose transcriptome and the link to metabolic disease

    Directory of Open Access Journals (Sweden)

    Lamb John

    2009-02-01

    Full Text Available Abstract Background Circadian (diurnal rhythm is an integral part of the physiology of the body; specifically, sleep, feeding behavior and metabolism are tightly linked to the light-dark cycle dictated by earth's rotation. Methods The present study examines the effect of diurnal rhythm on gene expression in the subcutaneous adipose tissue of overweight to mildly obese, healthy individuals. In this well-controlled clinical study, adipose biopsies were taken in the morning, afternoon and evening from individuals in three study arms: treatment with the weight loss drug sibutramine/fasted, placebo/fed and placebo/fasted. Results The results indicated that diurnal rhythm was the most significant driver of gene expression variation in the human adipose tissue, with at least 25% of the genes having had significant changes in their expression levels during the course of the day. The mRNA expression levels of core clock genes at a specific time of day were consistent across multiple subjects on different days in all three arms, indicating robust diurnal regulation irrespective of potential confounding factors. The genes essential for energy metabolism and tissue physiology were part of the diurnal signature. We hypothesize that the diurnal transition of the expression of energy metabolism genes reflects the shift in the adipose tissue from an energy-expending state in the morning to an energy-storing state in the evening. Consistent with this hypothesis, the diurnal transition was delayed by fasting and treatment with sibutramine. Finally, an in silico comparison of the diurnal signature with data from the publicly-available Connectivity Map demonstrated a significant association with transcripts that were repressed by mTOR inhibitors, suggesting a possible link between mTOR signaling, diurnal gene expression and metabolic regulation. Conclusion Diurnal rhythm plays an important role in the physiology and regulation of energy metabolism in the adipose

  20. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    International Nuclear Information System (INIS)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki

    2013-01-01

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA

  1. Diphenylarsinic acid, a chemical warfare-related neurotoxicant, promotes liver carcinogenesis via activation of aryl hydrocarbon receptor signaling and consequent induction of oxidative DAN damage in rats

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Min; Yamada, Takanori; Yamano, Shotaro; Kato, Minoru; Kakehashi, Anna; Fujioka, Masaki; Tago, Yoshiyuki; Kitano, Mistuaki; Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp

    2013-11-15

    Diphenylarsinic acid (DPAA), a chemical warfare-related neurotoxic organic arsenical, is present in the groundwater and soil in some regions of Japan due to illegal dumping after World War II. Inorganic arsenic is carcinogenic in humans and its organic arsenic metabolites are carcinogenic in animal studies, raising serious concerns about the carcinogenicity of DPAA. However, the carcinogenic potential of DPAA has not yet been evaluated. In the present study we found that DPAA significantly enhanced the development of diethylnitrosamine-induced preneoplastic lesions in the liver in a medium-term rat liver carcinogenesis assay. Evaluation of the expression of cytochrome P450 (CYP) enzymes in the liver revealed that DPAA induced the expression of CYP1B1, but not any other CYP1, CYP2, or CYP3 enzymes, suggesting that CYP1B1 might be the enzyme responsible for the metabolic activation of DPAA. We also found increased oxidative DNA damage, possibly due to elevated CYP1B1 expression. Induction of CYP1B1 has generally been linked with the activation of AhR, and we found that DPAA activates the aryl hydrocarbon receptor (AhR). Importantly, the promotion effect of DPAA was observed only at a dose that activated the AhR, suggesting that activation of AhR and consequent induction of AhR target genes and oxidative DNA damage plays a vital role in the promotion effects of DPAA. The present study provides, for the first time, evidence regarding the carcinogenicity of DPAA and indicates the necessity of comprehensive evaluation of its carcinogenic potential using long-term carcinogenicity studies. - Highlights: • DPAA, an environmental neurotoxicant, promotes liver carcinogenesis in rats. • DPAA is an activator of AhR signaling pathway. • DPAA promoted oxidative DNA damage in rat livers. • AhR target gene CYP 1B1 might be involved in the metabolism of DPAA.

  2. A synthetic system links FeFe-hydrogenases to essential E. coli sulfur metabolism

    Directory of Open Access Journals (Sweden)

    Grandl Gerald

    2011-05-01

    Full Text Available Abstract Background FeFe-hydrogenases are the most active class of H2-producing enzymes known in nature and may have important applications in clean H2 energy production. Many potential uses are currently complicated by a crucial weakness: the active sites of all known FeFe-hydrogenases are irreversibly inactivated by O2. Results We have developed a synthetic metabolic pathway in E. coli that links FeFe-hydrogenase activity to the production of the essential amino acid cysteine. Our design includes a complementary host strain whose endogenous redox pool is insulated from the synthetic metabolic pathway. Host viability on a selective medium requires hydrogenase expression, and moderate O2 levels eliminate growth. This pathway forms the basis for a genetic selection for O2 tolerance. Genetically selected hydrogenases did not show improved stability in O2 and in many cases had lost H2 production activity. The isolated mutations cluster significantly on charged surface residues, suggesting the evolution of binding surfaces that may accelerate hydrogenase electron transfer. Conclusions Rational design can optimize a fully heterologous three-component pathway to provide an essential metabolic flux while remaining insulated from the endogenous redox pool. We have developed a number of convenient in vivo assays to aid in the engineering of synthetic H2 metabolism. Our results also indicate a H2-independent redox activity in three different FeFe-hydrogenases, with implications for the future directed evolution of H2-activating catalysts.

  3. A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases.

    Science.gov (United States)

    Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A

    2016-07-01

    A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ

  4. 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice.

    Science.gov (United States)

    Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala; Khan, Nayaab S; Katsurada, Akemi; Majid, Dewan S A; Gonzalez, Frank J; Navar, L Gabriel; Malik, Kafait U

    2017-06-01

    Cytochrome P450 1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1 -/- , ovariectomized female, and Cyp1b1 +/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1 -/- and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1 +/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice and Cyp1b1 +/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice but not in Cyp1b1 +/+ male mice. The G protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1 +/+ female mice. These data suggest that 2-methoxyestradiol reduces Ang II-induced hypertension and associated end-organ damage in intact Cyp1b1 -/- , ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice, and Cyp1b1 +/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. © 2017 American Heart Association, Inc.

  5. Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.

    Science.gov (United States)

    Gan, Zhenji; Rumsey, John; Hazen, Bethany C; Lai, Ling; Leone, Teresa C; Vega, Rick B; Xie, Hui; Conley, Kevin E; Auwerx, Johan; Smith, Steven R; Olson, Eric N; Kralli, Anastasia; Kelly, Daniel P

    2013-06-01

    The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.

  6. Genome-Wide Association Study of Metabolic Traits Reveals Novel Gene-Metabolite-Disease Links

    Science.gov (United States)

    Nicholls, Andrew W.; Salek, Reza M.; Marques-Vidal, Pedro; Morya, Edgard; Sameshima, Koichi; Montoliu, Ivan; Da Silva, Laeticia; Collino, Sebastiano; Martin, François-Pierre; Rezzi, Serge; Steinbeck, Christoph; Waterworth, Dawn M.; Waeber, Gérard; Vollenweider, Peter; Beckmann, Jacques S.; Le Coutre, Johannes; Mooser, Vincent; Bergmann, Sven; Genick, Ulrich K.; Kutalik, Zoltán

    2014-01-01

    Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on 1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10−8) and independent associations between single nucleotide polymorphisms (SNP) and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10−44) and lysine (rs8101881, P = 1.2×10−33), respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers. PMID:24586186

  7. Mitochondrial NUDIX hydrolases: A metabolic link between NAD catabolism, GTP and mitochondrial dynamics.

    Science.gov (United States)

    Long, Aaron; Klimova, Nina; Kristian, Tibor

    2017-10-01

    NAD + catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD + catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism. Mitochondrial and cytosolic NUDIX hydrolases (NUDT9α and NUDT9β) can affect mitochondrial and cellular AMP levels by hydrolyzing ADP- ribose (ADPr) and subsequently altering the levels of GTP and ATP. Poly (ADP-ribose) polymerase 1 (PARP1) is activated after DNA damage, which depletes NAD + pools and results in the PARylation of nuclear and mitochondrial proteins. In the mitochondria, ADP-ribosyl hydrolase-3 (ARH3) hydrolyzes PAR to ADPr, while NUDT9α metabolizes ADPr to AMP. Elevated AMP levels have been reported to reduce mitochondrial ATP production by inhibiting the adenine nucleotide translocase (ANT), allosterically activating AMPK by altering the cellular AMP: ATP ratio, and by depleting mitochondrial GTP pools by being phosphorylated by adenylate kinase 3 (AK3), which uses GTP as a phosphate donor. Recently, activated AMPK was reported to phosphorylate mitochondria fission factor (MFF), which increases Drp1 localization to the mitochondria and promotes mitochondrial fission. Moreover, the increased AK3 activity could deplete mitochondrial GTP pools and possibly inhibit normal activity of GTP-dependent fusion enzymes, thus altering mitochondrial dynamics. Published by Elsevier Ltd.

  8. Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health

    Science.gov (United States)

    Ha, Connie WY; Lam, Yan Y; Holmes, Andrew J

    2014-01-01

    Gut microbes comprise a high density, biologically active community that lies at the interface of an animal with its nutritional environment. Consequently their activity profoundly influences many aspects of the physiology and metabolism of the host animal. A range of microbial structural components and metabolites directly interact with host intestinal cells and tissues to influence nutrient uptake and epithelial health. Endocrine, neuronal and lymphoid cells in the gut also integrate signals from these microbial factors to influence systemic responses. Dysregulation of these host-microbe interactions is now recognised as a major risk factor in the development of metabolic dysfunction. This is a two-way process and understanding the factors that tip host-microbiome homeostasis over to dysbiosis requires greater appreciation of the host feedbacks that contribute to regulation of microbial community composition. To date, numerous studies have employed taxonomic profiling approaches to explore the links between microbial composition and host outcomes (especially obesity and its comorbidities), but inconsistent host-microbe associations have been reported. Available data indicates multiple factors have contributed to discrepancies between studies. These include the high level of functional redundancy in host-microbiome interactions combined with individual variation in microbiome composition; differences in study design, diet composition and host system between studies; and inherent limitations to the resolution of rRNA-based community profiling. Accounting for these factors allows for recognition of the common microbial and host factors driving community composition and development of dysbiosis on high fat diets. New therapeutic intervention options are now emerging. PMID:25469018

  9. Cytochrome P450 1B1 and 2C9 genotypes and risk of ischemic vascular disease, cancer, and chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Kaur-Knudsen, Diljit; Bojesen, Stig E; Nordestgaard, Børge G

    2012-01-01

    The aim of this review is to summarize present knowledge of genetic variation in cytochrome P450 1B1 (CYP1B1) and 2C9 (CYP2C9) genes and risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease. The CYP1B1 and CYP2C9 enzymes metabolize pol...

  10. Epigenetic control and the circadian clock: linking metabolism to neuronal responses.

    Science.gov (United States)

    Orozco-Solis, R; Sassone-Corsi, P

    2014-04-04

    Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape. Published by Elsevier Ltd.

  11. Protein O-linked ß-N-acetylglucosamine: A novel effector of cardiomyocyte metabolism and function

    Science.gov (United States)

    Darley-Usmar, Victor M.; Ball, Lauren E.; Chatham, John C.

    2014-01-01

    The post-translational modification of serine and threonine residues of nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide ß-N-acetyl-glucosamine (O-GlcNAc) is emerging as an important mechanism for the regulation of numerous biological processes critical for normal cell function. Active synthesis of O-GlcNAc is essential for cell viability and acute activation of pathways resulting in increased protein O-GlcNAc levels improves the tolerance of cells to a wide range of stress stimuli. Conversely sustained increases in O-GlcNAc levels have been implicated in numerous chronic disease states, especially as a pathogenic contributor to diabetic complications. There has been increasing interest in the role of O-GlcNAc in the heart and vascular system and acute activation of O-GlcNAc levels have been shown to reduce ischemia/reperfusion injury attenuate vascular injury responses as well mediate some of the detrimental effects of diabetes and hypertension on cardiac and vascular function. Here we provide an overview of our current understanding of pathways regulating protein O-GlcNAcylation, summarize the different methodologies for identifying and characterizing O-GlcNAcylated proteins and subsequently focus on two emerging areas: 1) the role of O-GlcNAc as a potential regulator of cardiac metabolism and 2) the cross talk between O-GlcNAc and reactive oxygen species. PMID:21878340

  12. Reciprocal links between metabolic and ionic events in islet cells. Their relevance to the rhythmics of insulin release.

    Science.gov (United States)

    Malaisse, W J

    1998-02-01

    The notion of reciprocal links between metabolic and ionic events in islet cells and the rhythmics of insulin release is based on (i) the rhythmic pattern of hormonal release from isolated perfused rat pancreas, which supports the concept of an intrapancreatic pacemaker; (ii) the assumption that this phasic pattern is due to the integration of secretory activity in distinct functional units, e.g. distinct islets; and (iii) the fact that reciprocal coupling between metabolic and ionic events is operative in the secretory sequence.

  13. Docosahexaenoic Acid Levels in Blood and Metabolic Syndrome in Obese Children: Is There a Link?

    Science.gov (United States)

    Lassandro, Carlotta; Banderali, Giuseppe; Radaelli, Giovanni; Borghi, Elisa; Moretti, Francesca; Verduci, Elvira

    2015-08-21

    Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF) criteria has been suggested in children. Docosahexaenoic acid (DHA) has been associated with beneficial effects on health. The evidence about the relationship of DHA status in blood and components of the metabolic syndrome is unclear. This review discusses the possible association between DHA content in plasma and erythrocytes and components of the metabolic syndrome included in the IDF criteria (obesity, alteration of glucose metabolism, blood lipid profile, and blood pressure) and non-alcoholic fatty liver disease in obese children. The current evidence is inconsistent and no definitive conclusion can be drawn in the pediatric population. Well-designed longitudinal and powered trials need to clarify the possible association between blood DHA status and metabolic syndrome.

  14. Docosahexaenoic Acid Levels in Blood and Metabolic Syndrome in Obese Children: Is There a Link?

    Directory of Open Access Journals (Sweden)

    Carlotta Lassandro

    2015-08-01

    Full Text Available Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF criteria has been suggested in children. Docosahexaenoic acid (DHA has been associated with beneficial effects on health. The evidence about the relationship of DHA status in blood and components of the metabolic syndrome is unclear. This review discusses the possible association between DHA content in plasma and erythrocytes and components of the metabolic syndrome included in the IDF criteria (obesity, alteration of glucose metabolism, blood lipid profile, and blood pressure and non-alcoholic fatty liver disease in obese children. The current evidence is inconsistent and no definitive conclusion can be drawn in the pediatric population. Well-designed longitudinal and powered trials need to clarify the possible association between blood DHA status and metabolic syndrome.

  15. Docosahexaenoic acid levels in blood and metabolic syndrome in obese children: is there a link?

    OpenAIRE

    Lassandro, C.; Banderali, G.; Radaelli, G.; Borghi, E.; Moretti, F.; Verduci, E.

    2015-01-01

    Prevalence of metabolic syndrome is increasing in the pediatric population. Considering the different existing criteria to define metabolic syndrome, the use of the International Diabetes Federation (IDF) criteria has been suggested in children. Docosahexaenoic acid (DHA) has been associated with beneficial effects on health. The evidence about the relationship of DHA status in blood and components of the metabolic syndrome is unclear. This review discusses the possible association between DH...

  16. Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p

    DEFF Research Database (Denmark)

    Moxley, Joel F.; Jewett, Michael Christopher; Antoniewicz, Maciek R.

    2009-01-01

    . However, the potential of systems biology approaches is limited by difficulties in integrating metabolic measurements across the functional levels of the cell despite their being most closely linked to cellular phenotype. To address this limitation, we developed a model-based approach to correlate m......RNA and metabolic flux data that combines information from both interaction network models and flux determination models. We started by quantifying 5,764 mRNAs, 54 metabolites, and 83 experimental C-13-based reaction fluxes in continuous cultures of yeast under stress in the absence or presence of global regulator...... of metabolic flux (i.e., use of different reaction pathways) by transcriptional regulation and metabolite interaction density (i.e., level of pairwise metabolite-protein interactions) as a key biosynthetic control determinant. Furthermore, this model predicted flux rewiring in studies of follow...

  17. Drosophila as a Model to Study the Link between Metabolism and Cancer

    DEFF Research Database (Denmark)

    Herranz, Hector; Cohen, Stephen M.

    2017-01-01

    new approaches to therapy. Drosophila melanogaster is emerging as a valuable model to study multiple aspects of tumor formation and malignant transformation. In this review, we discuss the use of Drosophila as model to study how changes in cellular metabolism, as well as metabolic disease, contribute...

  18. Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

    DEFF Research Database (Denmark)

    Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.

    2015-01-01

    Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...

  19. Analysis and metabolic engineering of lipid-linked oligosaccharides in glycosylation-deficient CHO cells

    International Nuclear Information System (INIS)

    Jones, Meredith B.; Tomiya, Noboru; Betenbaugh, Michael J.; Krag, Sharon S.

    2010-01-01

    Glycosylation-deficient Chinese Hamster Ovary (CHO) cell lines can be used to expand our understanding of N-glycosylation pathways and to study Congenital Disorders of Glycosylation, diseases caused by defects in the synthesis of N-glycans. The mammalian N-glycosylation pathway involves the step-wise assembly of sugars onto a dolichol phosphate (P-Dol) carrier, forming a lipid-linked oligosaccharide (LLO), followed by the transfer of the completed oligosaccharide onto the protein of interest. In order to better understand how deficiencies in this pathway affect the availability of the completed LLO donor for use in N-glycosylation, we used a non-radioactive, HPLC-based assay to examine the intermediates in the LLO synthesis pathway for CHO-K1 cells and for three different glycosylation-deficient CHO cell lines. B4-2-1 cells, which have a mutation in the dolichol phosphate-mannose synthase (DPM2) gene, accumulated LLO with the structure Man 5 GlcNAc 2 -P-P-Dol, while MI8-5 cells, which lack glucosyltransferase I (ALG6) activity, accumulated Man 9 GlcNAc 2 -P-P-Dol. CHO-K1 and MI5-4 cells both produced primarily the complete LLO, Glc 3 Man 9 GlcNAc 2 -P-P-Dol, though the relative quantity was lower in MI5-4. MI5-4 cells have reduced hexokinase activity which could affect the availability of many of the substrates required for LLO synthesis and, consequently, impair production of the final LLO donor. Increasing hexokinase activity by overexpressing hexokinase II in MI5-4 caused a decrease in the relative quantities of the incomplete LLO intermediates from Man 5 GlcNAc 2 -PP-Dol through Glc 1 Man 9 GlcNAc 2 -PP-Dol, and an increase in the relative quantity of the final LLO donor, Glc 3 Man 9 GlcNAc 2 -P-P-Dol. This study suggests that metabolic engineering may be a useful strategy for improving LLO availability for use in N-glycosylation.

  20. Analysis and metabolic engineering of lipid-linked oligosaccharides in glycosylation-deficient CHO cells

    Energy Technology Data Exchange (ETDEWEB)

    Jones, Meredith B., E-mail: mbauman7@jhu.edu [Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Maryland Hall 221, Baltimore, MD 21218 (United States); Tomiya, Noboru, E-mail: ntomiya1@jhu.edu [Department of Biology, Johns Hopkins University, 3400 North Charles Street, Mudd Hall 104A, Baltimore, MD 21218 (United States); Betenbaugh, Michael J., E-mail: beten@jhu.edu [Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Maryland Hall 221, Baltimore, MD 21218 (United States); Krag, Sharon S., E-mail: skrag@jhsph.edu [Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205 (United States)

    2010-04-23

    Glycosylation-deficient Chinese Hamster Ovary (CHO) cell lines can be used to expand our understanding of N-glycosylation pathways and to study Congenital Disorders of Glycosylation, diseases caused by defects in the synthesis of N-glycans. The mammalian N-glycosylation pathway involves the step-wise assembly of sugars onto a dolichol phosphate (P-Dol) carrier, forming a lipid-linked oligosaccharide (LLO), followed by the transfer of the completed oligosaccharide onto the protein of interest. In order to better understand how deficiencies in this pathway affect the availability of the completed LLO donor for use in N-glycosylation, we used a non-radioactive, HPLC-based assay to examine the intermediates in the LLO synthesis pathway for CHO-K1 cells and for three different glycosylation-deficient CHO cell lines. B4-2-1 cells, which have a mutation in the dolichol phosphate-mannose synthase (DPM2) gene, accumulated LLO with the structure Man{sub 5}GlcNAc{sub 2}-P-P-Dol, while MI8-5 cells, which lack glucosyltransferase I (ALG6) activity, accumulated Man{sub 9}GlcNAc{sub 2}-P-P-Dol. CHO-K1 and MI5-4 cells both produced primarily the complete LLO, Glc{sub 3}Man{sub 9}GlcNAc{sub 2}-P-P-Dol, though the relative quantity was lower in MI5-4. MI5-4 cells have reduced hexokinase activity which could affect the availability of many of the substrates required for LLO synthesis and, consequently, impair production of the final LLO donor. Increasing hexokinase activity by overexpressing hexokinase II in MI5-4 caused a decrease in the relative quantities of the incomplete LLO intermediates from Man{sub 5}GlcNAc{sub 2}-PP-Dol through Glc{sub 1}Man{sub 9}GlcNAc{sub 2}-PP-Dol, and an increase in the relative quantity of the final LLO donor, Glc{sub 3}Man{sub 9}GlcNAc{sub 2}-P-P-Dol. This study suggests that metabolic engineering may be a useful strategy for improving LLO availability for use in N-glycosylation.

  1. 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...

  2. The vagus nerve and the inflammatory reflex—linking immunity and metabolism

    Science.gov (United States)

    Pavlov, Valentin A.; Tracey, Kevin J.

    2014-01-01

    The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders. PMID:23169440

  3. Endocrine and metabolic mechanisms linking postpartum glucose with early embryonic and foetal development in dairy cows.

    Science.gov (United States)

    Lucy, M C; Butler, S T; Garverick, H A

    2014-05-01

    Milk and milk solids production per cow is increasing annually in dairy systems. Peak milk production is in early lactation when the uterus and ovary are recovering from the previous pregnancy. The competing processes of milk production and restoration of reproductive function can be at odds, particularly if unique homeorhetic mechanisms that typify early lactation become imbalanced and cows experience metabolic disease. Homeorhesis leads to an increase in the synthesis of glucose that is irreversibly lost to milk lactose. Irreversible loss of glucose during lactation can invoke an endocrine and metabolic state that impinges upon postpartum uterine health, oestrous cyclicity and subsequent establishment of pregnancy. The first 30 days postpartum may be most critical in terms of the impact that metabolites and metabolic hormones have on reproduction. Depressed immune function caused in part by the postpartum metabolic profile leads to a failure in uterine involution and uterine disease. Oestrous cyclicity (interval to first ovulation and subsequent periodicity) is affected by the same hormones and metabolites that control postpartum immune function. Slower growth of the embryo or foetus perhaps explained by the unique metabolic profile during lactation may predispose cows to pregnancy loss. Understanding homeorhetic mechanisms that involve glucose and collectively affect postpartum uterine health, oestrous cyclicity and the establishment of pregnancy should lead to methods to improve postpartum fertility in dairy cows.

  4. Molecular Paths Linking Metabolic Diseases, Gut Microbiota Dysbiosis and Enterobacteria Infections.

    Science.gov (United States)

    Serino, Matteo

    2018-03-02

    Alterations of both ecology and functions of gut microbiota are conspicuous traits of several inflammatory pathologies, notably metabolic diseases such as obesity and type 2 diabetes. Moreover, the proliferation of enterobacteria, subdominant members of the intestinal microbial ecosystem, has been shown to be favored by Western diet, the strongest inducer of both metabolic diseases and gut microbiota dysbiosis. The inner interdependence between the host and the gut microbiota is based on a plethora of molecular mechanisms by which host and intestinal microbes modify each other. Among these mechanisms are as follows: (i) the well-known metabolic impact of short chain fatty acids, produced by microbial fermentation of complex carbohydrates from plants; (ii) a mutual modulation of miRNAs expression, both on the eukaryotic (host) and prokaryotic (gut microbes) side; (iii) the production by enterobacteria of virulence factors such as the genotoxin colibactin, shown to alter the integrity of host genome and induce a senescence-like phenotype in vitro; (iv) the microbial excretion of outer-membrane vesicles, which, in addition to other functions, may act as a carrier for multiple molecules such as toxins to be delivered to target cells. In this review, I describe the major molecular mechanisms by which gut microbes exert their metabolic impact at a multi-organ level (the gut barrier being in the front line) and support the emerging triad of metabolic diseases, gut microbiota dysbiosis and enterobacteria infections. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders.

    Science.gov (United States)

    Meng, Qingying; Ying, Zhe; Noble, Emily; Zhao, Yuqi; Agrawal, Rahul; Mikhail, Andrew; Zhuang, Yumei; Tyagi, Ethika; Zhang, Qing; Lee, Jae-Hyung; Morselli, Marco; Orozco, Luz; Guo, Weilong; Kilts, Tina M; Zhu, Jun; Zhang, Bin; Pellegrini, Matteo; Xiao, Xinshu; Young, Marian F; Gomez-Pinilla, Fernando; Yang, Xia

    2016-05-01

    Nutrition plays a significant role in the increasing prevalence of metabolic and brain disorders. Here we employ systems nutrigenomics to scrutinize the genomic bases of nutrient-host interaction underlying disease predisposition or therapeutic potential. We conducted transcriptome and epigenome sequencing of hypothalamus (metabolic control) and hippocampus (cognitive processing) from a rodent model of fructose consumption, and identified significant reprogramming of DNA methylation, transcript abundance, alternative splicing, and gene networks governing cell metabolism, cell communication, inflammation, and neuronal signaling. These signals converged with genetic causal risks of metabolic, neurological, and psychiatric disorders revealed in humans. Gene network modeling uncovered the extracellular matrix genes Bgn and Fmod as main orchestrators of the effects of fructose, as validated using two knockout mouse models. We further demonstrate that an omega-3 fatty acid, DHA, reverses the genomic and network perturbations elicited by fructose, providing molecular support for nutritional interventions to counteract diet-induced metabolic and brain disorders. Our integrative approach complementing rodent and human studies supports the applicability of nutrigenomics principles to predict disease susceptibility and to guide personalized medicine. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation.

    Science.gov (United States)

    Lozoya, Oswaldo A; Martinez-Reyes, Inmaculada; Wang, Tianyuan; Grenet, Dagoberto; Bushel, Pierre; Li, Jianying; Chandel, Navdeep; Woychik, Richard P; Santos, Janine H

    2018-04-18

    Mitochondrial function affects many aspects of cellular physiology, and, most recently, its role in epigenetics has been reported. Mechanistically, how mitochondrial function alters DNA methylation patterns in the nucleus remains ill defined. Using a cell culture model of induced mitochondrial DNA (mtDNA) depletion, in this study we show that progressive mitochondrial dysfunction leads to an early transcriptional and metabolic program centered on the metabolism of various amino acids, including those involved in the methionine cycle. We find that this program also increases DNA methylation, which occurs primarily in the genes that are differentially expressed. Maintenance of mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation in the context of mtDNA loss rescues methionine salvage and polyamine synthesis and prevents changes in DNA methylation and gene expression but does not affect serine/folate metabolism or transsulfuration. This work provides a novel mechanistic link between mitochondrial function and epigenetic regulation of gene expression that involves polyamine and methionine metabolism responding to changes in the tricarboxylic acid (TCA) cycle. Given the implications of these findings, future studies across different physiological contexts and in vivo are warranted.

  7. Linking carbon and nitrogen metabolism to depth distribution of submersed macrophytes using high ammonium dosing tests and a lake survey.

    Science.gov (United States)

    Yuan, Guixiang; Cao, Te; Fu, Hui; Ni, Leyi; Zhang, Xiaolin; Li, Wei; Song, Xin; Xie, Ping; Jeppesen, Erik

    2013-12-01

    Strategies of carbon (C) and nitrogen (N) utilisation are among the factors determining plant distribution. It has been argued that submersed macrophytes adapted to lower light environments are more efficient in maintaining C metabolic homeostasis due to their conservative C strategy and ability to balance C shortage. We studied how depth distributions of 12 submersed macrophytes in Lake Erhai, China, were linked to their C-N metabolic strategies when facing acute [Formula: see text] dosing.[Formula: see text] dosing changed C-N metabolism significantly by decreasing the soluble carbohydrate (SC) content and increasing the [Formula: see text]-N and free amino acid (FAA) content of plant tissues.The proportional changes in SC contents in the leaves and FAA contents in the stems induced by [Formula: see text] dosing were closely correlated (positive for SC and negative for FAA) with the colonising water depths of the plants in Lake Erhai, the plants adapted to lower light regimes being more efficient in maintaining SC and FAA homeostasis.These results indicate that conservative carbohydrate metabolism of submersed macrophytes allowed the plants to colonise greater water depths in eutrophic lakes, where low light availability in the water column diminishes carbohydrate production by the plants.

  8. Metabolic Features of Protochlamydia amoebophila Elementary Bodies – A Link between Activity and Infectivity in Chlamydiae

    Science.gov (United States)

    Watzka, Margarete; Wultsch, Anna; Tziotis, Dimitrios; Montanaro, Jacqueline; Richter, Andreas; Schmitt-Kopplin, Philippe; Horn, Matthias

    2013-01-01

    The Chlamydiae are a highly successful group of obligate intracellular bacteria, whose members are remarkably diverse, ranging from major pathogens of humans and animals to symbionts of ubiquitous protozoa. While their infective developmental stage, the elementary body (EB), has long been accepted to be completely metabolically inert, it has recently been shown to sustain some activities, including uptake of amino acids and protein biosynthesis. In the current study, we performed an in-depth characterization of the metabolic capabilities of EBs of the amoeba symbiont Protochlamydia amoebophila. A combined metabolomics approach, including fluorescence microscopy-based assays, isotope-ratio mass spectrometry (IRMS), ion cyclotron resonance Fourier transform mass spectrometry (ICR/FT-MS), and ultra-performance liquid chromatography mass spectrometry (UPLC-MS) was conducted, with a particular focus on the central carbon metabolism. In addition, the effect of nutrient deprivation on chlamydial infectivity was analyzed. Our investigations revealed that host-free P. amoebophila EBs maintain respiratory activity and metabolize D-glucose, including substrate uptake as well as host-free synthesis of labeled metabolites and release of labeled CO2 from 13C-labeled D-glucose. The pentose phosphate pathway was identified as major route of D-glucose catabolism and host-independent activity of the tricarboxylic acid (TCA) cycle was observed. Our data strongly suggest anabolic reactions in P. amoebophila EBs and demonstrate that under the applied conditions D-glucose availability is essential to sustain metabolic activity. Replacement of this substrate by L-glucose, a non-metabolizable sugar, led to a rapid decline in the number of infectious particles. Likewise, infectivity of Chlamydia trachomatis, a major human pathogen, also declined more rapidly in the absence of nutrients. Collectively, these findings demonstrate that D-glucose is utilized by P. amoebophila EBs and provide

  9. Metabolic features of Protochlamydia amoebophila elementary bodies--a link between activity and infectivity in Chlamydiae.

    Directory of Open Access Journals (Sweden)

    Barbara S Sixt

    Full Text Available The Chlamydiae are a highly successful group of obligate intracellular bacteria, whose members are remarkably diverse, ranging from major pathogens of humans and animals to symbionts of ubiquitous protozoa. While their infective developmental stage, the elementary body (EB, has long been accepted to be completely metabolically inert, it has recently been shown to sustain some activities, including uptake of amino acids and protein biosynthesis. In the current study, we performed an in-depth characterization of the metabolic capabilities of EBs of the amoeba symbiont Protochlamydia amoebophila. A combined metabolomics approach, including fluorescence microscopy-based assays, isotope-ratio mass spectrometry (IRMS, ion cyclotron resonance Fourier transform mass spectrometry (ICR/FT-MS, and ultra-performance liquid chromatography mass spectrometry (UPLC-MS was conducted, with a particular focus on the central carbon metabolism. In addition, the effect of nutrient deprivation on chlamydial infectivity was analyzed. Our investigations revealed that host-free P. amoebophila EBs maintain respiratory activity and metabolize D-glucose, including substrate uptake as well as host-free synthesis of labeled metabolites and release of labeled CO2 from (13C-labeled D-glucose. The pentose phosphate pathway was identified as major route of D-glucose catabolism and host-independent activity of the tricarboxylic acid (TCA cycle was observed. Our data strongly suggest anabolic reactions in P. amoebophila EBs and demonstrate that under the applied conditions D-glucose availability is essential to sustain metabolic activity. Replacement of this substrate by L-glucose, a non-metabolizable sugar, led to a rapid decline in the number of infectious particles. Likewise, infectivity of Chlamydia trachomatis, a major human pathogen, also declined more rapidly in the absence of nutrients. Collectively, these findings demonstrate that D-glucose is utilized by P. amoebophila

  10. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation

    DEFF Research Database (Denmark)

    Aamand, Rasmus; Dalsgaard, Thomas; Jensen, Frank Bo

    2009-01-01

    In catalyzing the reversible hydration of CO2 to bicarbonate and protons, the ubiquitous enzyme carbonic anhydrase (CA) plays a crucial role in CO2 transport, in acid-base balance, and in linking local acidosis to O2 unloading from hemoglobin. Considering the structural similarity between...... bicarbonate and nitrite, we hypothesized that CA uses nitrite as a substrate to produce the potent vasodilator nitric oxide (NO) to increase local blood flow to metabolically active tissues. Here we show that CA readily reacts with nitrite to generate NO, particularly at low pH, and that the NO produced...

  11. A transcription factor links growth rate and metabolism in the hypersaline adapted archaeon Halobacterium salinarum.

    Science.gov (United States)

    Todor, Horia; Dulmage, Keely; Gillum, Nicholas; Bain, James R; Muehlbauer, Michael J; Schmid, Amy K

    2014-09-01

    Co-ordinating metabolism and growth is a key challenge for all organisms. Despite fluctuating environments, cells must produce the same metabolic outputs to thrive. The mechanisms underlying this 'growth homeostasis' are known in bacteria and eukaryotes, but remain unexplored in archaea. In the model archaeon Halobacterium salinarum, the transcription factor TrmB regulates enzyme-coding genes in diverse metabolic pathways in response to glucose. However, H. salinarum is thought not to catabolize glucose. To resolve this discrepancy, we demonstrate that TrmB regulates the gluconeogenic production of sugars incorporated into the cell surface S-layer glycoprotein. Additionally, we show that TrmB-DNA binding correlates with instantaneous growth rate, likely because S-layer glycosylation is proportional to growth. This suggests that TrmB transduces a growth rate signal to co-regulated metabolic pathways including amino acid, purine, and cobalamin biosynthesis. Remarkably, the topology and function of this growth homeostatic network appear conserved across domains despite extensive alterations in protein components. © 2014 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.

  12. Biochemical trade-offs: evidence for ecologically linked secondary metabolism of the sponge Oscarella balibaloi.

    Directory of Open Access Journals (Sweden)

    Julijana Ivanisevic

    Full Text Available Secondary metabolite production is assumed to be costly and therefore the resource allocation to their production should be optimized with respect to primary biological functions such as growth or reproduction. Sponges are known to produce a great diversity of secondary metabolites with powerful biological activities that may explain their domination in some hard substrate communities both in terms of diversity and biomass. Oscarella balibaloi (Homoscleromorpha is a recently described, highly dynamic species, which often overgrows other sessile marine invertebrates. Bioactivity measurements (standardized Microtox assay and metabolic fingerprints were used as indicators of the baseline variations of the O. balibaloi secondary metabolism, and related to the sponge reproductive effort over two years. The bioactivity showed a significant seasonal variation with the lowest values at the end of spring and in early summer followed by the highest bioactivity in the late summer and autumn. An effect of the seawater temperature was detected, with a significantly higher bioactivity in warm conditions. There was also a tendency of a higher bioactivity when O. balibaloi was found overgrowing other sponge species. Metabolic fingerprints revealed the existence of three principal metabolic phenotypes: phenotype 1 exhibited by a majority of low bioactive, female individuals, whereas phenotypes 2 and 3 correspond to a majority of highly bioactive, non-reproductive individuals. The bioactivity was negatively correlated to the reproductive effort, minimal bioactivities coinciding with the period of embryogenesis and larval development. Our results fit the Optimal Defense Theory with an investment in the reproduction mainly shaping the secondary metabolism variability, and a less pronounced influence of other biotic (species interaction and abiotic (temperature factors.

  13. Microbial pathways in colonic sulfur metabolism and links with health and disease

    Directory of Open Access Journals (Sweden)

    Franck eCarbonero

    2012-11-01

    Full Text Available Sulfur is both crucial to life and a potential threat to health. While colonic sulfur metabolism mediated by eukaryotic cells is relatively well studied, much less is known about sulfur metabolism within gastrointestinal microbes. Sulfated compounds in the colon are either of inorganic (e.g., sulfates, sulfites or organic (e.g., dietary amino acids and host mucins origin. The most extensively studied of the microbes involved in colonic sulfur metabolism are the sulfate-reducing bacteria, which are common colonic inhabitants. Many other microbial pathways are likely to shape colonic sulfur metabolism as well as the composition and availability of sulfated compounds, and these interactions need to be examined in more detail. Hydrogen sulfide is the sulfur derivative that has attracted the most attention in the context of colonic health, and the extent to which it is detrimental or beneficial remains in debate. Several lines of evidence point to sulfate-reducing bacteria or exogenous hydrogen sulfide as potential players in the etiology of intestinal disorders, inflammatory bowel diseases and colorectal cancer in particular. Generation of hydrogen sulfide via pathways other than dissimilatory sulfate reduction may be as, or more, important than those involving the sulfate-reducing bacteria. We suggest here that a novel axis of research is to assess the effects of hydrogen sulfide in shaping colonic microbiome structure. Clearly, in-depth characterization of the microbial pathways involved in colonic sulfur metabolism is necessary for a better understanding of its contribution to colonic disorders and development of therapeutic strategies.

  14. Biochemical trade-offs: evidence for ecologically linked secondary metabolism of the sponge Oscarella balibaloi.

    Science.gov (United States)

    Ivanisevic, Julijana; Thomas, Olivier P; Pedel, Laura; Pénez, Nicolas; Ereskovsky, Alexander V; Culioli, Gérald; Pérez, Thierry

    2011-01-01

    Secondary metabolite production is assumed to be costly and therefore the resource allocation to their production should be optimized with respect to primary biological functions such as growth or reproduction. Sponges are known to produce a great diversity of secondary metabolites with powerful biological activities that may explain their domination in some hard substrate communities both in terms of diversity and biomass. Oscarella balibaloi (Homoscleromorpha) is a recently described, highly dynamic species, which often overgrows other sessile marine invertebrates. Bioactivity measurements (standardized Microtox assay) and metabolic fingerprints were used as indicators of the baseline variations of the O. balibaloi secondary metabolism, and related to the sponge reproductive effort over two years. The bioactivity showed a significant seasonal variation with the lowest values at the end of spring and in early summer followed by the highest bioactivity in the late summer and autumn. An effect of the seawater temperature was detected, with a significantly higher bioactivity in warm conditions. There was also a tendency of a higher bioactivity when O. balibaloi was found overgrowing other sponge species. Metabolic fingerprints revealed the existence of three principal metabolic phenotypes: phenotype 1 exhibited by a majority of low bioactive, female individuals, whereas phenotypes 2 and 3 correspond to a majority of highly bioactive, non-reproductive individuals. The bioactivity was negatively correlated to the reproductive effort, minimal bioactivities coinciding with the period of embryogenesis and larval development. Our results fit the Optimal Defense Theory with an investment in the reproduction mainly shaping the secondary metabolism variability, and a less pronounced influence of other biotic (species interaction) and abiotic (temperature) factors.

  15. The phosphorylation-dependent regulation of nuclear SREBP1 during mitosis links lipid metabolism and cell growth

    Science.gov (United States)

    Bengoechea-Alonso, Maria Teresa; Ericsson, Johan

    2016-01-01

    ABSTRACT The SREBP transcription factors are major regulators of lipid metabolism. Disturbances in lipid metabolism are at the core of several health issues facing modern society, including cardiovascular disease, obesity and diabetes. In addition, the role of lipid metabolism in cancer cell growth is receiving increased attention. Transcriptionally active SREBP molecules are unstable and rapidly degraded in a phosphorylation-dependent manner by Fbw7, a ubiquitin ligase that targets several cell cycle regulatory proteins for degradation. We have previously demonstrated that active SREBP1 is stabilized during mitosis. We have now delineated the mechanisms involved in the stabilization of SREBP1 in mitotic cells. This process is initiated by the phosphorylation of a specific serine residue in nuclear SREBP1 by the mitotic kinase Cdk1. The phosphorylation of this residue creates a docking site for a separate mitotic kinase, Plk1. Plk1 interacts with nuclear SREBP1 in mitotic cells and phosphorylates a number of residues in the C-terminal domain of the protein, including a threonine residue in close proximity of the Fbw7 docking site in SREBP1. The phosphorylation of these residues by Plk1 blocks the interaction between SREBP1 and Fbw7 and attenuates the Fbw7-dependent degradation of nuclear SREBP1 during cell division. Inactivation of SREBP1 results in a mitotic defect, suggesting that SREBP1 could regulate cell division. We propose that the mitotic phosphorylation and stabilization of nuclear SREBP1 during cell division provides a link between lipid metabolism and cell proliferation. Thus, the current study provides additional support for the emerging hypothesis that SREBP-dependent lipid metabolism may be important for cell growth. PMID:27579997

  16. Metabolism

    Science.gov (United States)

    ... Are More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood Test: Basic Metabolic Panel (BMP) Activity: Endocrine System Growth Disorders Diabetes Center Thyroid Disorders Your Endocrine System Movie: Endocrine ...

  17. Cocoa procyanidins modulate transcriptional pathways linked to inflammation and metabolism in human dendritic cells

    DEFF Research Database (Denmark)

    Midttun, Helene L E; Ramsay, Aina; Mueller-Harvey, Irene

    2018-01-01

    the mechanistic basis of this inhibition, here we conducted transcriptomic analysis on DCs cultured with either LPS or LPS combined with oligomeric cocoa PC. Procyanidins suppressed a number of genes encoding cytokines and chemokines such as CXCL1, but also genes involved in the cGMP pathway such as GUCY1A3...... (encoding guanylate cyclase soluble subunit alpha-3). Upregulated genes were involved in diverse metabolic pathways, but notably two of the four most upregulated genes (NMB, encoding neuromedin B and ADCY3, encoding adenyl cyclase type 3) were involved in the cAMP signalling pathway. Gene-set enrichment...... analysis demonstrated that upregulated gene pathways were primarily involved in nutrient transport, carbohydrate metabolism and lysosome function, whereas down-regulated gene pathways involved cell cycle, signal transduction and gene transcription, as well as immune function. qPCR analysis verified...

  18. Differential proteomic analysis reveals novel links between primary metabolism and antibiotic production in Amycolatopsis balhimycina

    DEFF Research Database (Denmark)

    Gallo, G.; Renzone, G.; Alduina, R.

    2010-01-01

    A differential proteomic analysis, based on 2-DE and MS procedures, was performed on Amycolatopsis balhimycina DSM5908, the actinomycete producing the vancomycin-like antibiotic balhimycin. A comparison of proteomic profiles before and during balhimycin production characterized differentially...... available over the World Wide Web as interactive web pages (http://www.unipa.it/ampuglia/Abal-proteome-maps). Functional clustering analysis revealed that differentially expressed proteins belong to functional groups involved in central carbon metabolism, amino acid metabolism and protein biosynthesis...... intermediates, were upregulated during antibiotic production. qRT-PCR analysis revealed that 8 out of 14 upregulated genes showed a positive correlation between changes at translational and transcriptional expression level. Furthermore, proteomic analysis of two nonproducing mutants, restricted to a sub...

  19. Role of leptin as a link between metabolism and the immune system.

    Science.gov (United States)

    Pérez-Pérez, Antonio; Vilariño-García, Teresa; Fernández-Riejos, Patricia; Martín-González, Jenifer; Segura-Egea, Juan José; Sánchez-Margalet, Víctor

    2017-06-01

    Leptin is an adipocyte-derived hormone not only with an important role in the central control of energy metabolism, but also with many pleiotropic effects in different physiological systems. One of these peripheral functions of leptin is a regulatory role in the interplay between energy metabolism and the immune system, being a cornerstone of the new field of immunometabolism. Leptin receptor is expressed throughout the immune system and the regulatory effects of leptin include cells from both the innate and adaptive immune system. Leptin is one of the adipokines responsible for the inflammatory state found in obesity that predisposes not only to type 2 diabetes, metabolic syndrome and cardiovascular disease, but also to autoimmune and allergic diseases. Leptin is an important mediator of the immunosuppressive state in undernutrition status. Placenta is the second source of leptin and it may play a role in the immunomodulation during pregnancy. Finally, recent work has pointed to the participation of leptin and leptin receptor in the pathophysiology of inflammation in oral biology. Therefore, leptin and leptin receptor should be considered for investigation as a marker of inflammation and immune activation in the frontier of innate-adaptive system, and as possible targets for intervention in the immunometabolic mediated pathophysiology. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Mitochondrial Carriers Link the Catabolism of Hydroxyaromatic Compounds to the Central Metabolism in Candida parapsilosis

    Directory of Open Access Journals (Sweden)

    Igor Zeman

    2016-12-01

    Full Text Available The pathogenic yeast Candida parapsilosis metabolizes hydroxyderivatives of benzene and benzoic acid to compounds channeled into central metabolism, including the mitochondrially localized tricarboxylic acid cycle, via the 3-oxoadipate and gentisate pathways. The orchestration of both catabolic pathways with mitochondrial metabolism as well as their evolutionary origin is not fully understood. Our results show that the enzymes involved in these two pathways operate in the cytoplasm with the exception of the mitochondrially targeted 3-oxoadipate CoA-transferase (Osc1p and 3-oxoadipyl-CoA thiolase (Oct1p catalyzing the last two reactions of the 3-oxoadipate pathway. The cellular localization of the enzymes indicates that degradation of hydroxyaromatic compounds requires a shuttling of intermediates, cofactors, and products of the corresponding biochemical reactions between cytosol and mitochondria. Indeed, we found that yeast cells assimilating hydroxybenzoates increase the expression of genes SFC1, LEU5, YHM2, and MPC1 coding for succinate/fumarate carrier, coenzyme A carrier, oxoglutarate/citrate carrier, and the subunit of pyruvate carrier, respectively. A phylogenetic analysis uncovered distinct evolutionary trajectories for sparsely distributed gene clusters coding for enzymes of both pathways. Whereas the 3-oxoadipate pathway appears to have evolved by vertical descent combined with multiple losses, the gentisate pathway shows a striking pattern suggestive of horizontal gene transfer to the evolutionarily distant Mucorales.

  1. The Cardiomyocyte RNA-Binding Proteome: Links to Intermediary Metabolism and Heart Disease

    Directory of Open Access Journals (Sweden)

    Yalin Liao

    2016-08-01

    Full Text Available RNA functions through the dynamic formation of complexes with RNA-binding proteins (RBPs in all clades of life. We determined the RBP repertoire of beating cardiomyocytic HL-1 cells by jointly employing two in vivo proteomic methods, mRNA interactome capture and RBDmap. Together, these yielded 1,148 RBPs, 391 of which are shared with all other available mammalian RBP repertoires, while 393 are thus far unique to cardiomyocytes. RBDmap further identified 568 regions of RNA contact within 368 RBPs. The cardiomyocyte mRNA interactome composition reflects their unique biology. Proteins with roles in cardiovascular physiology or disease, mitochondrial function, and intermediary metabolism are all highly represented. Notably, we identified 73 metabolic enzymes as RBPs. RNA-enzyme contacts frequently involve Rossmann fold domains with examples in evidence of both, mutual exclusivity of, or compatibility between RNA binding and enzymatic function. Our findings raise the prospect of previously hidden RNA-mediated regulatory interactions among cardiomyocyte gene expression, physiology, and metabolism.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Influence of Hypothyroidism on Separate Links of Metabolism, Structure and Function of the Heart in Insulin Resistance

    Directory of Open Access Journals (Sweden)

    T.Yu. Yuzvenko

    2014-05-01

    Full Text Available The article presents research findings of reduced thyroid function impact on the background of insulin resistance on the specific links of metabolism, structure and function of the heart. It is found that in thyroid dysfunction, the main nosological form of myocardial lesion in female patients without concomitant cardiovascular disease is the development of metabolic endocrine cardiomyopathy. Feature of cardiac lesion is the absence of cardiosclerotic, myocardial and ischemic processes in hypothyroidism. Obscure clinical symptoms of the heart both in apparent and subclinical hypothyroidism are detected. Features of clinical, instrumental and laboratory changes in female patients with impaired thyroid function are a trend to systolic blood pressure increase, the absence of significant dyslipidemia, dysglycemia, and cardiocytolysis and hepatocytolysis. Thyroid hormone deficiency is associated with increased myocardial repolarization heterogeneity: subclinical hypothyroidism is accompanied by violation of repolarization processes and the development of electrical heterogeneity of ventricular myocardium, and in the apparent hypothyroidism changes are more linked with the violation of the homogeneity of the electrical impulse to the atria.

  4. The Glycerate and Phosphorylated Pathways of Serine Synthesis in Plants: The Branches of Plant Glycolysis Linking Carbon and Nitrogen Metabolism.

    Science.gov (United States)

    Igamberdiev, Abir U; Kleczkowski, Leszek A

    2018-01-01

    Serine metabolism in plants has been studied mostly in relation to photorespiration where serine is formed from two molecules of glycine. However, two other pathways of serine formation operate in plants and represent the branches of glycolysis diverging at the level of 3-phosphoglyceric acid. One branch (the glycerate - serine pathway) is initiated in the cytosol and involves glycerate formation from 3-phosphoglycerate, while the other (the phosphorylated serine pathway) operates in plastids and forms phosphohydroxypyruvate as an intermediate. Serine formed in these pathways becomes a precursor of glycine, formate and glycolate accumulating in stress conditions. The pathways can be linked to GABA shunt via transamination reactions and via participation of the same reductase for both glyoxylate and succinic semialdehyde. In this review paper we present a hypothesis of the regulation of redox balance in stressed plant cells via participation of the reactions associated with glycerate and phosphorylated serine pathways. We consider these pathways as important processes linking carbon and nitrogen metabolism and maintaining cellular redox and energy levels in stress conditions.

  5. Correlative link ages between indices of bone metabolism and thyroid hormones in rats with periodontitis

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    Vitaliy Shcherba

    2017-12-01

    Full Text Available Introduction: It has been established that changes in the bone tissue of the jaw are present in all cases where there are at least small pathological inflammatory changes in the mucous membrane of the oral cavity. This suggests a significantly greater pathogenetic relationship between inflammatory changes in the mucosa and changes in the bone part of the periodontal disease. Despite a large number of studies, the molecular mechanisms of the influence of thyroid hormones on the bone metabolism have not been completely studied.  The aim of study: to clarify mechanisms of the periodontitis development in rats with thyroid dysfunction based on a comparative analysis of the correlations between the bone metabolism indices and the concentration of  thyroid stimulating hormone,  free thyroxine and free triiodothyronine. Material and methods: Experimental studies were conducted on male, nonliner, white rats of around 4 months of age.  The experimental animals were divided into the following groups: І – control animals;  ІІ – animals with periodontitis; ІІІ – animals with periodontitis combined with hyperthyroidism; IV – animals with periodontitis combined with hypothyroidism. Total calcium, ionized calcium, phosphorus, osteocalcin concentration and  activity of phosphatases were measured. Correlation analysis was performed between all the studied indices. Coefficient of linear correlation (r and its fidelity (p was calculated that was accordingly denoted in the tables (correlation matrices. The correlation coefficient was significant at p<0.05. Results: The conducted correlative analysis shows that there are different interconnections between the indices of calcium-phosphorus metabolism, bone formation and bone resorption with free triiodothyronine, free thyroxine and thyroid stimulating hormone, in case of the experimental periodontitis combined with thyroid dysfunction. In animals with modelled periodontitis combined with

  6. A Green Algae Mixture of Scenedesmus and Schroederiella Attenuates Obesity-Linked Metabolic Syndrome in Rats

    Science.gov (United States)

    Kumar, Senthil Arun; Magnusson, Marie; Ward, Leigh C.; Paul, Nicholas A.; Brown, Lindsay

    2015-01-01

    This study investigated the responses to a green algae mixture of Scenedesmus dimorphus and Schroederiella apiculata (SC) containing protein (46.1% of dry algae), insoluble fibre (19.6% of dry algae), minerals (3.7% of dry algae) and omega-3 fatty acids (2.8% of dry algae) as a dietary intervention in a high carbohydrate, high fat diet-induced metabolic syndrome model in four groups of male Wistar rats. Two groups were fed with a corn starch diet containing 68% carbohydrates as polysaccharides, while the other two groups were fed a diet high in simple carbohydrates (fructose and sucrose in food, 25% fructose in drinking water, total 68%) and fats (saturated and trans fats from beef tallow, total 24%). High carbohydrate, high fat-fed rats showed visceral obesity with hypertension, insulin resistance, cardiovascular remodelling, and nonalcoholic fatty liver disease. SC supplementation (5% of food) lowered total body and abdominal fat mass, increased lean mass, and attenuated hypertension, impaired glucose and insulin tolerance, endothelial dysfunction, infiltration of inflammatory cells into heart and liver, fibrosis, increased cardiac stiffness, and nonalcoholic fatty liver disease in the high carbohydrate, high fat diet-fed rats. This study suggests that the insoluble fibre or protein in SC helps reverse diet-induced metabolic syndrome. PMID:25875119

  7. SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Jorge L. Gutierrez-Pajares

    2016-10-01

    Full Text Available Studies have demonstrated the significant role of cholesterol and lipoprotein metabolism in the progression of cancer. The SCARB1 gene encodes the scavenger receptor class B type I (SR-BI, which is an 82-kDa glycoprotein with two transmembrane domains separated by a large extracellular loop. SR-BI plays an important role in the regulation of cholesterol exchange between cells and high-density lipoproteins. Accordingly, hepatic SR-BI has been shown to play an essential role in the regulation of the reverse cholesterol transport pathway, which promotes the removal and excretion of excess body cholesterol. In the context of atherosclerosis, SR-BI has been implicated in the regulation of intracellular signaling, lipid accumulation, foam cell formation, and cellular apoptosis. Furthermore, since lipid metabolism is a relevant target for cancer treatment, recent studies have focused on examining the role of SR-BI in this pathology. While signaling pathways have initially been explored in non-tumoral cells, studies with cancer cells have now demonstrated SR-BI’s function in tumor progression. In this review, we will discuss the role of SR-BI during tumor development and malignant progression. In addition, we will provide insights into the transcriptional and post-transcriptional regulation of the SCARB1 gene. Overall, studying the role of SR-BI in tumor development and progression should allow us to gain useful information for the development of new therapeutic strategies.

  8. Special K: testing the potassium link between radioactive rubidium (86Rb) turnover and metabolic rate.

    Science.gov (United States)

    Tomlinson, Sean; Mathialagan, Priya D; Maloney, Shane K

    2014-04-01

    The measurement of (86)Rb turnover recently has been suggested as a useful method for measuring field metabolic rate in small animals. We investigated a proposed mechanism of (86)Rb turnover, its analogy to K(+), by comparing the turnover of (86)Rb in a model insect, the rhinoceros beetle Xylotrupes gideon, fed a diet of plum jam or plum jam enriched with K(+) or Rb(+). The turnover of (86)Rb in the beetles on the K(+) and the Rb(+) diets was higher than that for beetles on the jam diet (F2,311=32.4; P=1.58×10(-13)). We also exposed the beetles to different ambient temperatures to induce differences in metabolic rate ( ) while feeding them the jam and K(+) diets. was higher at higher ambient temperature (Ta) for both jam (F1,11=14.56; P=0.003) and K(+) (F1,8=15.39; P=0.004) dietary groups, and the turnover of (86)Rb was higher at higher Ta for both jam (F1,11=10.80; P=0.007) and K(+) (F1,8=12.34; P=0.008) dietary groups. There was a significant relationship between (86)Rb turnover and for both the jam (F1,11=35.00; P=1.0×10(-3)) and the K(+) (F1,8=64.33; P=4.3×10(-5)) diets, but the relationship differed between the diets (F1,19=14.07; P=0.001), with a higher (86)Rb turnover in beetles on the K(+)-enriched than on the jam diet at all Ta. We conclude that (86)Rb turnover is related to K(+) metabolism, and that this is the mechanism of the relationship between (86)Rb turnover and . Studies relating (86)Rb turnover to should maintain dietary [K] as close as possible to that of natural diets for the most accurate calibrations for free-ranging animals.

  9. P-Ser-HPr-a link between carbon metabolism and the virulence of some pathogenic bacteria

    DEFF Research Database (Denmark)

    Mijakovic, Ivan

    2005-01-01

    HPr kinase/phosphorylase phosphorylates HPr, a phosphocarrier protein of the phosphoenolpyruvate:carbohydrate phosphotransferase system, at serine-46. P-Ser-HPr is the central regulator of carbon metabolism in Gram-positive bacteria, but also plays a role in virulence development of certain...... pathogens. In Listeria monocytogenes, several virulence genes, which depend on the transcription activator PrfA, are repressed by glucose, fructose, etc., in a catabolite repressor (CcpA)-independent mechanism. However, the catabolite co-repressor P-Ser-HPr was found to inhibit the activity of Prf...... is preceded by an operator site, which serves as target for the CcpA/P-Ser-HPr complex. Numerous Gram-negative pathogens also contain hprK, which is often organised in an operon with transcription regulators necessary for the development of virulence, indicating that in these organisms P-Ser-HPr also plays...

  10. Linking levels of societal and ecosystems metabolism of water in a Mediterranean watershed

    Science.gov (United States)

    Cabello, V.

    2014-12-01

    Water resources degradation is a complex environmental problem that involves multiple dimensions and scales of analysis. The Socio-Ecological Systems Water Metabolism has been proposed as a general holistic framework to deal with integrated analysis of water use sustainability (Madrid and Giampietro 2014). The innovation of the approach is that it sets the research focus beyond the classical supply-demand modeling to societal integrity and ecosystems integrity. To do so, it integrates quantitative grammars of water use (relating water exchange to societal and ecosystems organization) and qualitative methods (discourse analysis). This work presents the first case study focused at a river basin extent: the Upper Andarax, in South-East Spain. Water metabolism is indicated at multiple levels for ecosystems and society. To deal with the interfaces among them, relational indicators of water exploitation, water use and impact over ecosystems are used alongside policies and narratives analysis.While being a rather not intensively exploited river basin (year Water Exploitation Index~0.3 blue water,~0.15 green water), impacts over water bodies are yet important (periodic aquifer overdraft, biological degradation of the river) especially during dry season. Perceived mayor problems of water sustainability are generated by the not integration of different policies at European, national and regional scales: while the water authority establishes a compulsory reduction over water withdrawal to attend environmental flows, agricultural markets force to raise productivity increasing water demands. Adaptation strategies are divided among irrigation efficiency improvement and a reorientation of the economy towards touristic activities. Both of them entail specific trade-offs to be deemed. Aquifer-river interactions and climate change impacts are yet mayor research challenges.

  11. Topographical body fat distribution links to amino acid and lipid metabolism in healthy obese women [corrected].

    Directory of Open Access Journals (Sweden)

    Francois-Pierre J Martin

    Full Text Available Visceral adiposity is increasingly recognized as a key condition for the development of obesity related disorders, with the ratio between visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT reported as the best correlate of cardiometabolic risk. In this study, using a cohort of 40 obese females (age: 25-45 y, BMI: 28-40 kg/m(2 under healthy clinical conditions and monitored over a 2 weeks period we examined the relationships between different body composition parameters, estimates of visceral adiposity and blood/urine metabolic profiles. Metabonomics and lipidomics analysis of blood plasma and urine were employed in combination with in vivo quantitation of body composition and abdominal fat distribution using iDXA and computerized tomography. Of the various visceral fat estimates, VAT/SAT and VAT/total abdominal fat ratios exhibited significant associations with regio-specific body lean and fat composition. The integration of these visceral fat estimates with metabolic profiles of blood and urine described a distinct amino acid, diacyl and ether phospholipid phenotype in women with higher visceral fat. Metabolites important in predicting visceral fat adiposity as assessed by Random forest analysis highlighted 7 most robust markers, including tyrosine, glutamine, PC-O 44∶6, PC-O 44∶4, PC-O 42∶4, PC-O 40∶4, and PC-O 40∶3 lipid species. Unexpectedly, the visceral fat associated inflammatory profiles were shown to be highly influenced by inter-days and between-subject variations. Nevertheless, the visceral fat associated amino acid and lipid signature is proposed to be further validated for future patient stratification and cardiometabolic health diagnostics.

  12. Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?

    Science.gov (United States)

    Gertsch, Jürg

    2017-06-01

    The endocannabinoid system (ECS) is a major lipid signalling network that plays important pro-homeostatic (allostatic) roles not only in the nervous system but also in peripheral organs. There is increasing evidence that there is a dietary component in the modulation of the ECS. Cannabinoid receptors in hominids co-evolved with diet, and the ECS constitutes a feedback loop for food selection and energy metabolism. Here, it is postulated that the mismatch of ancient lipid genes of hunter-gatherers and pastoralists with the high-carbohydrate diet introduced by agriculture could be compensated for via dietary modulation of the ECS. In addition to the fatty acid precursors of endocannabinoids, the potential role of dietary cannabimimetic phytochemicals in agriculturist nutrition is discussed. Dietary secondary metabolites from vegetables and spices able to enhance the activity of cannabinoid-type 2 (CB 2 ) receptors may provide adaptive metabolic advantages and counteract inflammation. In contrast, chronic CB 1 receptor activation in hedonic obese individuals may enhance pathophysiological processes related to hyperlipidaemia, diabetes, hepatorenal inflammation and cardiometabolic risk. Food able to modulate the CB 1 /CB 2 receptor activation ratio may thus play a role in the nutrition transition of Western high-calorie diets. In this review, the interplay between diet and the ECS is highlighted from an evolutionary perspective. The emerging potential of cannabimimetic food as a nutraceutical strategy is critically discussed. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

  13. Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways.

    Directory of Open Access Journals (Sweden)

    Adam M Wentzell

    2007-09-01

    Full Text Available Phenotypic variation between individuals of a species is often under quantitative genetic control. Genomic analysis of gene expression polymorphisms between individuals is rapidly gaining popularity as a way to query the underlying mechanistic causes of variation between individuals. However, there is little direct evidence of a linkage between global gene expression polymorphisms and phenotypic consequences. In this report, we have mapped quantitative trait loci (QTLs-controlling glucosinolate content in a population of 403 Arabidopsis Bay x Sha recombinant inbred lines, 211 of which were previously used to identify expression QTLs controlling the transcript levels of biosynthetic genes. In a comparative study, we have directly tested two plant biosynthetic pathways for association between polymorphisms controlling biosynthetic gene transcripts and the resulting metabolites within the Arabidopsis Bay x Sha recombinant inbred line population. In this analysis, all loci controlling expression variation also affected the accumulation of the resulting metabolites. In addition, epistasis was detected more frequently for metabolic traits compared to transcript traits, even when both traits showed similar distributions. An analysis of candidate genes for QTL-controlling networks of transcripts and metabolites suggested that the controlling factors are a mix of enzymes and regulatory factors. This analysis showed that regulatory connections can feedback from metabolism to transcripts. Surprisingly, the most likely major regulator of both transcript level for nearly the entire pathway and aliphatic glucosinolate accumulation is variation in the last enzyme in the biosynthetic pathway, AOP2. This suggests that natural variation in transcripts may significantly impact phenotypic variation, but that natural variation in metabolites or their enzymatic loci can feed back to affect the transcripts.

  14. A clinical perspective of the link between metabolic syndrome and hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Cauchy F

    2015-02-01

    Full Text Available François Cauchy, Jacques BelghitiHPB and Liver Transplantation Unit, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, FranceAbstract: Metabolic syndrome (MS, which is defined as a constellation of clinico-biological features closely related to insulin-resistance has reached epidemic levels in Western Europe and Northern America. Non-alcoholic fatty liver disease (NAFLD represents the hepatic manifestation of MS. As its incidence parallels that of MS, NAFLD is currently becoming one of the most frequent chronic liver diseases in Western countries. On one hand, MS favors the development of hepatocellular carcinoma (HCC either through NAFLD liver parenchymal alterations (steatosis; steatohepatitis; fibrosis, or in the absence of significant underlying liver parenchyma changes. In this setting, HCC are often diagnosed incidentally, tend to be larger than in patients developing HCC on cirrhosis and therefore frequently require major liver resections. On the other hand, MS patients are at increased risk of both liver-related postoperative complications and increased cardiorespiratory events leading to non-negligible mortality rates following liver surgery. These deleterious effects seem to be related to the existence of impaired liver function even in the absence of severe fibrosis but also higher cardiorespiratory sensitivity in a setting of MS/NAFLD. Hence, specific medical and surgical improvements in the perioperative management of these patients are required. These include complete preoperative cardiorespiratory work-up and the wide use of preoperative liver volume modulation. Finally, the long-term prognosis after curative surgery for MS-related HCC does not seem to be worse than for other HCC occurring on classical chronic liver diseases. This is probably related to less aggressive tumor behavior with lower micro vascular invasion and decreased rates of poorly differentiated lesions. In this setting, several medical therapies

  15. Metabolism

    Science.gov (United States)

    ... lin), which signals cells to increase their anabolic activities. Metabolism is a complicated chemical process, so it's not ... how those enzymes or hormones work. When the metabolism of body chemicals is ... Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism ...

  16. IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity.

    Science.gov (United States)

    Chaves Filho, Adriano José Maia; Lima, Camila Nayane Carvalho; Vasconcelos, Silvânia Maria Mendes; de Lucena, David Freitas; Maes, Michael; Macedo, Danielle

    2018-01-03

    Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-γ, TNFα and IL-1β, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Possible Link between Metabolic Syndrome and Chronic Kidney Disease in the Development of Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Kosaku Nitta

    2011-01-01

    Full Text Available Metabolic syndrome (MetS is a clinical syndrome that consists of visceral obesity, dyslipidemia, hypertension, and impaired insulin sensitivity. Although individual components of MetS have been implicated in the development of chronic kidney disease (CKD, few studies have examined the effect of combinations of the components of MetS on the development of CKD and cardiovascular disease (CVD. The prevalence of MetS is increasing worldwide in both developing and developed countries, and early detection and treatment of MetS would be a cost-effective strategy for preventing the development of CKD. Visceral obesity and insulin resistance are two important features of MetS that may be associated with renal damage. Lifestyle modifications, including caloric restriction and exercise, are necessary to treat MetS. Initial antihypertensive therapy should consist of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. An improved understanding of the mechanism responsible for the association between MetS and renal damage should be helpful in determining the treatment regimens directed at cardiovascular and renal protection.

  18. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

    Science.gov (United States)

    Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O.; Sovio, Ulla; Taal, H. Rob; Hennig, Branwen J.; Bradfield, Jonathan P.; St. Pourcain, Beate; Evans, David M.; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L.; Lehtimäki, Terho; Kreiner-Møller, Eskil; Warrington, Nicole M.; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J.; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J.; Shields, Beverley M.; Kerkhof, Marjan; van Leeuwen, Elisabeth M.; Fulford, Anthony J.; Kutalik, Zoltán; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T.; Harder, Marie N.; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M.; Jameson, Karen A.; Zhou, Kaixin; Monies, Dorota M.; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S.; Alkuraya, Fowzan S.; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J.; Blakemore, Alexandra I.F.; Buxton, Jessica L.; Dallongeville, Jean; Das, Shikta; de Geus, Eco J. C.; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M.; Gottrand, Frédéric; Groves, Christopher J.; Hansen, Torben; Hirschhorn, Joel N.; Hofman, Albert; Hollegaard, Mads V.; Hougaard, David M.; Hyppönen, Elina; Inskip, Hazel M.; Isaacs, Aaron; Jørgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P.; Kiess, Wieland; Kilpeläinen, Tuomas O.; Klopp, Norman; Knight, Bridget A.; Kuzawa, Christopher W.; McMahon, George; Newnham, John P.; Niinikoski, Harri; Oostra, Ben A.; Pedersen, Louise; Postma, Dirkje S.; Ring, Susan M.; Rivadeneira, Fernando; Robertson, Neil R.; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M.T.; Tönjes, Anke; Vaag, Allan; Viikari, Jorma S.; Vink, Jacqueline M.; Vissing, Nadja Hawwa; Wareham, Nicholas J.; Willemsen, Gonneke; Witte, Daniel R.; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Stumvoll, Michael; Prentice, Andrew M.; Meyer, Brian F.; Pearson, Ewan R.; Boreham, Colin A.G.; Cooper, Cyrus; Gillman, Matthew W.; Dedoussis, George V.; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L.; Boomsma, Dorret I.; Saw, Seang-Mei; Lakka, Timo A.; Körner, Antje; Loos, Ruth J.F.; Ong, Ken K.; Vollenweider, Peter; van Duijn, Cornelia M.; Koppelman, Gerard H.; Hattersley, Andrew T.; Holloway, John W.; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mònica; Pennell, Craig E.; Bønnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G.; Widén, Elisabeth; Hakonarson, Hakon; Uitterlinden, André G.; Pouta, Anneli; Lawlor, Debbie A.; Smith, George Davey; Frayling, Timothy M.; McCarthy, Mark I.; Grant, Struan F.A.; Jaddoe, Vincent W.V.; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Prokopenko, Inga; Freathy, Rachel M.

    2012-01-01

    Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. PMID:23202124

  19. A close link between metabolic activity and functional connectivity in the resting human brain

    Energy Technology Data Exchange (ETDEWEB)

    Passow, Susanne [Department of Biological and Medical Psychology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Specht, Karsten [Department of Biological and Medical Psychology, University of Bergen (Norway); Department of Clinical Engineering, Haukeland University Hospital, Bergen (Norway); Adamsen, Tom Christian [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Chemistry, University of Bergen (Norway); Biermann, Martin; Brekke, Njål [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen (Norway); Craven, Alexander Richard [Department of Biological and Medical Psychology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Ersland, Lars [Department of Clinical Engineering, Haukeland University Hospital, Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Grüner, Renate [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Physics and Technology, University of Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway); Kleven-Madsen, Nina [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Physics and Technology, University of Bergen (Norway); Kvernenes, Ole-Heine [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Schwarzlmüller, Thomas [Department of Radiology, Haukeland University Hospital, Bergen (Norway); Department of Clinical Medicine, University of Bergen (Norway); Olesen, Rasmus [Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University, Aarhus (Denmark); Hugdahl, Kenneth [Department of Biological and Medical Psychology, University of Bergen (Norway); Department of Radiology, Haukeland University Hospital, Bergen (Norway); Division of Psychiatry, Haukeland University Hospital, Bergen (Norway); NORMENT Center of Excellence, University of Oslo (Norway)

    2015-05-18

    Default-mode network (DMN) functional connectivity and its task-dependent down-regulation have attracted a lot of attention in the field of neuroscience. Nevertheless, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood oxygen level-dependent (BOLD) signal, are still not completely understood. To investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest, the present study combined for the first time 2-Deoxy-2-[18F]fluoroglucose positron emission tomography (FDG-PET), proton magnetic resonance spectroscopy (1H-MRS), and resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based correlation analyses, using a key region of the DMN i.e. the dorsal posterior cingulate cortex as seed, revealed overall striking spatial similarities between fluctuations in FDG-uptake and the BOLD signal. More specifically, a conjunction analysis across both modalities showed that DMN areas as the inferior parietal lobe, angular gyrus, precuneus, middle and medial frontal gyrus were positively correlated with the dorsal posterior cingulate cortex. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, posterior cingulate cortex and left angular gyrus was associated with functional connectivity within the DMN. We did not find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results provide further evidence for a close association between local metabolic activity and functional connectivity and enable further insights towards a better understanding of the underlying mechanisms of the BOLD signal.

  20. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.

    Directory of Open Access Journals (Sweden)

    Sri Devi Narasimhan

    2011-04-01

    Full Text Available The insulin/IGF-1 signaling (IIS pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase, AGE-1 (PI 3-kinase, and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.

  1. A close link between metabolic activity and functional connectivity in the resting human brain

    International Nuclear Information System (INIS)

    Passow, Susanne; Specht, Karsten; Adamsen, Tom Christian; Biermann, Martin; Brekke, Njål; Craven, Alexander Richard; Ersland, Lars; Grüner, Renate; Kleven-Madsen, Nina; Kvernenes, Ole-Heine; Schwarzlmüller, Thomas; Olesen, Rasmus; Hugdahl, Kenneth

    2015-01-01

    Default-mode network (DMN) functional connectivity and its task-dependent down-regulation have attracted a lot of attention in the field of neuroscience. Nevertheless, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood oxygen level-dependent (BOLD) signal, are still not completely understood. To investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest, the present study combined for the first time 2-Deoxy-2-[18F]fluoroglucose positron emission tomography (FDG-PET), proton magnetic resonance spectroscopy (1H-MRS), and resting-state functional magnetic resonance imaging (rs-fMRI). Seed-based correlation analyses, using a key region of the DMN i.e. the dorsal posterior cingulate cortex as seed, revealed overall striking spatial similarities between fluctuations in FDG-uptake and the BOLD signal. More specifically, a conjunction analysis across both modalities showed that DMN areas as the inferior parietal lobe, angular gyrus, precuneus, middle and medial frontal gyrus were positively correlated with the dorsal posterior cingulate cortex. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, posterior cingulate cortex and left angular gyrus was associated with functional connectivity within the DMN. We did not find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results provide further evidence for a close association between local metabolic activity and functional connectivity and enable further insights towards a better understanding of the underlying mechanisms of the BOLD signal.

  2. Metabolic endotoxaemia--a potential novel link between ovarian inflammation and impaired progesterone production.

    Science.gov (United States)

    Tremellen, Kelton; Syedi, Naeema; Tan, Sze; Pearce, Karma

    2015-04-01

    Medical conditions such as obesity and inflammatory bowel disease are associated with impaired luteal function, menstrual disturbance and infertility. It is proposed that the disturbance in gut wall integrity ("leaky gut") seen in these conditions may result in the passage of bacterial endotoxin (LPS) from the colonic lumen into the circulation that may initiate inflammation in the ovary and subsequently impair hormone production. Quantify the association between systemic levels of LBP, a marker of endotoxin exposure, and levels of inflammation in the ovary (follicular fluid IL-6), plus steroid hormone production in 45 women undergoing IVF treatment. Endotoxaemia (LBP) were positively correlated with plasma CRP and inflammation within the ovary (follicular fluid IL-6). Furthermore, endotoxaemia was negatively correlated with progesterone production. The observed correlations, together with previously published animal studies linking endotoxin exposure to impaired luteal function, suggest that the translocation of bacterial endotoxin from the gut lumen into the circulation has the potential to interfere with progesterone production and result in luteal deficiency.

  3. Uncoupling protein homologs may provide a link between mitochondria, metabolism and lifespan.

    Science.gov (United States)

    Wolkow, Catherine A; Iser, Wendy B

    2006-05-01

    Uncoupling proteins (UCPs), which dissipate the mitochondrial proton gradient, have the ability to decouple mitochodrial respiration from ATP production. Since mitochondrial electron transport is a major source of free radical production, it is possible that UCP activity might impact free radical production. Free radicals can react with and damage cellular proteins, DNA and lipids. Accumulated damage from oxidative stress is believed to be a major contributor to cellular decline during aging. If UCP function were to impact mitochondrial free radical production, then one would expect to find a link between UCP activity and aging. This theory has recently been tested in a handful of organisms whose genomes contain UCP1 homologs. Interestingly, these experiments indicate that UCP homologs can affect lifespan, although they do not support a simple relationship between UCP activity and aging. Instead, UCP-like proteins appear to have a variety of effects on lifespan, and on pathways implicated in lifespan regulation. One possible explanation for this complex picture is that UCP homologs may have tissue-specific effects that complicate their effects on aging. Furthermore, the functional analysis of UCP1 homologs is incomplete. Thus, these proteins may perform functions in addition to, or instead of, mitochondrial uncoupling. Although these studies have not revealed a clear picture of UCP effects on aging, they have contributed to the growing knowledge base for these interesting proteins. Future biochemical and genetic investigation of UCP-like proteins will do much to clarify their functions and to identify the regulatory networks in which they are involved.

  4. Patterns of ecosystem metabolism in the Tonle Sap Lake, Cambodia with links to capture fisheries.

    Directory of Open Access Journals (Sweden)

    Gordon W Holtgrieve

    Full Text Available The Tonle Sap Lake in Cambodia is a dynamic flood-pulsed ecosystem that annually increases its surface area from roughly 2,500 km(2 to over 12,500 km(2 driven by seasonal flooding from the Mekong River. This flooding is thought to structure many of the critical ecological processes, including aquatic primary and secondary productivity. The lake also has a large fishery that supports the livelihoods of nearly 2 million people. We used a state-space oxygen mass balance model and continuous dissolved oxygen measurements from four locations to provide the first estimates of gross primary productivity (GPP and ecosystem respiration (ER for the Tonle Sap. GPP averaged 4.1±2.3 g O2 m(-3 d(-1 with minimal differences among sites. There was a negative correlation between monthly GPP and lake level (r = 0.45 and positive correlation with turbidity (r = 0.65. ER averaged 24.9±20.0 g O2 m(-3 d(-1 but had greater than six-fold variation among sites and minimal seasonal change. Repeated hypoxia was observed at most sampling sites along with persistent net heterotrophy (GPPmetabolism of organic matter that is likely incorporated into the larger food web. Using our measurements of GPP, we calibrated a hydrodynamic-productivity model and predicted aquatic net primary production (aNPP of 2.0±0.2 g C m(-2 d(-1 (2.4±0.2 million tonnes C y(-1. Considering a range of plausible values for the total fisheries catch, we estimate that fisheries harvest is an equivalent of 7-69% of total aNPP, which is substantially larger than global average for marine and freshwater systems. This is likely due to relatively efficient carbon transfer through the food web and support of fish production from terrestrial NPP. These analyses are an important first-step in quantifying the resource pathways that support this important ecosystem.

  5. Cognitive impairment and Alzheimer’s disease: Links with oxidative stress and cholesterol metabolism

    Directory of Open Access Journals (Sweden)

    Alejandra Sekler

    2008-08-01

    Full Text Available Alejandra Sekler1,2, José M Jiménez2, Leonel Rojo2, Edgard Pastene3, Patricio Fuentes4, Andrea Slachevsky4, Ricardo B Maccioni1,21Center of Cognitive Neurosciences, International Center for Biomedicine (ICC, Santiago, Chile; 2Laboratory of Cellular, Molecular Biology and Neurosciences, Faculty of Sciences, Universidad de Chile, Santiago, Chile; 3Department of Pharmacy, Faculty of Pharmacy, University of Concepcion, Concepción, Chile; 4Unidad de Neurología Cognitiva y Demencias, Servicio de Neurología, Hospital del Salvador, Santiago, ChileAbstract: Oxidative stress has been implicated in the progression of a number of neurodegenerative diseases, including Alzheimer’s disease (AD, Parkinson’s disease and amyotrophic lateral sclerosis. We carried out an in-depth study of cognitive impairment and its relationships with oxidative stress markers such as ferric-reducing ability of plasma (FRAP, plasma malondialdehyde and total antioxidative capacity (TAC, as well as cholesterol parameters, in two subsets of subjects, AD patients (n = 59 and a control group of neurologically normal subjects (n = 29, attending the University Hospital Salvador in Santiago, Chile. Cognitive impairment was assessed by a set of neuropsychological tests (Mini-Mental State Examination, Boston Naming Test, Ideomotor Praxia by imitation, Semantic Verbal Fluency of animals or words with initial A, Test of Memory Alteration, Frontal Assessment Battery, while the levels of those oxidative stress markers and cholesterol metabolism parameters were determined according with standard bioassays in fresh plasma samples of the two subgroups of patients. No significant differences were observed when the cholesterol parameters (low-, high-density lipoprotein, total cholesterol of the AD group were compared with normal controls. Interestingly, a correlation was evidenced when the levels of cognitive impairment were analyzed with respect to the plasma antioxidant capacity (AOC of

  6. Structural and metabolic studies of O-linked fucose-containing proteins of normal and virally-transformed rat fibroblasts

    International Nuclear Information System (INIS)

    Morton, P.A.

    1985-01-01

    Previous studies in this laboratory have demonstrated that cultured human and rodent cells contain a series of low molecular weight glycosylated amino acids of unusual structure, designated amino acid fucosides. The incorporation of radiolabelled-fucose into one of these components, designated FL4a (glucosylfucosylthreonine), is markedly-reduced in transformed epithelial and fibroblastic cells. The authors have examined fucose-labelled normal and virally-transformed rat fibroblast cell lines for glycoproteins which might be precursors to amino acid fucosides. Using milk alkaline/borohydride treatment (the beta-elimination reaction) to release O-linked oligosaccharides from proteins, they have isolated and partially characterized two low M/sub r/ reaction products (designated DS-ol and TS-ol) released from macromolecular cell material. The identity of one of these components (DS-ol, glucosylfucitol) suggested the existence in these cells of a direct protein precursor to FL4a. They examined fucose-labelled macromolecular cell material for proteins which release DS-ol (DS-proteins.). Using gel filtration chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with subsequent autoradiography, they have observed DS-proteins which appear to exhibit a broad molecular weight size range, and are also present in culture medium from normal and transformed cells. The findings suggest that mammalian cells contain DS-proteins and TS-proteins with a novel carbohydrate-peptide linkage wherein L-fucose is O-linked to a polypeptide backbone. Metabolic studies were undertaken to examine both the relationship between DS-protein and FL4a and the biochemical basis for the decreased level of FL4a and the biochemical basis for the decreased level of FL4a observed in transformed cells

  7. Cellular Assays for Ferredoxins: A Strategy for Understanding Electron Flow through Protein Carriers That Link Metabolic Pathways.

    Science.gov (United States)

    Atkinson, Joshua T; Campbell, Ian; Bennett, George N; Silberg, Jonathan J

    2016-12-27

    The ferredoxin (Fd) protein family is a structurally diverse group of iron-sulfur proteins that function as electron carriers, linking biochemical pathways important for energy transduction, nutrient assimilation, and primary metabolism. While considerable biochemical information about individual Fd protein electron carriers and their reactions has been acquired, we cannot yet anticipate the proportion of electrons shuttled between different Fd-partner proteins within cells using biochemical parameters that govern electron flow, such as holo-Fd concentration, midpoint potential (driving force), molecular interactions (affinity and kinetics), conformational changes (allostery), and off-pathway electron leakage (chemical oxidation). Herein, we describe functional and structural gaps in our Fd knowledge within the context of a sequence similarity network and phylogenetic tree, and we propose a strategy for improving our understanding of Fd sequence-function relationships. We suggest comparing the functions of divergent Fds within cells whose growth, or other measurable output, requires electron transfer between defined electron donor and acceptor proteins. By comparing Fd-mediated electron transfer with biochemical parameters that govern electron flow, we posit that models that anticipate energy flow across Fd interactomes can be built. This approach is expected to transform our ability to anticipate Fd control over electron flow in cellular settings, an obstacle to the construction of synthetic electron transfer pathways and rational optimization of existing energy-conserving pathways.

  8. The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression.

    Science.gov (United States)

    Dienel, Gerald A

    2017-01-10

    Glucose, glycogen, and lactate are traditionally identified with brain energetics, ATP turnover, and pathophysiology. However, recent studies extend their roles to include involvement in astrocytic signaling, memory consolidation, and gene expression. Emerging roles for these brain fuels and a readily-diffusible by-product are linked to differential fluxes in glycolytic and oxidative pathways, astrocytic glycogen dynamics, redox shifts, neuron-astrocyte interactions, and regulation of astrocytic activities by noradrenaline released from the locus coeruleus. Disproportionate utilization of carbohydrate compared with oxygen during brain activation is influenced by catecholamines, but its physiological basis is not understood and its magnitude may be affected by technical aspects of metabolite assays. Memory consolidation and gene expression are impaired by glycogenolysis blockade, and prevention of these deficits by injection of abnormally-high concentrations of lactate was interpreted as a requirement for astrocyte-to-neuron lactate shuttling in memory and gene expression. However, lactate transport was not measured and evidence for presumed shuttling is not compelling. In fact, high levels of lactate used to preserve memory consolidation and induce gene expression are sufficient to shut down neuronal firing via the HCAR1 receptor. In contrast, low lactate levels activate a receptor in locus coeruleus that stimulates noradrenaline release that may activate astrocytes throughout brain. Physiological relevance of exogenous concentrations of lactate used to mimic and evaluate metabolic, molecular, and behavioral effects of lactate requires close correspondence with the normal lactate levels, the biochemical and cellular sources and sinks, and specificity of lactate delivery to target cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Elevated serum advanced glycation endproducts in obese indicate risk for the metabolic syndrome: a link between healthy and unhealthy obesity?

    Science.gov (United States)

    Uribarri, Jaime; Cai, Weijing; Woodward, Mark; Tripp, Elizabeth; Goldberg, Laurie; Pyzik, Renata; Yee, Kalle; Tansman, Laurie; Chen, Xue; Mani, Venkatesh; Fayad, Zahi A; Vlassara, Helen

    2015-05-01

    Although obesity can predispose to the metabolic syndrome (MS), diabetes, and cardiovascular disease, not all obese subjects develop MS, hence the need for new indicators of risk for this syndrome. Advanced glycation end products (AGEs) correlate with factors involved in the MS, including inflammation and insulin resistance (IR). Because AGEs can be derived from food and are modifiable, it is important to determine whether they are a risk factor for MS. The objective of this study was to assess the association of endogenous and exogenous AGEs with MS criteria. The following data were collected in a cross-sectional study of subjects with and without the MS: serum AGEs (sAGEs) and mononuclear cell AGEs, metabolites, pro- and antiinflammatory markers, body fat mass measures, including abdominal magnetic resonance imaging, and caloric and dietary AGE (dAGE) consumption. The study was conducted in the general community. Participants included 130 MS and 139 non-MS subjects of both sexes, older than 50 years. sAGEs ((ϵ)N-carboxymethyllysine, methylglyoxal) were markedly elevated in obese persons with more than one other MS criteria but not in obese without MS criteria. sAGEs directly correlated with markers of IR (HOMA) and inflammation (leptin, TNFα, RAGE) and inversely with innate defenses (SIRT1, AGE receptor 1 [AGER1], glyoxalase-I, adiponectin). sAGEs correlated with dAGEs but not with calories, nutrient consumption, or fat mass measures. Consumption of dAGE, but not of calories, was markedly higher in MS than in non-MS. High sAGEs, a modifiable risk factor for IR, may indicate risk for the MS, type 2 diabetes, and cardiovascular disease. High dietary AGE consumption and serum AGE levels may link healthy obesity to at-risk obesity.

  10. High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched-Chain Amino Acids and Energy Metabolism

    Directory of Open Access Journals (Sweden)

    Xi Zhang

    2018-04-01

    Full Text Available High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by 1H-NMR-based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death.

  11. Wildtype motoneurons, ALS-Linked SOD1 mutation and glutamate profoundly modify astrocyte metabolism and lactate shuttling.

    Science.gov (United States)

    Madji Hounoum, Blandine; Mavel, Sylvie; Coque, Emmanuelle; Patin, Franck; Vourc'h, Patrick; Marouillat, Sylviane; Nadal-Desbarats, Lydie; Emond, Patrick; Corcia, Philippe; Andres, Christian R; Raoul, Cédric; Blasco, Hélène

    2017-04-01

    The selective degeneration of motoneuron that typifies amyotrophic lateral sclerosis (ALS) implicates non-cell-autonomous effects of astrocytes. However, mechanisms underlying astrocyte-mediated neurotoxicity remain largely unknown. According to the determinant role of astrocyte metabolism in supporting neuronal function, we propose to explore the metabolic status of astrocytes exposed to ALS-associated conditions. We found a significant metabolic dysregulation including purine, pyrimidine, lysine, and glycerophospholipid metabolism pathways in astrocytes expressing an ALS-causing mutated superoxide dismutase-1 (SOD1) when co-cultured with motoneurons. SOD1 astrocytes exposed to glutamate revealed a significant modification of the astrocyte metabolic fingerprint. More importantly, we observed that SOD1 mutation and glutamate impact the cellular shuttling of lactate between astrocytes and motoneurons with a decreased in extra- and intra-cellular lactate levels in astrocytes. Based on the emergent strategy of metabolomics, this work provides novel insight for understanding metabolic dysfunction of astrocytes in ALS conditions and opens the perspective of therapeutics targets through focusing on these metabolic pathways. GLIA 2017 GLIA 2017;65:592-605. © 2017 Wiley Periodicals, Inc.

  12. Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen.

    Science.gov (United States)

    Czyż, Daniel M; Willett, Jonathan W; Crosson, Sean

    2017-08-01

    Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens. IMPORTANCE Brucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism

  13. Acyl-CoA synthetase activity links wild-type but not mutant a-Synuclein to brain arachidonate metabolism

    DEFF Research Database (Denmark)

    Golovko, Mikhail; Rosenberger, Thad; Færgeman, Nils J.

    2006-01-01

    Because alpha-synuclein (Snca) has a role in brain lipid metabolism, we determined the impact that the loss of alpha-synuclein had on brain arachidonic acid (20:4n-6) metabolism in vivo using Snca-/- mice. We measured [1-(14)C]20:4n-6 incorporation and turnover kinetics in brain phospholipids using......, our data demonstrate that alpha-synuclein has a major role in brain 20:4n-6 metabolism through its modulation of endoplasmic reticulum-localized acyl-CoA synthetase activity, although mutant forms of alpha-synuclein fail to restore this activity....

  14. 2500 high-quality genomes reveal that the biogeochemical cycles of C, N, S and H are cross-linked by metabolic handoffs in the terrestrial subsurface

    Science.gov (United States)

    Anantharaman, K.; Brown, C. T.; Hug, L. A.; Sharon, I.; Castelle, C. J.; Shelton, A.; Bonet, B.; Probst, A. J.; Thomas, B. C.; Singh, A.; Wilkins, M.; Williams, K. H.; Tringe, S. G.; Beller, H. R.; Brodie, E.; Hubbard, S. S.; Banfield, J. F.

    2015-12-01

    Microorganisms drive the transformations of carbon compounds in the terrestrial subsurface, a key reservoir of carbon on earth, and impact other linked biogeochemical cycles. Our current knowledge of the microbial ecology in this environment is primarily based on 16S rRNA gene sequences that paint a biased picture of microbial community composition and provide no reliable information on microbial metabolism. Consequently, little is known about the identity and metabolic roles of the uncultivated microbial majority in the subsurface. In turn, this lack of understanding of the microbial processes that impact the turnover of carbon in the subsurface has restricted the scope and ability of biogeochemical models to capture key aspects of the carbon cycle. In this study, we used a culture-independent, genome-resolved metagenomic approach to decipher the metabolic capabilities of microorganisms in an aquifer adjacent to the Colorado River, near Rifle, CO, USA. We sequenced groundwater and sediment samples collected across fifteen different geochemical regimes. Sequence assembly, binning and manual curation resulted in the recovery of 2,542 high-quality genomes, 27 of which are complete. These genomes represent 1,300 non-redundant organisms comprising both abundant and rare community members. Phylogenetic analyses involving ribosomal proteins and 16S rRNA genes revealed the presence of up to 34 new phyla that were hitherto unknown. Less than 11% of all genomes belonged to the 4 most commonly represented phyla that constitute 93% of all currently available genomes. Genome-specific analyses of metabolic potential revealed the co-occurrence of important functional traits such as carbon fixation, nitrogen fixation and use of electron donors and electron acceptors. Finally, we predict that multiple organisms are often required to complete redox pathways through a complex network of metabolic handoffs that extensively cross-link subsurface biogeochemical cycles.

  15. The metabolic regulator CodY links L. monocytogenes metabolism to virulence by directly activating the virulence regulatory gene, prfA

    Science.gov (United States)

    Lobel, Lior; Sigal, Nadejda; Borovok, Ilya; Belitsky, Boris R.; Sonenshein, Abraham L.; Herskovits, Anat A.

    2015-01-01

    Summary Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host-specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen Listeria monocytogenes responds to low availability of branched-chain amino acids (BCAA) within mammalian cells by up-regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA-responsive transcription regulator, CodY, but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L. monocytogenes master virulence activator gene, prfA, 15 nt downstream of its start codon, and that this binding results in up-regulation of prfA transcription specifically under low concentrations of BCAA. Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA, such as during growth in the presence of glucose-1-phosphate. This study highlights the tight crosstalk between L. monocytogenes metabolism and virulence' while revealing novel features of CodY-mediated regulation. PMID:25430920

  16. Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.

    Directory of Open Access Journals (Sweden)

    Melissa Rotunno

    2009-05-01

    Full Text Available Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs tested in candidate genes. We analyzed 25 SNPs (some previously untested in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS. Our findings emphasize the necessity of post

  17. 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.

  18. Comparing Enchytraeus albidus populations from contrasting climatic environments suggest a link between cold tolerance and metabolic activity.

    Science.gov (United States)

    Žagar, Anamarija; Holmstrup, Martin; Simčič, Tatjana; Debeljak, Barabara; Slotsbo, Stine

    2018-06-06

    Basal metabolic activity and freezing of body fluids create reactive oxygen species (ROS) in freeze-tolerant organisms. These sources of ROS can have an additive negative effect via oxidative stress. In cells, antioxidant systems are responsible for removing ROS in order to avoid damage due to oxidative stress. Relatively little is known about the importance of metabolic rate for the survival of freezing, despite a good understanding of several cold tolerance related physiological mechanisms. We hypothesized that low basal metabolism would be selected for in freeze-tolerant organisms where winter survival is important for fitness for two reasons. First, avoidance of the additive effect of ROS production from metabolism and freezing, and second, as an energy-saving mechanism under extended periods of freezing where the animal is metabolically active, but unable to feed. We used the terrestrial oligochaete, Enchytraeus albidus, which is widely distributed from Spain to the high Arctic and compared eight populations originating across a broad geographical and climatic gradient after they had been cold acclimated at 5 °C in a common garden experiment. Cold tolerance (lower lethal temperature: LT50) and the potential metabolic activity (PMA, an estimator of the maximal enzymatic potential of the mitochondrial respiration chain) of eight populations were positively correlated amongst each other and correlated negatively with latitude and positively with average yearly temperature and the average temperature of the coldest month. These results indicate that low PMA in cold tolerant populations is important for survival in extremely cold environments. Copyright © 2018. Published by Elsevier Inc.

  19. Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior.

    Science.gov (United States)

    Mirrione, Martine M; Schulz, Daniela; Lapidus, Kyle A B; Zhang, Samuel; Goodman, Wayne; Henn, Fritz A

    2014-01-01

    Uncontrollable stress can have a profound effect on an organism's ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive learned helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to learned helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET) and 2-deoxy-2[(18)F]fluoro-D-glucose ((18)FDG) to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.

  20. Increased metabolic activity in the septum and habenula during stress is linked to subsequent expression of learned helplessness behavior

    Directory of Open Access Journals (Sweden)

    Martine M Mirrione

    2014-02-01

    Full Text Available Uncontrollable stress can have a profound effect on an organism’s ability to respond effectively to future stressful situations. Behavior subsequent to uncontrollable stress can vary greatly between individuals, falling on a spectrum between healthy resilience and maladaptive learned helplessness. It is unclear whether dysfunctional brain activity during uncontrollable stress is associated with vulnerability to learned helplessness; therefore, we measured metabolic activity during uncontrollable stress that correlated with ensuing inability to escape future stressors. We took advantage of small animal positron emission tomography (PET and 2-deoxy-2[18F]fluoro-D-glucose (18FDG to probe in vivo metabolic activity in wild type Sprague Dawley rats during uncontrollable, inescapable, unpredictable foot-shock stress, and subsequently tested the animals response to controllable, escapable, predictable foot-shock stress. When we correlated metabolic activity during the uncontrollable stress with consequent behavioral outcomes, we found that the degree to which animals failed to escape the foot-shock correlated with increased metabolic activity in the lateral septum and habenula. When used a seed region, metabolic activity in the habenula correlated with activity in the lateral septum, hypothalamus, medial thalamus, mammillary nuclei, ventral tegmental area, central gray, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and rostromedial tegmental nucleus, caudal linear raphe, and subiculum transition area. Furthermore, the lateral septum correlated with metabolic activity in the preoptic area, medial thalamus, habenula, interpeduncular nuclei, periaqueductal gray, dorsal raphe, and caudal linear raphe. Together, our data suggest a group of brain regions involved in sensitivity to uncontrollable stress involving the lateral septum and habenula.

  1. River basins as social-ecological systems: linking levels of societal and ecosystem water metabolism in a semiarid watershed

    Directory of Open Access Journals (Sweden)

    Violeta Cabello

    2015-09-01

    Full Text Available River basin modeling under complexity requires analytical frameworks capable of dealing with the multiple scales and dimensions of environmental problems as well as uncertainty in the evolution of social systems. Conceptual and methodological developments can now be framed using the wide socio-eco-hydrological approach. We add hierarchy theory into the mix to discuss the conceptualization of river basins as complex, holarchic social-ecological systems. We operationalize the social-ecological systems water metabolism framework in a semiarid watershed in Spain, and add the governance dimension that shapes human-environment reciprocity. To this purpose, we integrate an eco-hydrological model with the societal metabolism accounting scheme for land use, human activity, and water use. We explore four types of interactions: between societal organization and water uses/demands, between ecosystem organization and their water requirements/supplies, between societal metabolism and aquatic ecosystem health, and between water demand and availability. Our results reveal a metabolic pattern of a high mountain rural system striving to face exodus and agricultural land abandonment with a multifunctional economy. Centuries of social-ecological evolution shaping waterscapes through traditional water management practices have influenced the eco-hydrological functioning of the basin, enabling adaptation to aridity. We found a marked spatial gradient on water supply, use pattern, and impact on water bodies from the head to the mouth of the basin. Management challenges posed by the European water regulatory framework as a new driver of social-ecological change are highlighted.

  2. Link between lipid metabolism and voluntary food intake in rainbow trout fed coconut oil rich in medium-chain TAG

    NARCIS (Netherlands)

    Figueiredo-Silva, A.C.; Kaushik, S.; Terrier, F.; Schrama, J.W.; Médale, F.; Geurden, I.

    2012-01-01

    We examined the long-term effect of feeding coconut oil (CO; rich in lauric acid, C12) on voluntary food intake and nutrient utilisation in rainbow trout (Oncorhynchus mykiss), with particular attention to the metabolic use (storage or oxidation) of ingested medium-chain TAG. Trout were fed for 15

  3. Sexual dimorphism and the effects of the X-linked Tfm locus on hexobarbitone metabolism and action in mice.

    Science.gov (United States)

    King, D K; Shapiro, B H

    1981-09-01

    1 Normal males of the testicular feminized strain of mice (Tfm) had longer hexobarbitone-induced sleeping times than females, and hepatic hexobarbitone hydroxylase activity different in that the Km was higher and the Vmax lower in the male. 2 Castration and androgen replacement studies indicated that testicular androgens were responsible for the sexual differences in drug metabolism found in this mouse strain. 3 Hepatic hexobarbitone metabolism and action were feminized in the intact, androgen-insensitive, genetically male Tfm mouse. Furthermore, hexobarbitone hydroxylase activities were less responsive to large doses of testosterone in Tfm mice than in normal males. 4 The Tfm mouse with a deficiency in androgen receptors responded to the enzyme-inductive effects of phenobarbitone and softwood bedding, indicating that these inducers do not act through the androgen receptors.

  4. Evolution of Energy Metabolism, Stem Cells and Cancer Stem Cells: How the Warburg and Barker Hypotheses Might Be Linked

    OpenAIRE

    Trosko, James E.; Kang, Kyung-Sun

    2012-01-01

    The evolutionary transition from single cells to the metazoan forced the appearance of adult stem cells and a hypoxic niche, when oxygenation of the environment forced the appearance of oxidative phosphorylation from that of glycolysis. The prevailing paradigm in the cancer field is that cancers start from the “immortalization” or “re-programming” of a normal, differentiated cell with many mitochondria, that metabolize via oxidative phosphorylation. This paradigm has been challenged with one ...

  5. DISP3, a sterol-sensing domain-containing protein that links thyroid hormone action and cholesterol metabolism

    Czech Academy of Sciences Publication Activity Database

    Zíková, Martina; Corlett, Alicia; Bendová, Zdeňka; Pajer, Petr; Bartůněk, Petr

    2009-01-01

    Roč. 23, č. 4 (2009), s. 520-528 ISSN 0888-8809 R&D Projects: GA AV ČR IAA500520705 Grant - others:EC(XE) LSHM-CT-2005-018652 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50110509 Keywords : thyroid hormone receptor * cholesterol metabolism * sterol-sensing domain Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.257, year: 2009

  6. Effect of two-linked mutations of the FMO3 gene on itopride metabolism in Chinese healthy volunteers.

    Science.gov (United States)

    Zhou, Li-Ping; Tan, Zhi-Rong; Chen, Hao; Guo, Dong; Chen, Yao; Huang, Wei-Hua; Wang, Lian-Sheng; Zhang, Guo-Gang

    2014-11-01

    Itopride is an effective gastroprokinetic agent mainly used for the treatment of functional dyspepsia. Flavin-containing monooxygenase 3 (FMO3) has been confirmed to be the key enzyme involved in the main itopride metabolic pathway. We investigated whether the FMO3 genotypes can affect itopride metabolism in Chinese healthy volunteers. Twelve healthy volunteers who had been genotyped for FMO3 gene were selected to participate in our study. Volunteers were given 50 mg itopride orally and then blood samples were collected from 0 to 24 h. The plasma concentrations of itopride and itopride N-oxide were determined by HPLC-MS/MS method. Itopride and itopride N-oxide both exhibit FMO3 genotype-dependent pharmacokinetic profiles. The area under the plasma concentration-time curve (AUC) of itopride increased by 127.82 ± 41.99 % (P itopride N-oxide decreased by 30.30 ± 25.70 % (P itopride and itopride N-oxide were observed between these two genotypes. The FMO3 allele can significantly affect the metabolism of itopride. The pharmacokinetic parameters of both itopride and itopride N-oxide were significantly different between these two genotypes.

  7. NatB domain-containing CRA-1 antagonizes hydrolase ACER-1 linking acetyl-CoA metabolism to the initiation of recombination during C. elegans meiosis.

    Directory of Open Access Journals (Sweden)

    Jinmin Gao

    2015-03-01

    Full Text Available The formation of DNA double-strand breaks (DSBs must take place during meiosis to ensure the formation of crossovers, which are required for accurate chromosome segregation, therefore avoiding aneuploidy. However, DSB formation must be tightly regulated to maintain genomic integrity. How this regulation operates in the context of different chromatin architectures and accessibility, and how it is linked to metabolic pathways, is not understood. We show here that global histone acetylation levels undergo changes throughout meiotic progression. Moreover, perturbations to global histone acetylation levels are accompanied by changes in the frequency of DSB formation in C. elegans. We provide evidence that the regulation of histone acetylation requires CRA-1, a NatB domain-containing protein homologous to human NAA25, which controls the levels of acetyl-Coenzyme A (acetyl-CoA by antagonizing ACER-1, a previously unknown and conserved acetyl-CoA hydrolase. CRA-1 is in turn negatively regulated by XND-1, an AT-hook containing protein. We propose that this newly defined protein network links acetyl-CoA metabolism to meiotic DSB formation via modulation of global histone acetylation.

  8. NatB domain-containing CRA-1 antagonizes hydrolase ACER-1 linking acetyl-CoA metabolism to the initiation of recombination during C. elegans meiosis.

    Science.gov (United States)

    Gao, Jinmin; Kim, Hyun-Min; Elia, Andrew E; Elledge, Stephen J; Colaiácovo, Monica P

    2015-03-01

    The formation of DNA double-strand breaks (DSBs) must take place during meiosis to ensure the formation of crossovers, which are required for accurate chromosome segregation, therefore avoiding aneuploidy. However, DSB formation must be tightly regulated to maintain genomic integrity. How this regulation operates in the context of different chromatin architectures and accessibility, and how it is linked to metabolic pathways, is not understood. We show here that global histone acetylation levels undergo changes throughout meiotic progression. Moreover, perturbations to global histone acetylation levels are accompanied by changes in the frequency of DSB formation in C. elegans. We provide evidence that the regulation of histone acetylation requires CRA-1, a NatB domain-containing protein homologous to human NAA25, which controls the levels of acetyl-Coenzyme A (acetyl-CoA) by antagonizing ACER-1, a previously unknown and conserved acetyl-CoA hydrolase. CRA-1 is in turn negatively regulated by XND-1, an AT-hook containing protein. We propose that this newly defined protein network links acetyl-CoA metabolism to meiotic DSB formation via modulation of global histone acetylation.

  9. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

    DEFF Research Database (Denmark)

    Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O

    2013-01-01

    -wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between...... diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome......Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2...

  10. [Effect of Low-Intensity 900 MHz Frequency Electromagnetic Radiation on Rat Brain Enzyme Activities Linked to Energy Metabolism].

    Science.gov (United States)

    Petrosyan, M S; Nersesova, L S; Gazaryants, M G; Meliksetyan, G O; Malakyan, M G; Bajinyan, S A; Akopian, J I

    2015-01-01

    The research deals with the effect of low-intensity 900 MHz frequency electromagnetic radiation (EMR), power density 25 μW/cm2, on the following rat brain and blood serum enzyme activities: creatine kinase (CK), playing a central role in the process of storing and distributing the cell energy, as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) that play a key role in providing the conjunction of carbohydrate and amino acid metabolism. The comparative analysis of the changes in the enzyme activity studied at different times following the two-hour single, as well as fractional, radiation equivalent of the total time showed that the most radiosensitive enzyme is the brain creatine kinase, which may then be recommended as a marker of the radio frequency radiation impact. According to the analysis of the changing dynamics of the CK, ALT and AST activity level, with time these changes acquire the adaptive character and are directed to compensate the damaged cell energy metabolism.

  11. Double silencing of relevant genes suggests the existence of the direct link between DNA replication/repair and central carbon metabolism in human fibroblasts.

    Science.gov (United States)

    Wieczorek, Aneta; Fornalewicz, Karolina; Mocarski, Łukasz; Łyżeń, Robert; Węgrzyn, Grzegorz

    2018-04-15

    Genetic evidence for a link between DNA replication and glycolysis has been demonstrated a decade ago in Bacillus subtilis, where temperature-sensitive mutations in genes coding for replication proteins could be suppressed by mutations in genes of glycolytic enzymes. Then, a strong influence of dysfunctions of particular enzymes from the central carbon metabolism (CCM) on DNA replication and repair in Escherichia coli was reported. Therefore, we asked if such a link occurs only in bacteria or it is a more general phenomenon. Here, we demonstrate that effects of silencing (provoked by siRNA) of expression of genes coding for proteins involved in DNA replication and repair (primase, DNA polymerase ι, ligase IV, and topoisomerase IIIβ) on these processes (less efficient entry into the S phase of the cell cycle and decreased level of DNA synthesis) could be suppressed by silencing of specific genes of enzymes from CMM. Silencing of other pairs of replication/repair and CMM genes resulted in enhancement of the negative effects of lower expression levels of replication/repair genes. We suggest that these results may be proposed as a genetic evidence for the link between DNA replication/repair and CMM in human cells, indicating that it is a common biological phenomenon, occurring from bacteria to humans. Copyright © 2018 Elsevier B.V. All rights reserved.

  12. Cardiovascular diseases in older patients with osteoporotic hip fracture: prevalence, disturbances in mineral and bone metabolism, and bidirectional links

    Directory of Open Access Journals (Sweden)

    Fisher A

    2013-02-01

    Full Text Available A Fisher,1,3 W Srikusalanukul,1 M Davis,1,3 P Smith2,31Departments of Geriatric Medicine, 2Orthopaedic Surgery, The Canberra Hospital, 3Australian National University Medical School, Canberra, ACT, AustraliaBackground: Considerable controversy exists regarding the contribution of mineral/bone metabolism abnormalities to the association between cardiovascular diseases (CVDs and osteoporotic fractures.Aims and methods: To determine the relationships between mineral/bone metabolism biomarkers and CVD in 746 older patients with hip fracture, clinical data were recorded and serum concentrations of parathyroid hormone (PTH, 25-hydroxyvitamin D, calcium, phosphate, magnesium, troponin I, parameters of bone turnover, and renal, liver, and thyroid functions were measured.Results: CVDs were diagnosed in 472 (63.3% patients. Vitamin D deficiency was similarly prevalent in patients with (78.0% and without (82.1% CVD. The CVD group had significantly higher mean PTH concentrations (7.6 vs 6.0 pmol/L, P < 0.001, a higher prevalence of secondary hyperparathyroidism (SPTH (PTH > 6.8 pmol/L, 43.0% vs 23.3%, P < 0.001, and excess bone resorption (urinary deoxypyridinoline corrected by creatinine [DPD/Cr] > 7.5 nmol/µmol, 87.9% vs 74.8%, P < 0.001. In multivariate regression analysis, SHPT (odds ratio [OR] 2.6, P = 0.007 and high DPD/Cr (OR 2.8, P = 0.016 were independent indictors of CVD. Compared to those with both PTH and DPD/Cr in the normal range, multivariate-adjusted ORs for the presence of CVD were 17.3 (P = 0.004 in subjects with SHPT and 9.7 (P < 0.001 in patients with high DPD/Cr. CVD was an independent predicator of SHPT (OR 2.8, P = 0.007 and excess DPD/Cr (OR 2.5, P = 0.031. CVD was predictive of postoperative myocardial injury, while SHPT was also an independent predictor of prolonged hospital stay and in-hospital death.Conclusion: SHPT and excess bone resorption are independent pathophysiological mediators underlying the bidirectional associations

  13. Partitioning the contributions of mega-, macro- and meiofauna to benthic metabolism on the upper continental slope of New Zealand: Potential links with environmental factors and trawling intensity

    Science.gov (United States)

    Leduc, Daniel; Pilditch, Conrad A.; Nodder, Scott D.

    2016-02-01

    Understanding and predicting change in deep-sea benthic ecosystem function remains a major challenge. Here, we conducted analyses combining data on the abundance and biomass of benthic fauna and sediment community oxygen consumption (SCOC) on New Zealand's continental margin to estimate and compare the contributions of meio-, macro-, and megafauna to total benthic metabolism and identify potential links with environmental factors and trawling intensity. We focussed on two regions in close proximity-the high surface primary productivity Chatham Rise and low surface productivity Challenger Plateau. Mean megafauna biomass was twenty times greater on Chatham Rise than Challenger Plateau, likely reflecting differences in food supply between the two regions; this contrast in megafaunal biomass was mainly due to differences in mean body weight rather than abundance. Meio- and macrofauna made similar contributions to SCOC and together accounted for 12% of benthic metabolism on average. In contrast, the estimated contribution of megafauna never exceeded 1.5%. Significant positive correlations between faunal respiration and food availability indicate a link between food supply and benthic community function. Our analyses also show that fauna made a greater contribution to SCOC in conditions of high food availability, and that microorganisms (i.e., the proportion of SCOC not accounted for by the fauna) tended to be more dominant at sites with low food availability. These findings provide support for the concept that large organisms are more strongly affected by a reduction in food resources than small organisms, which in turn underlies one of the most widely described patterns in the deep-sea benthos, i.e., the reduction in organism body size with depth. Because metabolism in deep-sea sediments is typically dominated by microorganisms and small fauna, the absence of a relationship between bottom trawling intensity and the respiration of benthic fauna in the present study may

  14. Sublethal Concentrations of Antibiotics Cause Shift to Anaerobic Metabolism in Listeria monocytogenes and Induce Phenotypes Linked to Antibiotic Tolerance

    DEFF Research Database (Denmark)

    Knudsen, Gitte Maegaard; Fromberg, Arvid; Ng, Yin

    2016-01-01

    The human pathogenic bacterium Listeria monocytogenes is exposed to antibiotics both during clinical treatment and in its saprophytic lifestyle. As one of the keys to successful treatment is continued antibiotic sensitivity, the purpose of this study was to determine if exposure to sublethal...... antibiotic concentrations would affect the bacterial physiology and induce antibiotic tolerance. Transcriptomic analyses demonstrated that each of the four antibiotics tested caused an antibiotic-specific gene expression pattern related to mode-of-action of the particular antibiotic. All four antibiotics...... in Imo1179 (eutE) encoding an aldehyde oxidoreductase where rerouting caused increased ethanol production was tolerant to three of four antibiotics tested. This shift in metabolism could be a survival strategy in response to antibiotics to avoid generation of ROS production from respiration by oxidation...

  15. Drug Metabolism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 3. Drug Metabolism: A Fascinating Link Between Chemistry and Biology. Nikhil Taxak Prasad V Bharatam. General Article Volume 19 Issue 3 March 2014 pp 259-282 ...

  16. Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    El Akoum Souhad

    2011-12-01

    Full Text Available Abstract Background Adverse effects of high-fat diets (HFD on metabolic homeostasis are linked to adipose tissue dysfunction. The goal of this study was to examine the effect of the HFD nature on adipose tissue activity, metabolic disturbances and glucose homeostasis alterations in male mice compared with female mice. Methods C57BL/6J mice were fed either a chow diet or HFD including vegetal (VD or animal (AD fat. Body weight, plasmatic parameters and adipose tissue mRNA expression levels of key genes were evaluated after 20 weeks of HFD feeding. Results HFD-fed mice were significantly heavier than control at the end of the protocol. Greater abdominal visceral fat accumulation was observed in mice fed with AD compared to those fed a chow diet or VD. Correlated with weight gain, leptin levels in systemic circulation were increased in HFD-fed mice in both sexes with a significant higher level in AD group compared to VD group. Circulating adiponectin levels as well as adipose tissue mRNA expression levels were significantly decreased in HFD-fed male mice. Although its plasma levels remained unchanged in females, adiponectin mRNA levels were significantly reduced in adipose tissue of both HFD-fed groups with a more marked decrease in AD group compared to VD group. Only HFD-fed male mice were diabetic with increased fasting glycaemia. On the other hand, insulin levels were only increased in AD-fed group in both sexes associated with increased resistin levels. VD did not induce any apparent metabolic alteration in females despite the increased weight gain. Peroxisome Proliferator-Activated Receptors gamma-2 (PPARγ2 and estrogen receptor alpha (ERα mRNA expression levels in adipose tissue were decreased up to 70% in HFD-fed mice but were more markedly reduced in male mice as compared with female mice. Conclusions The nature of dietary fat determines the extent of metabolic alterations reflected in adipocytes through modifications in the pattern of

  17. Changes in the Phosphoproteome and Metabolome Link Early Signaling Events to Rearrangement of Photosynthesis and Central Metabolism in Salinity and Oxidative Stress Response in Arabidopsis.

    Science.gov (United States)

    Chen, Yanmei; Hoehenwarter, Wolfgang

    2015-12-01

    Salinity and oxidative stress are major factors affecting and limiting the productivity of agricultural crops. The molecular and biochemical processes governing the plant response to abiotic stress have often been researched in a reductionist manner. Here, we report a systemic approach combining metabolic labeling and phosphoproteomics to capture early signaling events with quantitative metabolome analysis and enzyme activity assays to determine the effects of salt and oxidative stress on plant physiology. K(+) and Na(+) transporters showed coordinated changes in their phosphorylation pattern, indicating the importance of dynamic ion homeostasis for adaptation to salt stress. Unique phosphorylation sites were found for Arabidopsis (Arabidopsis thaliana) SNF1 kinase homolog10 and 11, indicating their central roles in the stress-regulated responses. Seven Sucrose Non-fermenting1-Related Protein Kinase2 kinases showed varying levels of phosphorylation at multiple serine/threonine residues in their kinase domain upon stress, showing temporally distinct modulation of the various isoforms. Salinity and oxidative stress also lead to changes in protein phosphorylation of proteins central to photosynthesis, in particular the kinase State Transition Protein7 required for state transition and light-harvesting II complex proteins. Furthermore, stress-induced changes of the phosphorylation of enzymes of central metabolism were observed. The phosphorylation patterns of these proteins were concurrent with changes in enzyme activity. This was reflected by altered levels of metabolites, such as the sugars sucrose and fructose, glycolysis intermediates, and amino acids. Together, our study provides evidence for a link between early signaling in the salt and oxidative stress response that regulates the state transition of photosynthesis and the rearrangement of primary metabolism. © 2015 American Society of Plant Biologists. All Rights Reserved.

  18. Identification and functional verification of archaeal-type phosphoenolpyruvate carboxylase, a missing link in archaeal central carbohydrate metabolism.

    Science.gov (United States)

    Ettema, Thijs J G; Makarova, Kira S; Jellema, Gera L; Gierman, Hinco J; Koonin, Eugene V; Huynen, Martijn A; de Vos, Willem M; van der Oost, John

    2004-11-01

    Despite the fact that phosphoenolpyruvate carboxylase (PEPC) activity has been measured and in some cases even purified from some Archaea, the gene responsible for this activity has not been elucidated. Using sensitive sequence comparison methods, we detected a highly conserved, uncharacterized archaeal gene family that is distantly related to the catalytic core of the canonical PEPC. To verify the predicted function of this archaeal gene family, we cloned a representative from the hyperthermophilic acidophile Sulfolobus solfataricus and functionally produced the corresponding enzyme as a fusion with the Escherichia coli maltose-binding protein. The purified fusion protein indeed displayed highly thermostable PEPC activity. The structural and biochemical properties of the characterized archaeal-type PEPC (atPEPC) from S. solfataricus are in good agreement with previously reported biochemical analyses of other archaeal PEPC enzymes. The newly identified atPEPC, with its distinct properties, constitutes yet another example of the versatility of the enzymes of the central carbon metabolic pathways in the archaeal domain.

  19. Constraints on energy intake in fish: the link between diet composition, energy metabolism, and energy intake in rainbow trout.

    Directory of Open Access Journals (Sweden)

    Subramanian Saravanan

    Full Text Available The hypothesis was tested that fish fed to satiation with iso-energetic diets differing in macronutrient composition will have different digestible energy intakes (DEI but similar total heat production. Four iso-energetic diets (2 × 2 factorial design were formulated having a contrast in i the ratio of protein to energy (P/E: high (H(P/E vs. low (L(P/E and ii the type of non-protein energy (NPE source: fat vs. carbohydrate which were iso-energetically exchanged. Triplicate groups (35 fish/tank of rainbow trout were hand-fed each diet twice daily to satiation for 6 weeks under non-limiting water oxygen conditions. Feed intake (FI, DEI (kJ kg(-0.8 d(-1 and growth (g kg(-0.8 d(-1 of trout were affected by the interaction between P/E ratio and NPE source of the diet (P0.05. Our data suggest that the control of DEI in trout might be a function of heat production, which in turn might reflect a physiological limit related with oxidative metabolism.

  20. Quantitative proteomics links metabolic pathways to specific developmental stages of the plant-pathogenic oomycete Phytophthora capsici.

    Science.gov (United States)

    Pang, Zhili; Srivastava, Vaibhav; Liu, Xili; Bulone, Vincent

    2017-04-01

    The oomycete Phytophthora capsici is a plant pathogen responsible for important losses to vegetable production worldwide. Its asexual reproduction plays an important role in the rapid propagation and spread of the disease in the field. A global proteomics study was conducted to compare two key asexual life stages of P. capsici, i.e. the mycelium and cysts, to identify stage-specific biochemical processes. A total of 1200 proteins was identified using qualitative and quantitative proteomics. The transcript abundance of some of the enriched proteins was also analysed by quantitative real-time polymerase chain reaction. Seventy-three proteins exhibited different levels of abundance between the mycelium and cysts. The proteins enriched in the mycelium are mainly associated with glycolysis, the tricarboxylic acid (or citric acid) cycle and the pentose phosphate pathway, providing the energy required for the biosynthesis of cellular building blocks and hyphal growth. In contrast, the proteins that are predominant in cysts are essentially involved in fatty acid degradation, suggesting that the early infection stage of the pathogen relies primarily on fatty acid degradation for energy production. The data provide a better understanding of P. capsici biology and suggest potential metabolic targets at the two different developmental stages for disease control. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  1. Constraints on Energy Intake in Fish: The Link between Diet Composition, Energy Metabolism, and Energy Intake in Rainbow Trout

    Science.gov (United States)

    Saravanan, Subramanian; Schrama, Johan W.; Figueiredo-Silva, A. Claudia; Kaushik, Sadasivam J.; Verreth, Johan A. J.; Geurden, Inge

    2012-01-01

    The hypothesis was tested that fish fed to satiation with iso-energetic diets differing in macronutrient composition will have different digestible energy intakes (DEI) but similar total heat production. Four iso-energetic diets (2×2 factorial design) were formulated having a contrast in i) the ratio of protein to energy (P/E): high (HP/E) vs. low (LP/E) and ii) the type of non-protein energy (NPE) source: fat vs. carbohydrate which were iso-energetically exchanged. Triplicate groups (35 fish/tank) of rainbow trout were hand-fed each diet twice daily to satiation for 6 weeks under non-limiting water oxygen conditions. Feed intake (FI), DEI (kJ kg−0.8 d−1) and growth (g kg−0.8 d−1) of trout were affected by the interaction between P/E ratio and NPE source of the diet (Ptrout by ∼20%. The diet-induced differences in FI and DEI show that trout did not compensate for the dietary differences in digestible energy or digestible protein contents. Further, changes in body fat store and plasma glucose did not seem to exert a homeostatic feedback control on DEI. Independent of the diet composition, heat production of trout did not differ (P>0.05). Our data suggest that the control of DEI in trout might be a function of heat production, which in turn might reflect a physiological limit related with oxidative metabolism. PMID:22496852

  2. The Link of Self-Reported Insomnia Symptoms and Sleep Duration with Metabolic Syndrome: A Chinese Population-Based Study.

    Science.gov (United States)

    Lin, Shih-Chieh; Sun, Chien-An; You, San-Lin; Hwang, Lee-Ching; Liang, Chun-Yu; Yang, Tsan; Bai, Chyi-Huey; Chen, Chien-Hua; Wei, Cheng-Yu; Chou, Yu-Ching

    2016-06-01

    The aims of this study are to investigate the relationships of metabolic syndrome (MetS) with insomnia symptoms and sleep duration in a Chinese adult population. Data from a nationwide epidemiological survey conducted on residents from randomly selected districts in Taiwan in 2007 were used for this cross-sectional population-based study. A total of 4,197 participants were included in this study. Insomnia symptoms, including difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), were assessed using the Insomnia Self-Assessment Inventory questionnaire. Subjects were divided into 3 groups based upon their reported sleep duration (insomnia symptoms (OR [95% CI] was 1.54 [1.05-2.47]). However, there was no significant combined effect of insomnia symptoms and sleep duration on the prevalence of MetS. The current investigation shows that short sleep duration and insomnia symptoms, specifically DIS and DMS, were significant correlates of MetS. These findings should be replicated in prospective studies using both sleep duration and sleep quality measures. © 2016 Associated Professional Sleep Societies, LLC.

  3. Establishing research strategies, methodologies and technologies to link genomics and proteomics to seagrass productivity, community metabolism, and ecosystem carbon fluxes.

    Science.gov (United States)

    Mazzuca, Silvia; Björk, M; Beer, S; Felisberto, P; Gobert, S; Procaccini, G; Runcie, J; Silva, J; Borges, A V; Brunet, C; Buapet, P; Champenois, W; Costa, M M; D'Esposito, D; Gullström, M; Lejeune, P; Lepoint, G; Olivé, I; Rasmusson, L M; Richir, J; Ruocco, M; Serra, I A; Spadafora, A; Santos, Rui

    2013-01-01

    A complete understanding of the mechanistic basis of marine ecosystem functioning is only possible through integrative and interdisciplinary research. This enables the prediction of change and possibly the mitigation of the consequences of anthropogenic impacts. One major aim of the European Cooperation in Science and Technology (COST) Action ES0609 "Seagrasses productivity. From genes to ecosystem management," is the calibration and synthesis of various methods and the development of innovative techniques and protocols for studying seagrass ecosystems. During 10 days, 20 researchers representing a range of disciplines (molecular biology, physiology, botany, ecology, oceanography, and underwater acoustics) gathered at The Station de Recherches Sous-marines et Océanographiques (STARESO, Corsica) to study together the nearby Posidonia oceanica meadow. STARESO is located in an oligotrophic area classified as "pristine site" where environmental disturbances caused by anthropogenic pressure are exceptionally low. The healthy P. oceanica meadow, which grows in front of the research station, colonizes the sea bottom from the surface to 37 m depth. During the study, genomic and proteomic approaches were integrated with ecophysiological and physical approaches with the aim of understanding changes in seagrass productivity and metabolism at different depths and along daily cycles. In this paper we report details on the approaches utilized and we forecast the potential of the data that will come from this synergistic approach not only for P. oceanica but for seagrasses in general.

  4. Establishing research strategies, methodologies and technologies to link genomics and proteomics to seagrass productivity, community metabolism and ecosystem carbon fluxes

    Directory of Open Access Journals (Sweden)

    Silvia eMazzuca

    2013-03-01

    Full Text Available A complete understanding of the mechanistic basis of marine ecosystem functioning is only possible through integrative and interdisciplinary research. This enables the prediction of change and possibly the mitigation of the consequences of anthropogenic impacts. One major aim of the COST Action ES0609 Seagrasses productivity. From genes to ecosystem management, is the calibration and synthesis of various methods and the development of innovative techniques and protocols for studying seagrass ecosystems.During ten days, twenty researchers representing a range of disciplines (molecular biology, physiology, botany, ecology, oceanography, underwater acoustics gathered at the marine station of STARESO (Corsica to study together the nearby Posidonia oceanica meadow. The Station de Recherches Sous-marine et Océanographiques (STARESO is located in an oligotrophic area classified as "pristine site" where environmental disturbances caused by anthropogenic pressure are exceptionally low. The healthy P. oceanica meadow, that grows in front of the lab, colonizes the sea bottom from the surface to 37 m depth. During the study, genomic and proteomic approaches were integrated with ecophysiological and physical approaches with the aim of understanding changes in seagrass productivity and metabolism at different depths and along daily cycles. In this paper we report details on the approaches utilized and we forecast the potential of the data that will come from this synergistic approach not only for P. oceanica but for seagrasses in general.

  5. A novel link between Sus1 and the cytoplasmic mRNA decay machinery suggests a broad role in mRNA metabolism

    Directory of Open Access Journals (Sweden)

    Llopis Ana

    2010-03-01

    Full Text Available Abstract Background Gene expression is achieved by the coordinated action of multiple factors to ensure a perfect synchrony from chromatin epigenetic regulation through to mRNA export. Sus1 is a conserved mRNA export/transcription factor and is a key player in coupling transcription initiation, elongation and mRNA export. In the nucleus, Sus1 is associated to the transcriptional co-activator SAGA and to the NPC associated complex termed TREX2/THSC. Through these associations, Sus1 mediates the nuclear dynamics of different gene loci and facilitate the export of the new transcripts. Results In this study, we have investigated whether the yeast Sus1 protein is linked to factors involved in mRNA degradation pathways. We provide evidence for genetic interactions between SUS1 and genes coding for components of P-bodies such as PAT1, LSM1, LSM6 and DHH1. We demonstrate that SUS1 deletion is synthetic lethal with 5'→3' decay machinery components LSM1 and PAT1 and has a strong genetic interaction with LSM6 and DHH1. Interestingly, Sus1 overexpression led to an accumulation of Sus1 in cytoplasmic granules, which can co-localise with components of P-bodies and stress granules. In addition, we have identified novel physical interactions between Sus1 and factors associated to P-bodies/stress granules. Finally, absence of LSM1 and PAT1 slightly promotes the Sus1-TREX2 association. Conclusions In this study, we found genetic and biochemical association between Sus1 and components responsible for cytoplasmic mRNA metabolism. Moreover, Sus1 accumulates in discrete cytoplasmic granules, which partially co-localise with P-bodies and stress granules under specific conditions. These interactions suggest a role for Sus1 in gene expression during cytoplasmic mRNA metabolism in addition to its nuclear function.

  6. Cross-linking of sodium caseinate-structured emulsion with transglutaminase alters postprandial metabolic and appetite responses in healthy young individuals.

    Science.gov (United States)

    Juvonen, Kristiina R; Macierzanka, Adam; Lille, Martina E; Laaksonen, David E; Mykkänen, Hannu M; Niskanen, Leo K; Pihlajamäki, Jussi; Mäkelä, Kari A; Mills, Clare E N; Mackie, Alan R; Malcolm, Paul; Herzig, Karl-Heinz; Poutanen, Kaisa S; Karhunen, Leila J

    2015-08-14

    The physico-chemical and interfacial properties of fat emulsions influence lipid digestion and may affect postprandial responses. The aim of the present study was to determine the effects of the modification of the interfacial layer of a fat emulsion by cross-linking on postprandial metabolic and appetite responses. A total of fifteen healthy individuals (26.5 (sem 6.9) years and BMI 21.9 (sem 2.0) kg/m2) participated in a cross-over design experiment in which they consumed two isoenergetic (1924 kJ (460 kcal)) and isovolumic (250 g) emulsions stabilised with either sodium caseinate (Cas) or transglutaminase-cross-linked sodium caseinate (Cas-TG) in a randomised order. Blood samples were collected from the individuals at baseline and for 6 h postprandially for the determination of serum TAG and plasma NEFA, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), glucose and insulin responses. Appetite was assessed using visual analogue scales. Postprandial TAG and NEFA responses and gastric emptying (GE) rates were comparable between the emulsions. CCK increased more after the ingestion of Cas-TG than after the ingestion of Cas (P< 0.05), while GLP-1 responses did not differ between the two test emulsions. Glucose and insulin profiles were lower after consuming Cas-TG than after consuming Cas (P< 0.05). The overall insulin, glucose and CCK responses, expressed as areas above/under the curve, did not differ significantly between the Cas and Cas-TG meal conditions. Satiety ratings were reduced and hunger, desire to eat and thirst ratings increased more after the ingestion of Cas-TG than after the ingestion of Cas (P< 0.05). The present results suggest that even a subtle structural modification of the interfacial layer of a fat emulsion can alter the early postprandial profiles of glucose, insulin, CCK, appetite and satiety through decreased protein digestion without affecting significantly on GE or overall lipid digestion.

  7. Associations among hair loss, oral sulfur-containing gases, and gastrointestinal and metabolic linked diseases in Japanese elderly men: pilot study

    Directory of Open Access Journals (Sweden)

    Hamasaki Tomoko

    2009-03-01

    Full Text Available Abstract Background Male pattern baldness (MPB, an observable trait, has been reported to be associated with various diseases, such as prostate cancer and cardiovascular disease. Oral sulfur-containing gases have also been suggested to be useful as markers of systemic health condition. However, there are no known reports regarding the associations among MPB, and oral sulfur-containing gases, and systemic health conditions in males. Methods We studied 170 male subjects aged either 60 or 65 years old. The degree of MPB was assessed using the Norwood-Hamilton Baldness scale. Oral sulfur-containing gases were measured using a compact-designed device. All subjects completed physical and laboratory blood examinations, a face-to-face medical questionnaire, and an oral examination. Results There were significant differences between the levels of CH3SCH3 and baldness patterns, independent of age. When we analyzed whether the association was linked to systemic health condition, a strong significant association was observed between the level of CH3SCH3 and severe MPB in subjects with gastrointestinal diseases, hypertension, and hypercholesterolemia. Conclusion These results suggest that MPB is associated with the level of CH3SCH3, a sulfur-containing gas that causes oral malodor, in elderly Japanese males. Further, the association was intensified by the existence of gastrointestinal tract and metabolic disorders.

  8. [UNHEALTHY FOOD INTAKE IS LINKED TO HIGHER PREVALENCE OF METABOLIC SYNDROME IN CHILEAN ADULT POPULATION: CROSS SECTIONAL STUDY IN 2009-2010 NATIONAL HEALTH SURVEY].

    Science.gov (United States)

    Dussaillant, Catalina; Echeverría, Guadalupe; Villarroel, Luis; Marin, Pedro Paulo; Rigotti, Attilio

    2015-11-01

    metabolic syndrome (MS) is a clustering of risk factors known to promote cardiovascular disease and diabetes. Environmental factors, such as unhealthy diet, play a major role in the development of this condition. In this study, we evaluated the prevalence of MS and its association with food intake quality among Chilean adults. we analyzed data of 2 561 adults (≥ 18 years-old) included in the last National Health Survey (NHS 2009-2010) who had appropriate information to diagnose MS based on ATP III-NCEP guidelines. Consumption frequency of fish, whole grains, dairy, fruits and vegetables was also analyzed and associated with MS prevalence. Using a healthy diet score (HDS), we described the overall diet quality and further correlated it with MS prevalence. we found that lower whole grain intake was associated with greater MS prevalence (OR = 1.78; 95% CI: 1.088-2.919; p = 0.022). HDS showed better diet quality among women and in subjects with increasing age and higher educational level. A HDS Chilean adult population exhibits a high prevalence of MS linked to a poor diet quality. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  9. The missing link: Bordetella petrii is endowed with both the metabolic versatility of environmental bacteria and virulence traits of pathogenic Bordetellae

    Directory of Open Access Journals (Sweden)

    Schneiker-Bekel Susanne

    2008-09-01

    Full Text Available Abstract Background Bordetella petrii is the only environmental species hitherto found among the otherwise host-restricted and pathogenic members of the genus Bordetella. Phylogenetically, it connects the pathogenic Bordetellae and environmental bacteria of the genera Achromobacter and Alcaligenes, which are opportunistic pathogens. B. petrii strains have been isolated from very different environmental niches, including river sediment, polluted soil, marine sponges and a grass root. Recently, clinical isolates associated with bone degenerative disease or cystic fibrosis have also been described. Results In this manuscript we present the results of the analysis of the completely annotated genome sequence of the B. petrii strain DSMZ12804. B. petrii has a mosaic genome of 5,287,950 bp harboring numerous mobile genetic elements, including seven large genomic islands. Four of them are highly related to the clc element of Pseudomonas knackmussii B13, which encodes genes involved in the degradation of aromatics. Though being an environmental isolate, the sequenced B. petrii strain also encodes proteins related to virulence factors of the pathogenic Bordetellae, including the filamentous hemagglutinin, which is a major colonization factor of B. pertussis, and the master virulence regulator BvgAS. However, it lacks all known toxins of the pathogenic Bordetellae. Conclusion The genomic analysis suggests that B. petrii represents an evolutionary link between free-living environmental bacteria and the host-restricted obligate pathogenic Bordetellae. Its remarkable metabolic versatility may enable B. petrii to thrive in very different ecological niches.

  10. Detection of denitrification genes by in situ rolling circle amplification - fluorescence in situ hybridization (in situ RCA-FISH) to link metabolic potential with identity inside bacterial cells

    DEFF Research Database (Denmark)

    Hoshino, Tatsuhiko; Schramm, Andreas

    2010-01-01

    target site. Finally, the RCA product inside the cells was detected by standard fluorescence in situ hybridization (FISH). The optimized protocol showed high specificity and signal-to-noise ratio but low detection frequency (up to 15% for single-copy genes and up to 43% for the multi-copy 16S rRNA gene...... as Candidatus Accumulibacter phosphatis by combining in situ RCA-FISH with 16S rRNA-targeted FISH. While not suitable for quantification because of its low detection frequency, in situ RCA-FISH will allow to link metabolic potential with 16S rRNA (gene)-based identification of single microbial cells.......). Nevertheless, multiple genes (nirS and nosZ; nirS and the 16S rRNA gene) could be detected simultaneously in P. stutzeri. Environmental application of in situ RCA-FISH was demonstrated on activated sludge by the differential detection of two types of nirS-defined denitrifiers; one of them was identified...

  11. Actions of p-synephrine on hepatic enzyme activities linked to carbohydrate metabolism and ATP levels in vivo and in the perfused rat liver.

    Science.gov (United States)

    Maldonado, Marcos Rodrigues; Bracht, Lívia; de Sá-Nakanishi, Anacharis Babeto; Corrêa, Rúbia Carvalho Gomes; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

    2018-01-01

    p-Synephrine is one of the main active components of the fruit of Citrus aurantium (bitter orange). Extracts of the bitter orange and other preparations containing p-synephrine have been used worldwide to promote weight loss and for sports performance. The purpose of the study was to measure the action of p-synephrine on hepatic enzyme activities linked to carbohydrate and energy metabolism and the levels of adenine mononucleotides. Enzymes and adenine mononucleotides were measured in the isolated perfused rat liver and in vivo after oral administration of the drug (50 and 300 mg/kg) by using standard techniques. p-Synephrine increased the activity of glycogen phosphorylase in vivo and in the perfused liver. It decreased, however, the activities of pyruvate kinase and pyruvate dehydrogenase also in vivo and in the perfused liver. p-Synephrine increased the hepatic pools of adenosine diphosphate and adenosine triphosphate. Stimulation of glycogen phosphorylase is consistent with the reported increased glycogenolysis in the perfused liver and increased glycemia in rats. The decrease in the pyruvate dehydrogenase activity indicates that p-synephrine is potentially capable of inhibiting the transformation of carbohydrates into lipids. The capability of increasing the adenosine triphosphate-adenosine diphosphate pool indicates a beneficial effect of p-synephrine on the cellular energetics. Copyright © 2017 John Wiley & Sons, Ltd.

  12. A systems biology approach reveals a link between systemic cytokines and skeletal muscle energy metabolism in a rodent smoking model and human COPD.

    Science.gov (United States)

    Davidsen, Peter K; Herbert, John M; Antczak, Philipp; Clarke, Kim; Ferrer, Elisabet; Peinado, Victor I; Gonzalez, Constancio; Roca, Josep; Egginton, Stuart; Barberá, Joan A; Falciani, Francesco

    2014-01-01

    CXCL10 and CXCL9 are promising candidate inflammatory signals linked to the regulation of central metabolism genes in skeletal muscles. On a methodological level, our work also shows that a system level analysis of animal models of diseases can be very effective to generate clinically relevant hypothesis.

  13. HITS-CLIP analysis uncovers a link between the Kaposi's sarcoma-associated herpesvirus ORF57 protein and host pre-mRNA metabolism.

    Directory of Open Access Journals (Sweden)

    Emi Sei

    2015-02-01

    Full Text Available The Kaposi's sarcoma associated herpesvirus (KSHV is an oncogenic virus that causes Kaposi's sarcoma, primary effusion lymphoma (PEL, and some forms of multicentric Castleman's disease. The KSHV ORF57 protein is a conserved posttranscriptional regulator of gene expression that is essential for virus replication. ORF57 is multifunctional, but most of its activities are directly linked to its ability to bind RNA. We globally identified virus and host RNAs bound by ORF57 during lytic reactivation in PEL cells using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP. As expected, ORF57-bound RNA fragments mapped throughout the KSHV genome, including the known ORF57 ligand PAN RNA. In agreement with previously published ChIP results, we observed that ORF57 bound RNAs near the oriLyt regions of the genome. Examination of the host RNA fragments revealed that a subset of the ORF57-bound RNAs was derived from transcript 5' ends. The position of these 5'-bound fragments correlated closely with the 5'-most exon-intron junction of the pre-mRNA. We selected four candidates (BTG1, EGR1, ZFP36, and TNFSF9 and analyzed their pre-mRNA and mRNA levels during lytic phase. Analysis of both steady-state and newly made RNAs revealed that these candidate ORF57-bound pre-mRNAs persisted for longer periods of time throughout infection than control RNAs, consistent with a role for ORF57 in pre-mRNA metabolism. In addition, exogenous expression of ORF57 was sufficient to increase the pre-mRNA levels and, in one case, the mRNA levels of the putative ORF57 targets. These results demonstrate that ORF57 interacts with specific host pre-mRNAs during lytic reactivation and alters their processing, likely by stabilizing pre-mRNAs. These data suggest that ORF57 is involved in modulating host gene expression in addition to KSHV gene expression during lytic reactivation.

  14. Effects of starvation, refeeding, and insulin on energy-linked metabolic processes in catfish (Rhamdia hilarii) adapted to a carbohydrate-rich diet

    International Nuclear Information System (INIS)

    Machado, C.R.; Garofalo, M.A.; Roselino, J.E.; Kettelhut, I.C.; Migliorini, R.H.

    1988-01-01

    The effects of starvation and of a short period of refeeding on energy-linked metabolic processes, as well as the effects of insulin administration, were investigated in an omnivorous fish (catfish, Rhamdia hilarii) previously adapted to a carbohydrate-rich diet. Following food deprivation blood sugar levels declined progressively to about 50% of fed values after 30 days. During the same period plasma free fatty acid (FFA) concentration increased twofold. Starvation resulted in reduced concentrations of lipid and glycogen in the liver and of glycogen, lipid, and protein in white muscle. However, taking into account the initial and final concentrations of tissue constituents, the liver weight, and the large fractions of body weight represented by muscle, it could be estimated that most of the energy utilized during starvation derived from the catabolism of muscle lipid and protein. Refeeding starved fishes for 48 hr induced several-fold increases in the rates of in vivo and in vitro incorporation of [14C]glucose into liver and muscle lipid and of [14C]glycine into liver and muscle protein. Incorporation of [14C]glucose into liver glycogen was also increased. However; refeeding did not affect the incorporation of labeled glucose into muscle glycogen, neither in vivo nor in vitro. Administration of pharmacological doses of insulin to normally fed catfishes resulted in marked increases in the in vivo incorporation of 14C from glucose into lipid and protein in both liver and muscle. In contrast, labeled glucose incorporation into muscle glycogen was not affected by insulin and label incorporation into liver glycogen was actually lower than that in noninjected controls

  15. Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans

    Science.gov (United States)

    Zhang, Xinxing; Jones, Rachel A.; Bruner, Steven D.; Butcher, Rebecca A.

    2016-01-01

    Caenorhabditis elegans secretes ascarosides as pheromones to communicate with other worms and to coordinate the development and behavior of the population. Peroxisomal β-oxidation cycles shorten the side chains of ascaroside precursors to produce the short-chain ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, have different side chain-length specificities and enable C. elegans to regulate the production of specific ascaroside pheromones. Here, we determine the crystal structure of the acyl-CoA oxidase 1 (ACOX-1) homodimer and the ACOX-2 homodimer bound to its substrate. Our results provide a molecular basis for the substrate specificities of the acyl-CoA oxidases and reveal why some of these enzymes have a very broad substrate range, whereas others are quite specific. Our results also enable predictions to be made for the roles of uncharacterized acyl-CoA oxidases in C. elegans and in other nematode species. Remarkably, we show that most of the C. elegans acyl-CoA oxidases that participate in ascaroside biosynthesis contain a conserved ATP-binding pocket that lies at the dimer interface, and we identify key residues in this binding pocket. ATP binding induces a structural change that is associated with tighter binding of the FAD cofactor. Mutations that disrupt ATP binding reduce FAD binding and reduce enzyme activity. Thus, ATP may serve as a regulator of acyl-CoA oxidase activity, thereby directly linking ascaroside biosynthesis to ATP concentration and metabolic state. PMID:27551084

  16. Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans.

    Science.gov (United States)

    Zhang, Xinxing; Li, Kunhua; Jones, Rachel A; Bruner, Steven D; Butcher, Rebecca A

    2016-09-06

    Caenorhabditis elegans secretes ascarosides as pheromones to communicate with other worms and to coordinate the development and behavior of the population. Peroxisomal β-oxidation cycles shorten the side chains of ascaroside precursors to produce the short-chain ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, have different side chain-length specificities and enable C. elegans to regulate the production of specific ascaroside pheromones. Here, we determine the crystal structure of the acyl-CoA oxidase 1 (ACOX-1) homodimer and the ACOX-2 homodimer bound to its substrate. Our results provide a molecular basis for the substrate specificities of the acyl-CoA oxidases and reveal why some of these enzymes have a very broad substrate range, whereas others are quite specific. Our results also enable predictions to be made for the roles of uncharacterized acyl-CoA oxidases in C. elegans and in other nematode species. Remarkably, we show that most of the C. elegans acyl-CoA oxidases that participate in ascaroside biosynthesis contain a conserved ATP-binding pocket that lies at the dimer interface, and we identify key residues in this binding pocket. ATP binding induces a structural change that is associated with tighter binding of the FAD cofactor. Mutations that disrupt ATP binding reduce FAD binding and reduce enzyme activity. Thus, ATP may serve as a regulator of acyl-CoA oxidase activity, thereby directly linking ascaroside biosynthesis to ATP concentration and metabolic state.

  17. Glucose Induces Slow-Wave Sleep by Exciting the Sleep-Promoting Neurons in the Ventrolateral Preoptic Nucleus: A New Link between Sleep and Metabolism.

    Science.gov (United States)

    Varin, Christophe; Rancillac, Armelle; Geoffroy, Hélène; Arthaud, Sébastien; Fort, Patrice; Gallopin, Thierry

    2015-07-08

    fundamental and intimate link between sleep and metabolism. Copyright © 2015 the authors 0270-6474/15/359900-12$15.00/0.

  18. Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease

    Science.gov (United States)

    Madison, Cindee; Baker, Suzanne; Rabinovici, Gil; Jagust, William

    2016-01-01

    Abstract See Hansson and Gouras (doi:10.1093/aww146) for a scientific commentary on this article. Although some brain regions such as precuneus and lateral temporo-parietal cortex have been shown to be more vulnerable to Alzheimer’s disease than other areas, a mechanism underlying the differential regional vulnerability to Alzheimer’s disease remains to be elucidated. Using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography imaging glucose metabolism and amyloid-β deposition, we tested whether and how life-long changes in glucose metabolism relate to amyloid-β deposition and Alzheimer’s disease-related hypometabolism. Nine healthy young adults (age range: 20–30), 96 cognitively normal older adults (age range: 61–96), and 20 patients with Alzheimer’s disease (age range: 50–90) were scanned using fluorodeoxyglucose and Pittsburgh compound B positron emission tomography. Among cognitively normal older subjects, 32 were further classified as amyloid-positive, with 64 as amyloid-negative. To assess the contribution of glucose metabolism to the regional vulnerability to amyloid-β deposition, we defined the highest and lowest metabolic regions in young adults and examined differences in amyloid deposition between these regions across groups. Two-way analyses of variance were conducted to assess regional differences in age and amyloid-β-related changes in glucose metabolism. Multiple regressions were applied to examine the association between amyloid-β deposition and regional glucose metabolism. Both region of interest and whole-brain voxelwise analyses were conducted to complement and confirm the results derived from the other approach. Regional differences in glucose metabolism between the highest and lowest metabolism regions defined in young adults (T = 12.85, P glucose metabolism regions defined in young adults (T = 2.05, P glucose metabolism were found such that frontal glucose metabolism was reduced with age, while glucose

  19. Suppression of the Escherichia coli dnaA46 mutation by changes in the activities of the pyruvate-acetate node links DNA replication regulation to central carbon metabolism.

    Science.gov (United States)

    Tymecka-Mulik, Joanna; Boss, Lidia; Maciąg-Dorszyńska, Monika; Matias Rodrigues, João F; Gaffke, Lidia; Wosinski, Anna; Cech, Grzegorz M; Szalewska-Pałasz, Agnieszka; Węgrzyn, Grzegorz; Glinkowska, Monika

    2017-01-01

    To ensure faithful transmission of genetic material to progeny cells, DNA replication is tightly regulated, mainly at the initiation step. Escherichia coli cells regulate the frequency of initiation according to growth conditions. Results of the classical, as well as the latest studies, suggest that the DNA replication in E. coli starts at a predefined, constant cell volume per chromosome but the mechanisms coordinating DNA replication with cell growth are still not fully understood. Results of recent investigations have revealed a role of metabolic pathway proteins in the control of cell division and a direct link between metabolism and DNA replication has also been suggested both in Bacillus subtilis and E. coli cells. In this work we show that defects in the acetate overflow pathway suppress the temperature-sensitivity of a defective replication initiator-DnaA under acetogenic growth conditions. Transcriptomic and metabolic analyses imply that this suppression is correlated with pyruvate accumulation, resulting from alterations in the pyruvate dehydrogenase (PDH) activity. Consequently, deletion of genes encoding the pyruvate dehydrogenase subunits likewise resulted in suppression of the thermal-sensitive growth of the dnaA46 strain. We propose that the suppressor effect may be directly related to the PDH complex activity, providing a link between an enzyme of the central carbon metabolism and DNA replication.

  20. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes

    DEFF Research Database (Denmark)

    Pamp, Sünje Johanna; Gjermansen, Morten; Johansen, Helle Krogh

    2008-01-01

    -mediated killing in biofilms, conventional antimicrobial compounds such as ciprofloxacin and tetracycline were found to specifically kill the subpopulation of metabolically active biofilm cells, whereas the subpopulation exhibiting low metabolic activity survived the treatment. Consequently, targeting the two...... physiologically distinct subpopulations by combined antimicrobial treatment with either ciprofloxacin and colistin or tetracycline and colistin almost completely eradicated all biofilm cells....

  1. The shift work and health research agenda: Considering changes in gut microbiota as a pathway linking shift work, sleep loss and circadian misalignment, and metabolic disease.

    Science.gov (United States)

    Reynolds, Amy C; Paterson, Jessica L; Ferguson, Sally A; Stanley, Dragana; Wright, Kenneth P; Dawson, Drew

    2017-08-01

    Prevalence and impact of metabolic disease is rising. In particular, overweight and obesity are at epidemic levels and are a leading health concern in the Western world. Shift work increases the risk of overweight and obesity, along with a number of additional metabolic diseases, including metabolic syndrome and type 2 diabetes (T2D). How shift work contributes to metabolic disease has not been fully elucidated. Short sleep duration is associated with metabolic disease and shift workers typically have shorter sleep durations. Short sleep durations have been shown to elicit a physiological stress response, and both physiological and psychological stress disrupt the healthy functioning of the intestinal gut microbiota. Recent findings have shown altered intestinal microbial communities and dysbiosis of the gut microbiota in circadian disrupted mice and jet lagged humans. We hypothesize that sleep and circadian disruption in humans alters the gut microbiota, contributing to an inflammatory state and metabolic disease associated with shift work. A research agenda for exploring the relationship between insufficient sleep, circadian misalignment and the gut microbiota is provided. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Research Advances: Calorie Restriction and Increased Longevity Linked to Metabolic Changes; Isotope Ratios Reveal Trickery in the Produce Aisle; An Ancient Inca Tax and Metallurgy in Peru

    Science.gov (United States)

    King, Angela G.

    2007-01-01

    The different lifelong patterns related to different levels of energy metabolism and the activities of the microbes in various animals are described. The analysis shows that many important beneficial changes occur due to the activities of symbiotic bacteria living in the intestinal tract.

  3. Comparative liver accumulation of dioxin-like compounds in sheep and cattle: Possible role of AhR-mediated xenobiotic metabolizing enzymes.

    Science.gov (United States)

    Girolami, F; Spalenza, V; Benedetto, A; Manzini, L; Badino, P; Abete, M C; Nebbia, C

    2016-11-15

    PCDDs, PCDFs, and PCBs are persistent organic pollutants (POPs) that accumulate in animal products and may pose serious health problems. Those able to bind the aryl hydrocarbon receptor (AhR), eliciting a plethora of toxic responses, are defined dioxin-like (DL) compounds, while the remainders are called non-DL (NDL). An EFSA opinion has highlighted the tendency of ovine liver to specifically accumulate DL-compounds to a greater extent than any other farmed ruminant species. To examine the possible role in such an accumulation of xenobiotic metabolizing enzymes (XME) involved in DL-compound biotransformation, liver samples were collected from ewes and cows reared in an area known for low dioxin contamination. A related paper reported that sheep livers had about 5-fold higher DL-compound concentrations than cattle livers, while the content of the six marker NDL-PCBs did not differ between species. Specimens from the same animals were subjected to gene expression analysis for AhR, AhR nuclear translocator (ARNT) and AhR-dependent oxidative and conjugative pathways; XME protein expression and activities were also investigated. Both AhR and ARNT mRNA levels were about 2-fold lower in ovine samples and the same occurred for CYP1A1 and CYP1A2, being approximately 3- and 9-fold less expressed in sheep compared to cattle, while CYP1B1 could be detectable in cattle only. The results of the immunoblotting and catalytic activity (most notably EROD) measurements of the CYP1A family enzymes were in line with the gene expression data. By contrast, phase II enzyme expression and activities in sheep were higher (UGT1A) or similar (GSTA1, NQO1) to those recorded in cattle. The overall low expression of CYP1 family enzymes in the sheep is in line with the observed liver accumulation of DL-compounds and is expected to affect the kinetics and the dynamics of other POPs such as many polycyclic aromatic hydrocarbons, as well as of toxins (e.g. aflatoxins) or drugs (e.g. benzimidazole

  4. The effects of detergent, sodium tripoly-phosphate and ethoxyled oleyl-cetyl alcohol on metabolic parameters of the fungus Trichothecium roseum link

    Directory of Open Access Journals (Sweden)

    Stojanović Jelica

    2011-01-01

    Full Text Available The degradation of detergents that are dispersed in water and soil partially depends on the metabolic activities of fungi. Among the fungi that have this ability, Deuteromycetes are particularly noted for their biochemical characteristics. Taking this into account, it was of interest to analyze the influence of detergent and its main compounds, ethoxyled oleylcetyl alcohol (AOC and sodium tripoly-phosphate (TTP, on the metabolism of the fungus Trichothecium roseum. Our results revealed that both detergent and AOC had an inhibitory effect on the bioproduction of free organic acids, while TTP stimulated their production. Also, detergent inhibited the bioproduction of basic amino acids, with the exception of alanine. In addition, detergent applied at 1% concentration inhibited the bioproduction of proteins and the total biomass of the fungus, while AOC and TTP inhibited the production of proteins, but stimulatedl the production of Trichothecium.

  5. Single nucleotide polymorphisms linked to mitochondrial uncoupling protein genes UCP2 and UCP3 affect mitochondrial metabolism and healthy aging in female nonagenarians.

    Science.gov (United States)

    Kim, Sangkyu; Myers, Leann; Ravussin, Eric; Cherry, Katie E; Jazwinski, S Michal

    2016-08-01

    Energy expenditure decreases with age, but in the oldest-old, energy demand for maintenance of body functions increases with declining health. Uncoupling proteins have profound impact on mitochondrial metabolic processes; therefore, we focused attention on mitochondrial uncoupling protein genes. Alongside resting metabolic rate (RMR), two SNPs in the promoter region of UCP2 were associated with healthy aging. These SNPs mark potential binding sites for several transcription factors; thus, they may affect expression of the gene. A third SNP in the 3'-UTR of UCP3 interacted with RMR. This UCP3 SNP is known to impact UCP3 expression in tissue culture cells, and it has been associated with body weight and mitochondrial energy metabolism. The significant main effects of the UCP2 SNPs and the interaction effect of the UCP3 SNP were also observed after controlling for fat-free mass (FFM) and physical-activity related energy consumption. The association of UCP2/3 with healthy aging was not found in males. Thus, our study provides evidence that the genetic risk factors for healthy aging differ in males and females, as expected from the differences in the phenotypes associated with healthy aging between the two sexes. It also has implications for how mitochondrial function changes during aging.

  6. Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension : A Link between 11 beta-HSD1 and Intracranial Pressure Regulation?

    NARCIS (Netherlands)

    Sinclair, Alexandra J.; Walker, Elizabeth A.; Burdon, Michael A.; van Beek, Andre P.; Kema, Ido P.; Hughes, Beverly A.; Murray, Philip I.; Nightingale, Peter G.; Stewart, Paul M.; Rauz, Saaeha; Tomlinson, Jeremy W.

    2010-01-01

    Context: The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) activity. Objective: The aim was to characterize 11 beta-HSD1 in

  7. Milano summer particulate matter (PM10 triggers lung inflammation and extra pulmonary adverse events in mice.

    Directory of Open Access Journals (Sweden)

    Francesca Farina

    Full Text Available Recent studies have suggested a link between particulate matter (PM exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases; accumulating evidences point to a new role for air pollution in CNS diseases. The purpose of our study is to investigate PM10sum effects on lungs and extra pulmonary tissues. Milano PM10sum has been intratracheally instilled into BALB/c mice. Broncho Alveolar Lavage fluid, lung parenchyma, heart and brain were screened for markers of inflammation (cell counts, cytokines, ET-1, HO-1, MPO, iNOS, cytotoxicity (LDH, ALP, Hsp70, Caspase8-p18, Caspase3-p17 for a putative pro-carcinogenic marker (Cyp1B1 and for TLR4 pathway activation. Brain was also investigated for CD68, TNF-α, GFAP. In blood, cell counts were performed while plasma was screened for endothelial activation (sP-selectin, ET-1 and for inflammation markers (TNF-α, MIP-2, IL-1β, MPO. Genes up-regulation (HMOX1, Cyp1B1, IL-1β, MIP-2, MPO and miR-21 have been investigated in lungs and blood. Inflammation in the respiratory tract of PM10sum-treated mice has been confirmed in BALf and lung parenchyma by increased PMNs percentage, increased ET-1, MPO and cytokines levels. A systemic spreading of lung inflammation in PM10sum-treated mice has been related to the increased blood total cell count and neutrophils percentage, as well as to increased blood MPO. The blood-endothelium interface activation has been confirmed by significant increases of plasma ET-1 and sP-selectin. Furthermore PM10sum induced heart endothelial activation and PAHs metabolism, proved by increased ET-1 and Cyp1B1 levels. Moreover, PM10sum causes an increase in brain HO-1 and ET-1. These results state the translocation of inflammation mediators, ultrafine particles, LPS, metals associated to PM10sum, from lungs to bloodstream, thus triggering a systemic reaction, mainly involving heart and brain. Our results provided additional insight into the toxicity

  8. Involvement of alternative oxidase (AOX) in adventitious rooting of Olea europaea L. microshoots is linked to adaptive phenylpropanoid and lignin metabolism.

    Science.gov (United States)

    Santos Macedo, E; Sircar, D; Cardoso, H G; Peixe, A; Arnholdt-Schmitt, B

    2012-09-01

    Alternative oxidase (AOX) has been proposed as a functional marker candidate in a number of events involving cell differentiation, including rooting efficiency in semi-hardwood shoot cuttings of olive (Olea europaea L.). To ascertain the general importance of AOX in olive rooting, the auxin-induced rooting process was studied in an in vitro system for microshoot propagation. Inhibition of AOX by salicylhydroxamic acid (SHAM) significantly reduced rooting efficiency. However, the inhibitor failed to exhibit any effect on the preceding calli stage. This makes the system appropriate for distinguishing dedifferentiation and de novo differentiation during root induction. Metabolite analyses of microshoots showed that total phenolics, total flavonoids and lignin contents were significantly reduced upon SHAM treatment. It was concluded that the influence of alternative respiration on root formation was associated to adaptive phenylpropanoid and lignin metabolism. Transcript profiles of two olive AOX genes (OeAOX1a and OeAOX2) were examined during the process of auxin-induced root induction. Both genes displayed stable transcript accumulation in semi-quantitative RT-PCR analysis during all experimental stages. In contrary, when the reverse primer for OeAOX2 was designed from the 3'-UTR instead of the ORF, differential transcript accumulation was observed suggesting posttranscriptional regulation of OeAOX2 during metabolic acclimation. This result confirms former observations in olive semi-hardwood shoot cuttings on differential OeAOX2 expression during root induction. It further points to the importance of future studies on the functional role of sequence and length polymorphisms in the 3'-UTR of this gene. The manuscript reports the general importance of AOX in olive adventitious rooting and the association of alternative respiration to adaptive phenylpropanoid and lignin metabolism.

  9. Potential Links between Impaired One-Carbon Metabolism Due to Polymorphisms, Inadequate B-Vitamin Status, and the Development of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Barbara Troesch

    2016-12-01

    Full Text Available Alzheimer’s disease (AD is the major cause of dementia and no preventive or effective treatment has been established to date. The etiology of AD is poorly understood, but genetic and environmental factors seem to play a role in its onset and progression. In particular, factors affecting the one-carbon metabolism (OCM are thought to be important and elevated homocysteine (Hcy levels, indicating impaired OCM, have been associated with AD. We aimed at evaluating the role of polymorphisms of key OCM enzymes in the etiology of AD, particularly when intakes of relevant B-vitamins are inadequate. Our review indicates that a range of compensatory mechanisms exist to maintain a metabolic balance. However, these become overwhelmed if the activity of more than one enzyme is reduced due to genetic factors or insufficient folate, riboflavin, vitamin B6 and/or vitamin B12 levels. Consequences include increased Hcy levels and reduced capacity to synthetize, methylate and repair DNA, and/or modulated neurotransmission. This seems to favor the development of hallmarks of AD particularly when combined with increased oxidative stress e.g., in apolipoprotein E (ApoE ε4 carriers. However, as these effects can be compensated at least partially by adequate intakes of B-vitamins, achieving optimal B-vitamin status for the general population should be a public health priority.

  10. Uncoupling of collagen II metabolism in newly diagnosed, untreated rheumatoid arthritis is linked to inflammation and antibodies against cyclic citrullinated peptides

    DEFF Research Database (Denmark)

    Christensen, Anne Friesgaard; Hørslev-Petersen, Kim; Christgau, Stephan

    2010-01-01

    . METHODS: One hundred sixty patients with newly diagnosed, untreated RA entered the Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA) trial. Disease activity and radiograph status were measured at baseline and 4 years. The N-terminal propeptide of collagen IIA (PIIANP) and the cross-linked C...... associations of collagen II anabolism (PIIANP) and collagen II degradation (CTX-II) with anti-CCP, synovitis, and radiographic progression indicate that at this early stage of RA, cartilage collagen degradation is mainly driven by synovitis, while anti-CCP antibodies may interfere with cartilage regeneration...

  11. Linking climate change to community-level impacts on copepods via a new, trait-based model: Life-history and metabolic mechanisms compared

    DEFF Research Database (Denmark)

    Banas, Neil S.; Møller, Eva Friis; Nielsen, Torkel Gissel

    2017-01-01

    A new, trait-based copepod model ("Coltrane": Copepod Life-history Traits and Adaptation to Novel Environments) has been developed, drawing on past work on both optimal annual routines and trait-based plankton metacommunity models, in order to evaluate climate impacts on copepods via 1) phenology...... and physiology of local populations of C. finmarchicus, C. glacialis, and C. hyperboreus. Futhermore, the model replicates the observed range of stored lipid content of these copepod populations (30–60%, C. finmarchicus–C. hyperboreus), suggesting a means for linking changes in temperature and primary production...

  12. Linking climate change to community-level impacts on copepods via a new, trait-based model: Life-history and metabolic mechanisms compared

    DEFF Research Database (Denmark)

    Banas, Neil S.; Møller, Eva Friis; Nielsen, Torkel Gissel

    A new, trait-based copepod model ("Coltrane": Copepod Life-history Traits and Adaptation to Novel Environments) has been developed, drawing on past work on both optimal annual routines and trait-based plankton metacommunity models, in order to evaluate climate impacts on copepods via 1) phenology...... and physiology of local populations of C. finmarchicus, C. glacialis, and C. hyperboreus. Futhermore, the model replicates the observed range of stored lipid content of these copepod populations (30–60%, C. finmarchicus–C. hyperboreus), suggesting a means for linking changes in temperature and primary production...

  13. Exceptional longevity and exceptionally high metabolic rates in anthropoid primates are linked to a major modification of the ubiquinone reduction site of cytochrome b.

    Science.gov (United States)

    Rottenberg, Hagai

    2014-10-01

    The maximal lifespan of Anthropoid primates (monkeys, apes and humans) exceed the lifespan of most other mammals of equal body mass. Unexpectedly, their exceptional longevity is associated with exceptionally high metabolic rates, in apparent contradiction to the Free Radical Theory of Aging. It was therefore suggested that in anthropoid primates (and several other taxa of mammals and birds) the mitochondrial electron transport complexes evolved to modify the relationship between basal electron transport and superoxide generation to allow for the evolution of exceptional longevity. Cytochrome b, the core protein of the bc1 complex is a major source of superoxide. The amino-acid sequence of cytochrome b evolved much faster in anthropoid than in prosimian primates, and most other mammals, resulting in a large change in the amino-acids composition of the protein. As a result of these changes cytochrome b in anthropoid primates is significantly less hydrophobic and contains more polar residues than other primates and most other mammals. Most of these changes are clustered around the reduction site of uboiquinone. In particular a key positively charged residue, arginine 313, that interacts with propionate D of heme bH, and thus raises its redox potential, is substituted in anthropoid primates with the neutral residue glutamine, most likely resulting in a lower redox potential of heme bH and faster reduction of ubiquinone at high proton motive force. It is suggested that these changes contribute to the observed increased rates of basal metabolism and reduce the rates of superoxide production, thus allowing for increased lifespan.

  14. Investigation of metabolic encephalopathy

    African Journals Online (AJOL)

    cycle defects is the X-linked recessive disorder, ornithine ... life, or if the child is fed the compounds that they are unable .... as learning difficulties, drowsiness and avoidance of ... Table 2. Laboratory investigation of suspected metabolic encephalopathy. Laboratory .... Clinical approach to treatable inborn metabolic diseases:.

  15. Metabolism of vertebrate amino sugars with N-glycolyl groups: resistance of α2-8-linked N-glycolylneuraminic acid to enzymatic cleavage.

    Science.gov (United States)

    Davies, Leela R L; Pearce, Oliver M T; Tessier, Matthew B; Assar, Siavash; Smutova, Victoria; Pajunen, Maria; Sumida, Mizuki; Sato, Chihiro; Kitajima, Ken; Finne, Jukka; Gagneux, Pascal; Pshezhetsky, Alexey; Woods, Robert; Varki, Ajit

    2012-08-17

    The sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) and its hydroxylated derivative N-glycolylneuraminic acid (Neu5Gc) differ by one oxygen atom. CMP-Neu5Gc is synthesized from CMP-Neu5Ac, with Neu5Gc representing a highly variable fraction of total Sias in various tissues and among different species. The exception may be the brain, where Neu5Ac is abundant and Neu5Gc is reported to be rare. Here, we confirm this unusual pattern and its evolutionary conservation in additional samples from various species, concluding that brain Neu5Gc expression has been maintained at extremely low levels over hundreds of millions of years of vertebrate evolution. Most explanations for this pattern do not require maintaining neural Neu5Gc at such low levels. We hypothesized that resistance of α2-8-linked Neu5Gc to vertebrate sialidases is the detrimental effect requiring the relative absence of Neu5Gc from brain. This linkage is prominent in polysialic acid (polySia), a molecule with critical roles in vertebrate neural development. We show that Neu5Gc is incorporated into neural polySia and does not cause in vitro toxicity. Synthetic polymers of Neu5Ac and Neu5Gc showed that mammalian and bacterial sialidases are much less able to hydrolyze α2-8-linked Neu5Gc at the nonreducing terminus. Notably, this difference was not seen with acid-catalyzed hydrolysis of polySias. Molecular dynamics modeling indicates that differences in the three-dimensional conformation of terminal saccharides may partly explain reduced enzymatic activity. In keeping with this, polymers of N-propionylneuraminic acid are sensitive to sialidases. Resistance of Neu5Gc-containing polySia to sialidases provides a potential explanation for the rarity of Neu5Gc in the vertebrate brain.

  16. Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life cycle of malaria parasites.

    Directory of Open Access Journals (Sweden)

    Mathieu Brochet

    2014-03-01

    Full Text Available Many critical events in the Plasmodium life cycle rely on the controlled release of Ca²⁺ from intracellular stores to activate stage-specific Ca²⁺-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca²⁺ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca²⁺ effectors, PKG emerges as a unifying factor to control multiple cellular Ca²⁺ signals essential for malaria parasite development and transmission.

  17. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis.

    Science.gov (United States)

    Trosko, James E

    2016-06-15

    The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules ("quorum sensing"), the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or "connexin" genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC) in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision-making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global "metabolic disease" crisis.

  18. Evolution of Microbial Quorum Sensing to Human Global Quorum Sensing: An Insight into How Gap Junctional Intercellular Communication Might Be Linked to the Global Metabolic Disease Crisis

    Directory of Open Access Journals (Sweden)

    James E. Trosko

    2016-06-01

    Full Text Available The first anaerobic organism extracted energy for survival and reproduction from its source of nutrients, with the genetic means to ensure protection of its individual genome but also its species survival. While it had a means to communicate with its community via simple secreted molecules (“quorum sensing”, the eventual shift to an aerobic environment led to multi-cellular metazoan organisms, with evolutionary-selected genes to form extracellular matrices, stem cells, stem cell niches, and a family of gap junction or “connexin” genes. These germinal and somatic stem cells responded to extracellular signals that triggered intra-cellular signaling to regulate specific genes out of the total genome. These extra-cellular induced intra-cellular signals also modulated gap junctional intercellular communication (GJIC in order to regulate the new cellular functions of symmetrical and asymmetrical cell division, cell differentiation, modes of cell death, and senescence. Within the hierarchical and cybernetic concepts, differentiated by neurons organized in the brain of the Homo sapiens, the conscious mind led to language, abstract ideas, technology, myth-making, scientific reasoning, and moral decision–making, i.e., the creation of culture. Over thousands of years, this has created the current collision between biological and cultural evolution, leading to the global “metabolic disease” crisis.

  19. Cerebrospinal fluid corticosteroid levels and cortisol metabolism in patients with idiopathic intracranial hypertension: a link between 11beta-HSD1 and intracranial pressure regulation?

    Science.gov (United States)

    Sinclair, Alexandra J; Walker, Elizabeth A; Burdon, Michael A; van Beek, Andre P; Kema, Ido P; Hughes, Beverly A; Murray, Philip I; Nightingale, Peter G; Stewart, Paul M; Rauz, Saaeha; Tomlinson, Jeremy W

    2010-12-01

    The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. The aim was to characterize 11β-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11β-HSD1 activity after therapeutic weight loss in IIH. We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. 11β-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; Plevels correlated with weight loss (r=-0.512; P=0.018). Therapeutic weight loss in IIH is associated with a reduction in global 11β-HSD1 activity. Elevated 11β-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11β-HSD1 in IIH is needed, our results suggest that 11β-HSD1 inhibition may have therapeutic potential in IIH.

  20. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    International Nuclear Information System (INIS)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-01-01

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring

  1. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    Energy Technology Data Exchange (ETDEWEB)

    Girolami, Flavia [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Spalenza, Veronica [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Carletti, Monica [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Sacchi, Paola [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Rasero, Roberto [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Nebbia, Carlo [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy)

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring.

  2. Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes

    NARCIS (Netherlands)

    Yin, X.; Subramanian, S.; Willinger, C.M.; Chen, G.; Juhasz, P.; Courchesne, P.; Chen, B.H.; Li, X.; Hwang, S.J.; Fox, C.S.; O'Donnell, C.J.; Muntendam, P.; Fuster, V.; Bobeldijk-Pastorova, I.; Sookoian, S.C.; Pirola, C.J.; Gordon, N.; Adourian, A.; Larson, M.G.; Levy, D.

    2016-01-01

    Context: Metabolic dysregulation underlies key metabolic risk factors—obesity, dyslipidemia, and dysglycemia. Objective: To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor

  3. Operative Links

    DEFF Research Database (Denmark)

    Wistoft, Karen; Højlund, Holger

    2012-01-01

    educational goals, learning content, or value clarification. Health pedagogy is often a matter of retrospective rationalization rather than the starting point of planning. Health and risk behaviour approaches override health educational approaches. Conclusions: Operational links between health education......, health professionalism, and management strategies pose the foremost challenge. Operational links indicates cooperative levels that facilitate a creative and innovative effort across traditional professional boundaries. It is proposed that such links are supported by network structures, shared semantics...

  4. A weak link in metabolism: the metabolic capacity for glycine ...

    Indian Academy of Sciences (India)

    Prakash

    2009-12-03

    Dec 3, 2009 ... glyoxylate, threonine and trimethyllysine (carnitine synthesis), most of them ...... Participation of glycine in porphyrin biosynthesis. Eight glycine ...... normal and streptozotocin-induced diabetic rats; J. Dent. Res. 63 23–27.

  5. Inflammatory mediators accelerate metabolism of benzo[a]pyrene in rat alveolar type II cells: the role of enhanced cytochrome P450 1B1 expression

    Czech Academy of Sciences Publication Activity Database

    Šmerdová, Lenka; Neča, J.; Svobodová, J.; Topinka, Jan; Schmuczerová, Jana; Kubík, A.; Machala, M.; Vondráček, Jan

    2013-01-01

    Roč. 314, č. 1 (2013), s. 30-38 ISSN 0300-483X R&D Projects: GA ČR GAP503/11/0142 Grant - others:GA MZe(CZ) MZE0002716202; GA ČR(CZ) GAP503/11/1227 Program:GA Institutional research plan: CEZ:AV0Z50040702; CEZ:AV0Z50390703 Institutional support: RVO:68378041 ; RVO:68081707 Keywords : inflammation * CYP1B1 * polycyclic aromatic hydrocarbons Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.745, year: 2013

  6. Linking lab and field

    International Nuclear Information System (INIS)

    Cronje, P.B.

    1988-01-01

    The multitude of different supplements recommended for animals grazing natural pastures, which testifies to the need for a metabolic basis for supplementary feeding practices. The first approach to this problem was to simulate different feeding conditions in the laboratory, where the metabolic responses of body tissues to changes in the supply of purified nutrients could be studied using radioisotope techniques. The second step was to link these fundamental studies to field conditions. The results of these studies suggest that the efficiency of feed conversion and growth rates of ruminants grazing winter pastures in the highveld region of South Africa could be substantially improved by strategic supplementation with glucose precursors. Acetate clearance rate represents a valuable link in the process of applying information obtained from controlled laboratory experiments to field conditions. As this technique is inexpensive, quick and simple to carry out, it is ideally suited to application under field conditions where the use of isotopes is impractical. By providing a link with field conditions, it greatly extended the scope and practical application of isotope tracer techniques

  7. Dysregulated metabolism contributes to oncogenesis

    Science.gov (United States)

    Hirschey, Matthew D.; DeBerardinis, Ralph J.; Diehl, Anna Mae E.; Drew, Janice E.; Frezza, Christian; Green, Michelle F.; Jones, Lee W.; Ko, Young H.; Le, Anne; Lea, Michael A.; Locasale, Jason W.; Longo, Valter D.; Lyssiotis, Costas A.; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P.; Pedersen, Peter L.; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Sivanand, Sharanya; Vander Heiden, Matthew G.; Wellen, Kathryn E.

    2015-01-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069

  8. Operative Links

    DEFF Research Database (Denmark)

    Wistoft, Karen; Højlund, Holger

    2012-01-01

    and have been the object of great expectations concerning the ability to incorporate health concerns into every welfare area through health promotion strategies. The paper draws on results and analyses of a collective research project funded by the Danish National Research Council and carried out...... links' that indicate cooperative levels which facilitate a creative and innovative effort in disease prevention and health promotion targeted at children and adolescents - across traditional professional boundaries. It is proposed that such links are supported by network structures, shared semantics...

  9. Scandinavian links

    DEFF Research Database (Denmark)

    Matthiessen, Christian Wichmann; Knowles, Richard D.

    2014-01-01

    are impressive mega structures spanning international waterways. These waterways between the Baltic Sea and the North Sea have played major roles in history. The length of each of the crossings are around 20 km. The fixed links closes gaps between the Scandinavian and European motorway and rail networks...

  10. Cigarettes, genetic background, and menopausal timing: the presence of single nucleotide polymorphisms in cytochrome P450 genes is associated with increased risk of natural menopause in European-American smokers.

    Science.gov (United States)

    Butts, Samantha F; Sammel, Mary D; Greer, Christine; Rebbeck, Timothy R; Boorman, David W; Freeman, Ellen W

    2014-07-01

    This study aims to evaluate associations between variations in genes involved in the metabolism of environmental chemicals and steroid hormones and risk of menopause in smokers. Survival analysis was performed on 410 eligible participants from the Penn Ovarian Aging study (ongoing for 14 years), a cohort study of late-reproductive-age women. Single nucleotide polymorphisms at the following loci were studied: COMT Val158Met, CYP1B1*4 Asn452Ser, CYP1B1*3 Leu432Val, and CYP3A4*1B. Significant interactions between smoking and single nucleotide polymorphisms were observed in European-American carriers of CYP3A4*1B and CYP1B1*3, supporting a greater risk of menopause entry compared with those not carrying these alleles. Among CYP1B1*3 carriers, smokers had a greater risk of menopause entry than nonsmokers (adjusted hazard ratio [HR], 2.26; 95% CI, 1.4-3.67; median time to menopause, 10.42 and 11.07 y, respectively). No association between smoking and menopause was identified in CYP1B1 wild types. Among CYP3A4*1B carriers, smokers were at greater risk for menopause entry than nonsmokers (adjusted HR, 15.1; 95% CI, 3.31-69.2; median time to menopause, 11.36 and 13.91 y, respectively). Risk of menopause entry in CYP3A4 wild types who smoked was far lower (adjusted HR, 1.59; 95% CI, 1.03-2.44). Heavily smoking CYP1B1*3 carriers (adjusted HR, 3.0; 95% CI, 1.54-5.84; median time to menopause, 10.41 y) and heavily smoking CYP3A4*1B carriers (adjusted HR, 17.79; 95% CI, 3.21-98.65; median time to menopause, 5.09 y) had the greatest risk of menopause entry. Our finding that the risk of menopause entry in European-American smokers varies depending on genetic background represents a novel gene-environment interaction in reproductive aging.

  11. Metabolic Syndrome

    Science.gov (United States)

    Metabolic syndrome is a group of conditions that put you at risk for heart disease and diabetes. These conditions ... agree on the definition or cause of metabolic syndrome. The cause might be insulin resistance. Insulin is ...

  12. Metabolic complications in oncology

    International Nuclear Information System (INIS)

    Sycova-Mila, Z.

    2012-01-01

    Currently, a lot of space and time is devoted to the therapy of oncologic diseases itself. To reach the good therapy results, complex care of the oncologic patient is needed. Management of complications linked with the disease itself and management of complications emerged after administration of chemotherapy, radiotherapy or targeted therapy, plays a significant role. In addition to infectious, hematological, neurological, cardiac or other complications, metabolic complications are relatively extensive and serious. One of the most frequent metabolic complications in oncology is tumor lysis syndrome, hyperuricemia, hypercalcaemia and syndrome of inappropriate secretion of antidiuretic hormone. (author)

  13. Metabolic Adaptation to Muscle Ischemia

    Science.gov (United States)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  14. Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure

    DEFF Research Database (Denmark)

    Ghisari, Mandana; Eiberg, Hans; Long, Manhai

    2014-01-01

    BACKGROUND: We have previously reported that chemicals belonging to the persistent organic pollutants (POPs) such as perfluorinated compounds (PFAS) and polychlorinated biphenyls (PCBs) are risk factors in Breast Cancer (BC) development in Greenlandic Inuit women. The present case-control study...... on BC risk in Greenlandic Inuit women. METHODS: The study population consisted of 31 BC cases and 115 matched controls, with information on serum levels of POPs. Genotyping was conducted for CYP1A1 (Ile462Val; rs1048943), CYP1B1 (Leu432Val; rs1056836), COMT (Val158Met; rs4680), CYP17A1 (A1> A2; rs743572...... aimed to investigate the main effect of polymorphisms in genes involved in xenobiotic metabolism and estrogen biosynthesis, CYP1A1, CYP1B1, COMT and CYP17, CYP19 and the BRCA1 founder mutation in relation to BC risk and to explore possible interactions between the gene polymorphisms and serum POP levels...

  15. DNA Damage, Repair, and Cancer Metabolism

    Science.gov (United States)

    Turgeon, Marc-Olivier; Perry, Nicholas J. S.; Poulogiannis, George

    2018-01-01

    Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and DNA damage/DNA repair in cancer has yet to be appreciably explored. In this review, we examine the evidence connecting DNA damage and repair mechanisms with cell metabolism through three principal links. (1) Regulation of methyl- and acetyl-group donors through different metabolic pathways can impact DNA folding and remodeling, an essential part of accurate double strand break repair. (2) Glutamine, aspartate, and other nutrients are essential for de novo nucleotide synthesis, which dictates the availability of the nucleotide pool, and thereby influences DNA repair and replication. (3) Reactive oxygen species, which can increase oxidative DNA damage and hence the load of the DNA-repair machinery, are regulated through different metabolic pathways. Interestingly, while metabolism affects DNA repair, DNA damage can also induce metabolic rewiring. Activation of the DNA damage response (DDR) triggers an increase in nucleotide synthesis and anabolic glucose metabolism, while also reducing glutamine anaplerosis. Furthermore, mutations in genes involved in the DDR and DNA repair also lead to metabolic rewiring. Links between cancer metabolism and DNA damage/DNA repair are increasingly apparent, yielding opportunities to investigate the mechanistic basis behind potential metabolic vulnerabilities of a substantial fraction of tumors. PMID:29459886

  16. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area.

    Science.gov (United States)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. What is Metabolic Syndrome?

    Science.gov (United States)

    ... Intramural Research Home / Metabolic Syndrome Metabolic Syndrome Also known as What Is Metabolic syndrome ... metabolic risk factors to be diagnosed with metabolic syndrome. Metabolic Risk Factors A Large Waistline Having a large ...

  18. Ethanol potentiates the genotoxicity of the food-derived mammary carcinogen PhIP in human estrogen receptor-positive mammary cells: mechanistic support for lifestyle factors (cooked red meat and ethanol) associated with mammary cancer.

    Science.gov (United States)

    Malik, Durr-E-Shahwar; David, Rhiannon M; Gooderham, Nigel J

    2018-04-01

    Consumption of cooked/processed meat and ethanol are lifestyle risk factors in the aetiology of breast cancer. Cooking meat generates heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Epidemiology, mechanistic and animal studies indicate that PhIP is a mammary carcinogen that could be causally linked to breast cancer incidence; PhIP is DNA damaging, mutagenic and oestrogenic. PhIP toxicity involves cytochrome P450 (CYP1 family)-mediated metabolic activation to DNA-damaging species, and transcriptional responses through Aryl hydrocarbon receptor (AhR) and estrogen-receptor-α (ER-α). Ethanol consumption is a modifiable lifestyle factor strongly associated with breast cancer risk. Ethanol toxicity involves alcohol dehydrogenase metabolism to reactive acetaldehyde, and is also a substrate for CYP2E1, which when uncoupled generates reactive oxygen species (ROS) and DNA damage. Here, using human mammary cells that differ in estrogen-receptor status, we explore genotoxicity of PhIP and ethanol and mechanisms behind this toxicity. Treatment with PhIP (10 -7 -10 -4 M) significantly induced genotoxicity (micronuclei formation) preferentially in ER-α positive human mammary cell lines (MCF-7, ER-α+) compared to MDA-MB-231 (ER-α-) cells. PhIP-induced CYP1A2 in both cell lines but CYP1B1 was selectively induced in ER-α(+) cells. ER-α inhibition in MCF-7 cells attenuated PhIP-mediated micronuclei formation and CYP1B1 induction. PhIP-induced CYP2E1 and ROS via ER-α-STAT-3 pathway, but only in ER-α (+) MCF-7 cells. Importantly, simultaneous treatments of physiological concentrations ethanol (10 -3 -10 -1 M) with PhIP (10 -7 -10 -4 M) increased oxidative stress and genotoxicity in MCF-7 cells, compared to the individual chemicals. Collectively, these data offer a mechanistic basis for the increased risk of breast cancer associated with dietary cooked meat and ethanol lifestyle choices.

  19. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

  20. [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.

  1. Sex-linked dominant

    Science.gov (United States)

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  2. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    behind metabolic reactions, importance, and consequences with several ... required for drug action. ... lism, which is catalyzed by enzymes present in the above-men- ... catalyze the transfer of one atom of oxygen to a substrate produc-.

  3. Climate and vegetation in a semi-arid savanna: Development of a climate–vegetation response model linking plant metabolic performance to climate and the effects on forage availability for large herbivores

    Directory of Open Access Journals (Sweden)

    Armin H. Seydack

    2012-02-01

    Developing the climate–vegetation response model involved three main components, namely (1 defining indicators of forage availability to herbivores (nitrogen productivity, nitrogen quality, carbon-nutrient quality, (2 identifying herbivore species guilds of similar nutritional requirements with respect to these indicators [bulk feeders with tolerance to fibrous herbage (buffalo, waterbuck, bulk feeders with preference for high nitrogen quality forage (short grass preference grazers: blue wildebeest and zebra and selective feeders where dietary items of relatively high carbon-nutrient quality represented key forage resources (selective grazers: sable antelope, roan antelope, tsessebe, eland] and (3 developing a process model where the expected effects of plant metabolic responses to climate on key forage resources were made explicit. According to the climate–vegetation response model both shorter-term transient temperature acclimation pulses and longer-term shifts in plant metabolic functionality settings were predicted to have occurred in response to temperature trends over the past century. These temperature acclimation responses were expected to have resulted in transient pulses of increased forage availability (increased nitrogen- and carbon-nutrient quality, as well as the progressive long-term decline of the carbon-nutrient quality of forage. Conservation implications: The climate–vegetation response model represents a research framework for further studies contributing towards the enhanced understanding of landscape-scale functioning of savanna systems with reference to the interplay between climate, vegetation and herbivore population dynamics. Gains in such understanding can support sound conservation management.

  4. Metabolic Myopathies.

    Science.gov (United States)

    Tarnopolsky, Mark A

    2016-12-01

    Metabolic myopathies are genetic disorders that impair intermediary metabolism in skeletal muscle. Impairments in glycolysis/glycogenolysis (glycogen-storage disease), fatty acid transport and oxidation (fatty acid oxidation defects), and the mitochondrial respiratory chain (mitochondrial myopathies) represent the majority of known defects. The purpose of this review is to develop a diagnostic and treatment algorithm for the metabolic myopathies. The metabolic myopathies can present in the neonatal and infant period as part of more systemic involvement with hypotonia, hypoglycemia, and encephalopathy; however, most cases present in childhood or in adulthood with exercise intolerance (often with rhabdomyolysis) and weakness. The glycogen-storage diseases present during brief bouts of high-intensity exercise, whereas fatty acid oxidation defects and mitochondrial myopathies present during a long-duration/low-intensity endurance-type activity or during fasting or another metabolically stressful event (eg, surgery, fever). The clinical examination is often normal between acute events, and evaluation involves exercise testing, blood testing (creatine kinase, acylcarnitine profile, lactate, amino acids), urine organic acids (ketones, dicarboxylic acids, 3-methylglutaconic acid), muscle biopsy (histology, ultrastructure, enzyme testing), MRI/spectroscopy, and targeted or untargeted genetic testing. Accurate and early identification of metabolic myopathies can lead to therapeutic interventions with lifestyle and nutritional modification, cofactor treatment, and rapid treatment of rhabdomyolysis.

  5. Animal metabolism

    International Nuclear Information System (INIS)

    Walburg, H.E.

    1977-01-01

    Studies on placental transport included the following: clearance of tritiated water as a baseline measurement for transport of materials across perfused placentas; transport of organic and inorganic mercury across the perfused placenta of the guinea pig in late gestation; and transport of cadmium across the perfused placenta of the guinea pig in late gestation. Studies on cadmium absorption and metabolism included the following: intestinal absorption and retention of cadmium in neonatal rats; uptake and distribution of an oral dose of cadmium in postweanling male and female, iron-deficient and normal rats; postnatal viability and growth in rat pups after oral cadmium administration during gestation; and the effect of calcium and phosphorus on the absorption and toxicity of cadmium. Studies on gastrointestinal absorption and mineral metabolism included: uptake and distribution of orally administered plutonium complex compounds in male mice; gastrointestinal absorption of 144 Ce in the newborn mouse, rat, and pig; and gastrointestinal absorption of 95 Nb by rats of different ages. Studies on iodine metabolism included the following: influence of thyroid status and thiocyanate on iodine metabolism in the bovine; effects of simulated fallout radiation on iodine metabolism in dairy cattle; and effects of feeding iodine binding agents on iodine metabolism in the calf

  6. Nutrition, Epigenetics, and Metabolic Syndrome

    OpenAIRE

    Wang, Junjun; Wu, Zhenlong; Li, Defa; Li, Ning; Dindot, Scott V.; Satterfield, M. Carey; Bazer, Fuller W.; Wu, Guoyao

    2012-01-01

    Significance: Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults. Compelling experimental results also indicate that adverse effects of intrauterine growth restriction on offspring can be carried forward to subsequent generations through covalent modifications of DNA and core histones. Recent Advances: DNA methylation is catalyzed by S-adenosylmethionine-dependent DNA methyltransferases. Methylation...

  7. The Relation Between Metabolic Syndrome and Testosterone Level

    Directory of Open Access Journals (Sweden)

    Goel Prashant

    2018-03-01

    Full Text Available Metabolic syndrome is a group of conditions that increases the risk of developing diabetes and cardiovascular diseases. The most important pathogenic factors for metabolic syndrome are insulin resistance and obesity. The clinical presentation of this syndrome results from its influence on glucose and fat metabolism. Testosterone deficiency has a prevalence of up to 50% in men with metabolic syndrome and type 2 diabetes mellitus. A low level of testosterone is a factor for cardiovascular diseases and predictor of metabolic syndrome and, on the other hand, the components of metabolic syndrome can lead to low testosterone. This article reveals the bidirectional link between low testosterone level or hypogonadism and metabolic syndrome.

  8. [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.

  9. Diet-microbiota interactions as moderators of human metabolism

    DEFF Research Database (Denmark)

    Sonnenburg, Justin L; Bäckhed, Gert Fredrik

    2016-01-01

    It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity...

  10. Neuroinflammatory basis of metabolic syndrome.

    Science.gov (United States)

    Purkayastha, Sudarshana; Cai, Dongsheng

    2013-10-05

    Inflammatory reaction is a fundamental defense mechanism against threat towards normal integrity and physiology. On the other hand, chronic diseases such as obesity, type 2 diabetes, hypertension and atherosclerosis, have been causally linked to chronic, low-grade inflammation in various metabolic tissues. Recent cross-disciplinary research has led to identification of hypothalamic inflammatory changes that are triggered by overnutrition, orchestrated by hypothalamic immune system, and sustained through metabolic syndrome-associated pathophysiology. While continuing research is actively trying to underpin the identity and mechanisms of these inflammatory stimuli and actions involved in metabolic syndrome disorders and related diseases, proinflammatory IκB kinase-β (IKKβ), the downstream nuclear transcription factor NF-κB and some related molecules in the hypothalamus were discovered to be pathogenically significant. This article is to summarize recent progresses in the field of neuroendocrine research addressing the central integrative role of neuroinflammation in metabolic syndrome components ranging from obesity, glucose intolerance to cardiovascular dysfunctions.

  11. Journal of Biosciences | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Comparative docking studies of CYP1b1 and its PCG-associated mutant forms ... CYP1b1; molecular docking; molecular dynamics; oestradiol ... for docking were derived from molecular dynamics simulations of homology-modelled structures.

  12. Exploring the iron metabolism in multidrug resistant tuberculosis ...

    African Journals Online (AJOL)

    The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis. (MDR-TB) treated with second ...

  13. Exploring the iron metabolism in multidrug resistant tuberculosis ...

    African Journals Online (AJOL)

    The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis (MDR-TB) treated with second generation ...

  14. Metabolic reprogramming during neuronal differentiation.

    Science.gov (United States)

    Agostini, M; Romeo, F; Inoue, S; Niklison-Chirou, M V; Elia, A J; Dinsdale, D; Morone, N; Knight, R A; Mak, T W; Melino, G

    2016-09-01

    Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate-glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K-Akt-mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation.

  15. Xenobiotic Metabolism and Gut Microbiomes.

    Directory of Open Access Journals (Sweden)

    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.

  16. X-linked creatine transporter deficiency: clinical aspects and pathophysiology

    NARCIS (Netherlands)

    van de Kamp, J.M.; Mancini, G.M.; Salomons, G.S.

    2014-01-01

    Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter

  17. Nucleotide Metabolism

    DEFF Research Database (Denmark)

    Martinussen, Jan; Willemoës, M.; Kilstrup, Mogens

    2011-01-01

    Metabolic pathways are connected through their utilization of nucleotides as supplier of energy, allosteric effectors, and their role in activation of intermediates. Therefore, any attempt to exploit a given living organism in a biotechnological process will have an impact on nucleotide metabolis...

  18. Metabolic Surgery

    DEFF Research Database (Denmark)

    Pareek, Manan; Schauer, Philip R; Kaplan, Lee M

    2018-01-01

    The alarming rise in the worldwide prevalence of obesity is paralleled by an increasing burden of type 2 diabetes mellitus. Metabolic surgery is the most effective means of obtaining substantial and durable weight loss in individuals with obesity. Randomized trials have recently shown...... the superiority of surgery over medical treatment alone in achieving improved glycemic control, as well as a reduction in cardiovascular risk factors. The mechanisms seem to extend beyond the magnitude of weight loss alone and include improvements in incretin profiles, insulin secretion, and insulin sensitivity....... Moreover, observational data suggest that the reduction in cardiovascular risk factors translates to better patient outcomes. This review describes commonly used metabolic surgical procedures and their current indications and summarizes the evidence related to weight loss and glycemic outcomes. It further...

  19. Metabolic Syndrome

    Directory of Open Access Journals (Sweden)

    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

  20. Cellular metabolism

    International Nuclear Information System (INIS)

    Hildebrand, C.E.; Walters, R.A.

    1977-01-01

    Progress is reported on the following research projects: chromatin structure; the use of circular synthetic polydeoxynucleotides as substrates for the study of DNA repair enzymes; human cellular kinetic response following exposure to DNA-interactive compounds; histone phosphorylation and chromatin structure in cell proliferation; photoaddition products induced in chromatin by uv light; pollutants and genetic information transfer; altered RNA metabolism as a function of cadmium accumulation and intracellular distribution in cultured cells; and thymidylate chromophore destruction by water free radicals

  1. Linked data management

    CERN Document Server

    Hose, Katja; Schenkel, Ralf

    2014-01-01

    Linked Data Management presents techniques for querying and managing Linked Data that is available on today’s Web. The book shows how the abundance of Linked Data can serve as fertile ground for research and commercial applications. The text focuses on aspects of managing large-scale collections of Linked Data. It offers a detailed introduction to Linked Data and related standards, including the main principles distinguishing Linked Data from standard database technology. Chapters also describe how to generate links between datasets and explain the overall architecture of data integration systems based on Linked Data. A large part of the text is devoted to query processing in different setups. After presenting methods to publish relational data as Linked Data and efficient centralized processing, the book explores lookup-based, distributed, and parallel solutions. It then addresses advanced topics, such as reasoning, and discusses work related to read-write Linked Data for system interoperation. Desp...

  2. ER Stress and Lipid Metabolism in Adipocytes

    Directory of Open Access Journals (Sweden)

    Beth S. Zha

    2012-01-01

    Full Text Available The role of endoplasmic reticulum (ER stress is a rapidly emerging field of interest in the pathogenesis of metabolic diseases. Recent studies have shown that chronic activation of ER stress is closely linked to dysregulation of lipid metabolism in several metabolically important cells including hepatocytes, macrophages, β-cells, and adipocytes. Adipocytes are one of the major cell types involved in the pathogenesis of the metabolic syndrome. Recent advances in dissecting the cellular and molecular mechanisms involved in the regulation of adipogenesis and lipid metabolism indicate that activation of ER stress plays a central role in regulating adipocyte function. In this paper, we discuss the current understanding of the potential role of ER stress in lipid metabolism in adipocytes. In addition, we touch upon the interaction of ER stress and autophagy as well as inflammation. Inhibition of ER stress has the potential of decreasing the pathology in adipose tissue that is seen with energy overbalance.

  3. Flux networks in metabolic graphs

    International Nuclear Information System (INIS)

    Warren, P B; Queiros, S M Duarte; Jones, J L

    2009-01-01

    A metabolic model can be represented as a bipartite graph comprising linked reaction and metabolite nodes. Here it is shown how a network of conserved fluxes can be assigned to the edges of such a graph by combining the reaction fluxes with a conserved metabolite property such as molecular weight. A similar flux network can be constructed by combining the primal and dual solutions to the linear programming problem that typically arises in constraint-based modelling. Such constructions may help with the visualization of flux distributions in complex metabolic networks. The analysis also explains the strong correlation observed between metabolite shadow prices (the dual linear programming variables) and conserved metabolite properties. The methods were applied to recent metabolic models for Escherichia coli, Saccharomyces cerevisiae and Methanosarcina barkeri. Detailed results are reported for E. coli; similar results were found for other organisms

  4. Metabolic syndrome and cardiometabolic risk in PCOS.

    Science.gov (United States)

    Cussons, Andrea J; Stuckey, Bronwyn G A; Watts, Gerald F

    2007-02-01

    The cardiovascular risk associated with the polycystic ovary syndrome (PCOS) has recently attracted much interest. Women with PCOS are more likely to fulfill the diagnosis of the metabolic syndrome, a cluster of related cardiometabolic factors known to predict long-term risk of cardiovascular disease and type 2 diabetes. We review the literature pertaining to the link between the metabolic syndrome, cardiovascular disease, and PCOS. We focus on the influence of obesity and hyperandrogenemia, and on strategies for identifying cardiovascular risk in PCOS.

  5. Olfaction Under Metabolic Influences

    Science.gov (United States)

    2012-01-01

    Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis. PMID:22832483

  6. Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells.

    Science.gov (United States)

    Surichan, Somchaiya; Androutsopoulos, Vasilis P; Sifakis, Stavros; Koutala, Eleni; Tsatsakis, Aristidis; Arroo, Randolph R J; Boarder, Michael R

    2012-09-01

    Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells. Incubation of nobiletin in MCF7 cells produced one main metabolite (NM1) resulting from O-demethylation in either A or B rings of the flavone moiety. Among the three CYP1 isoforms, CYP1A1 exhibited the highest rate of metabolism of nobiletin in recombinant CYP microsomal enzymes. The intracellular CYP1-mediated bioconversion of the flavone was reduced in the presence of the CYP1A1 and CYP1B1-selective inhibitors α-napthoflavone and acacetin. In addition nobiletin induced CYP1 enzyme activity, CYP1A1 protein and CYP1B1 mRNA levels in MCF7 cells at a concentration dependent manner. MTT assays in MCF7 cells further revealed that nobiletin exhibited significantly lower IC50 (44 μM) compared to cells treated with nobiletin and CYP1A1 inhibitor (69 μM). FACS analysis demonstrated cell a cycle block at G1 phase that was attenuated in the presence of CYP1A1 inhibitor. Taken together the data suggests that the dietary flavonoid nobiletin induces its own metabolism and in turn enhances its cytostatic effect in MCF7 breast adenocarcinoma cells, via CYP1A1 and CYP1B1 upregulation. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. 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.

  8. Dynamic link: user's manual

    International Nuclear Information System (INIS)

    Harada, Hiroo; Asai, Kiyoshi; Kihara, Kazuhisa.

    1981-09-01

    The purpose of dynamic link facility is to link a load module dynamically only when it is used in execution time. The facility is very useful for development, execution and maintenance of a large scale computer program which is too big to be saved as one load module in main memory, or it is poor economy to save it due to many unused subroutines depending on an input. It is also useful for standardization and common utilization of programs. Standard usage of dynamic link facility of FACOM M-200 computer system, a software tool which analyzes the effect of dynamic link facility and application of dynamic link to nuclear codes are described. (author)

  9. An optimization model for metabolic pathways.

    Science.gov (United States)

    Planes, F J; Beasley, J E

    2009-10-15

    Different mathematical methods have emerged in the post-genomic era to determine metabolic pathways. These methods can be divided into stoichiometric methods and path finding methods. In this paper we detail a novel optimization model, based upon integer linear programming, to determine metabolic pathways. Our model links reaction stoichiometry with path finding in a single approach. We test the ability of our model to determine 40 annotated Escherichia coli metabolic pathways. We show that our model is able to determine 36 of these 40 pathways in a computationally effective manner.

  10. Bile Acid Metabolism in Liver Pathobiology

    Science.gov (United States)

    Chiang, John Y. L.; Ferrell, Jessica M.

    2018-01-01

    Bile acids facilitate intestinal nutrient absorption and biliary cholesterol secretion to maintain bile acid homeostasis, which is essential for protecting liver and other tissues and cells from cholesterol and bile acid toxicity. Bile acid metabolism is tightly regulated by bile acid synthesis in the liver and bile acid biotransformation in the intestine. Bile acids are endogenous ligands that activate a complex network of nuclear receptor farnesoid X receptor and membrane G protein-coupled bile acid receptor-1 to regulate hepatic lipid and glucose metabolic homeostasis and energy metabolism. The gut-to-liver axis plays a critical role in the regulation of enterohepatic circulation of bile acids, bile acid pool size, and bile acid composition. Bile acids control gut bacteria overgrowth, and gut bacteria metabolize bile acids to regulate host metabolism. Alteration of bile acid metabolism by high-fat diets, sleep disruption, alcohol, and drugs reshapes gut microbiome and causes dysbiosis, obesity, and metabolic disorders. Gender differences in bile acid metabolism, FXR signaling, and gut microbiota have been linked to higher prevalence of fatty liver disease and hepatocellular carcinoma in males. Alteration of bile acid homeostasis contributes to cholestatic liver diseases, inflammatory diseases in the digestive system, obesity, and diabetes. Bile acid-activated receptors are potential therapeutic targets for developing drugs to treat metabolic disorders. PMID:29325602

  11. Carbohydrate Metabolism Disorders

    Science.gov (United States)

    ... metabolic disorder, something goes wrong with this process. Carbohydrate metabolism disorders are a group of metabolic disorders. Normally your enzymes break carbohydrates down into glucose (a type of sugar). If ...

  12. Comprehensive metabolic panel

    Science.gov (United States)

    Metabolic panel - comprehensive; Chem-20; SMA20; Sequential multi-channel analysis with computer-20; SMAC20; Metabolic panel 20 ... Chernecky CC, Berger BJ. Comprehensive metabolic panel (CMP) - blood. In: ... Tests and Diagnostic Procedures . 6th ed. St Louis, MO: ...

  13. Sensitivity of animals to chemical compounds links to metabolic rate.

    NARCIS (Netherlands)

    Baas, J.; Kooijman, S.A.L.M.

    2015-01-01

    Ecotoxicological studies have shown considerable variation in species sensitivity for chemical compounds, but general patterns in sensitivity are still not known. A better understanding of this sensitivity is important in the context of environmental risk assessment but also in a more general

  14. Mitochondrial Metabolism - Neglected Link of CancerTransformation and Treatment

    Czech Academy of Sciences Publication Activity Database

    Pokorný, Jiří; Jandová, Anna; Nedbalová, M.; Jelínek, František; Cifra, Michal; Kučera, Ondřej; Havelka, Daniel; Vrba, J.; Vrba, J.; Čoček, A.; Kobilková, J.

    2012-01-01

    Roč. 113, č. 2 (2012), s. 81-94 ISSN 1214-6994 R&D Projects: GA ČR(CZ) GAP102/11/0649 Institutional support: RVO:67985882 Keywords : Electromagnetic fields * Cellular biophysics * Cancer Subject RIV: JB - Sensors, Measurment, Regulation

  15. Circadian Biology and Sleep: Missing Links in Obesity and Metabolism

    Science.gov (United States)

    2009-05-01

    large-scale N-ethyl-N- nitrosourea (ENU) mutagenesis screen using a wide range of nervous system and behavioral phenotypes, we have identified new...physiology. In addition to storing energy in the form of triglycerides, WAT is now known to act as an active endocrine tissue via the synthesis and

  16. Scaling of Metabolic Scaling within Physical Limits

    Directory of Open Access Journals (Sweden)

    Douglas S. Glazier

    2014-10-01

    Full Text Available Both the slope and elevation of scaling relationships between log metabolic rate and log body size vary taxonomically and in relation to physiological or developmental state, ecological lifestyle and environmental conditions. Here I discuss how the recently proposed metabolic-level boundaries hypothesis (MLBH provides a useful conceptual framework for explaining and predicting much, but not all of this variation. This hypothesis is based on three major assumptions: (1 various processes related to body volume and surface area exert state-dependent effects on the scaling slope for metabolic rate in relation to body mass; (2 the elevation and slope of metabolic scaling relationships are linked; and (3 both intrinsic (anatomical, biochemical and physiological and extrinsic (ecological factors can affect metabolic scaling. According to the MLBH, the diversity of metabolic scaling relationships occurs within physical boundary limits related to body volume and surface area. Within these limits, specific metabolic scaling slopes can be predicted from the metabolic level (or scaling elevation of a species or group of species. In essence, metabolic scaling itself scales with metabolic level, which is in turn contingent on various intrinsic and extrinsic conditions operating in physiological or evolutionary time. The MLBH represents a “meta-mechanism” or collection of multiple, specific mechanisms that have contingent, state-dependent effects. As such, the MLBH is Darwinian in approach (the theory of natural selection is also meta-mechanistic, in contrast to currently influential metabolic scaling theory that is Newtonian in approach (i.e., based on unitary deterministic laws. Furthermore, the MLBH can be viewed as part of a more general theory that includes other mechanisms that may also affect metabolic scaling.

  17. Visualisierung von typisierten Links in Linked Data

    Directory of Open Access Journals (Sweden)

    Georg Neubauer

    2017-09-01

    Full Text Available Das Themengebiet der Arbeit behandelt Visualisierungen von typisierten Links in Linked Data. Die wissenschaftlichen Gebiete, die im Allgemeinen den Inhalt des Beitrags abgrenzen, sind das Semantic Web, das Web of Data und Informationsvisualisierung. Das Semantic Web, das von Tim Berners Lee 2001 erfunden wurde, stellt eine Erweiterung zum World Wide Web (Web 2.0 dar. Aktuelle Forschungen beziehen sich auf die Verknüpfbarkeit von Informationen im World Wide Web. Um es zu ermöglichen, solche Verbindungen wahrnehmen und verarbeiten zu können sind Visualisierungen die wichtigsten Anforderungen als Hauptteil der Datenverarbeitung. Im Zusammenhang mit dem Sematic Web werden Repräsentationen von zuhammenhängenden Informationen anhand von Graphen gehandhabt. Der Grund des Entstehens dieser Arbeit ist in erster Linie die Beschreibung der Gestaltung von Linked Data-Visualisierungskonzepten, deren Prinzipien im Rahmen einer theoretischen Annäherung eingeführt werden. Anhand des Kontexts führt eine schrittweise Erweiterung der Informationen mit dem Ziel, praktische Richtlinien anzubieten, zur Vernetzung dieser ausgearbeiteten Gestaltungsrichtlinien. Indem die Entwürfe zweier alternativer Visualisierungen einer standardisierten Webapplikation beschrieben werden, die Linked Data als Netzwerk visualisiert, konnte ein Test durchgeführt werden, der deren Kompatibilität zum Inhalt hatte. Der praktische Teil behandelt daher die Designphase, die Resultate, und zukünftige Anforderungen des Projektes, die durch die Testung ausgearbeitet wurden.

  18. Introduction to the Thematic Minireview Series: Brain glycogen metabolism.

    Science.gov (United States)

    Carlson, Gerald M; Dienel, Gerald A; Colbran, Roger J

    2018-05-11

    The synthesis of glycogen allows for efficient intracellular storage of glucose molecules in a soluble form that can be rapidly released to enter glycolysis in response to energy demand. Intensive studies of glucose and glycogen metabolism, predominantly in skeletal muscle and liver, have produced innumerable insights into the mechanisms of hormone action, resulting in the award of several Nobel Prizes over the last one hundred years. Glycogen is actually present in all cells and tissues, albeit at much lower levels than found in muscle or liver. However, metabolic and physiological roles of glycogen in other tissues are poorly understood. This series of Minireviews summarizes what is known about the enzymes involved in brain glycogen metabolism and studies that have linked glycogen metabolism to multiple brain functions involving metabolic communication between astrocytes and neurons. Recent studies unexpectedly linking some forms of epilepsy to mutations in two poorly understood proteins involved in glycogen metabolism are also reviewed. © 2018 Carlson et al.

  19. Linking open vocabularies

    CERN Document Server

    Greifender, Elke; Seadle, Michael

    2013-01-01

    Linked Data (LD), Linked Open Data (LOD) and generating a web of data, present the new knowledge sharing frontier. In a philosophical context, LD is an evolving environment that reflects humankinds' desire to understand the world by drawing on the latest technologies and capabilities of the time. LD, while seemingly a new phenomenon did not emerge overnight; rather it represents the natural progression by which knowledge structures are developed, used, and shared. Linked Open Vocabularies is a significant trajectory of LD. Linked Open Vocabularies targets vocabularies that have traditionally b

  20. 4-Hydroxyestradiol induces mammary epithelial cell transformation through Nrf2-mediated heme oxygenase-1 overexpression

    OpenAIRE

    Park, Sin-Aye; Lee, Mee-Hyun; Na, Hye-Kyung; Surh, Young-Joon

    2016-01-01

    Estrogen (17?-estradiol, E2) undergoes oxidative metabolism by CYP1B1 to form 4-hydroxyestradiol (4-OHE2), a putative carcinogenic metabolite of estrogen. Our previous study showed that 4-OHE2-induced production of reactive oxygen species contributed to neoplastic transformation of human breast epithelial (MCF-10A) cells. In this study, 4-OHE2, but not E2, increased the expression of heme oxygenase-1 (HO-1), a sensor and regulator of oxidative stress, in MCF-10A cells. Silencing the HO-1 gene...

  1. Metabolic syndrome as a risk factor for neurological disorders.

    Science.gov (United States)

    Farooqui, Akhlaq A; Farooqui, Tahira; Panza, Francesco; Frisardi, Vincenza

    2012-03-01

    The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders. © Springer Basel AG 2011

  2. Gut microbiome and lipid metabolism : from associations to mechanisms

    NARCIS (Netherlands)

    Wang, Zheng; Koonen, Debby; Hofker, Marten; Fu, Jingyuan

    Purpose of review The gut microbiome has now been convincingly linked to human metabolic health but the underlying causality and mechanisms remain poorly understood. This review focuses on the recent progress in establishing the associations between gut microbiome species and lipid metabolism in

  3. Restructuring cities for sustainability : A metabolism approach

    NARCIS (Netherlands)

    Schremmer, C.; Stead, D.

    2009-01-01

    The FP7-funded SUME project (Sustainable Urban Metabolism for Europe) is focusing on the way how future urban systems can be designed to be consistently less damaging to the environment and particularly to climate change than in the present. Urban development scenarios linked with an agent-based

  4. Translation Factors Specify Cellular Metabolic State

    Directory of Open Access Journals (Sweden)

    Juan Mata

    2016-08-01

    Full Text Available In this issue of Cell Reports, Shah et al. present evidence that a subcomplex of the eIF3 translation initiation factor regulates translation of mRNAs encoding components of the mitochondrial electron transport chain and glycolytic enzymes, thus linking translational control with energy metabolism.

  5. Let's "Downscale" Linked Data

    NARCIS (Netherlands)

    Gueret, C.D.M.; de Boer, V.; Schlobach, K.S.

    2014-01-01

    Open data policies and linked data publication are powerful tools for increasing transparency, participatory governance, and accountability. The linked data community proudly emphasizes the economic and societal impact such technology shows. But a closer look proves that the design and deployment of

  6. Let's "Downscale" Linked Data

    NARCIS (Netherlands)

    Gueret, Christophe; de Boer, Victor; Schlobach, Stefan

    2014-01-01

    Open data policies and linked data publication are powerful tools for increasing transparency, participatory governance, and accountability. A closer look at linked data technologies, however, proves that their design and deployment exclude the majority of the world’s population. It will take small

  7. Weierstrass polynomials for links

    DEFF Research Database (Denmark)

    Hansen, Vagn Lundsgaard

    1997-01-01

    There is a natural way of identifying links in3-space with polynomial covering spaces over thecircle. Thereby any link in 3-space can be definedby a Weierstrass polynomial over the circle. Theequivalence relation for covering spaces over thecircle is, however, completely different from...

  8. [FETAL PROGRAMMING OF METABOLIC DISORDERS].

    Science.gov (United States)

    Varadinova, M R; Metodieva, R; Boyadzhieva, N

    2015-01-01

    Our knowledge of fetal programming has developed notably over the years and recent data suggest that an unbalanced diet prior and during pregnancy can have early-onset and long-lasting consequences on the health of the offspring. Specific negative influences of high dietary glucose and lipid consumption, as well as undernutrition, are associated with development of metabolic syndrome, insulin resistance and diabetes in the offspring. The mechanisms underlying the effects of maternal hyperglycemia on the fetus may involve structural, metabolic and epigenetic changes. The aim of this review is to illustrate how adverse intrauterine environment may influence molecular modifications in the fetus and cause epigenetic alterations in particular. It has been demonstrated that prenatal epigenetic modifications may be linked to the pathogenesis and progression of the adult chronic disorders. Studies on epigenetic alterations will contribute to a better understanding of the long-term effects of in utero exposure and may open new perspectives for disease prevention and treatment.

  9. 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.

  10. Global Metabolic Reconstruction and Metabolic Gene Evolution in the Cattle Genome

    Science.gov (United States)

    Kim, Woonsu; Park, Hyesun; Seo, Seongwon

    2016-01-01

    The sequence of cattle genome provided a valuable opportunity to systematically link genetic and metabolic traits of cattle. The objectives of this study were 1) to reconstruct genome-scale cattle-specific metabolic pathways based on the most recent and updated cattle genome build and 2) to identify duplicated metabolic genes in the cattle genome for better understanding of metabolic adaptations in cattle. A bioinformatic pipeline of an organism for amalgamating genomic annotations from multiple sources was updated. Using this, an amalgamated cattle genome database based on UMD_3.1, was created. The amalgamated cattle genome database is composed of a total of 33,292 genes: 19,123 consensus genes between NCBI and Ensembl databases, 8,410 and 5,493 genes only found in NCBI or Ensembl, respectively, and 266 genes from NCBI scaffolds. A metabolic reconstruction of the cattle genome and cattle pathway genome database (PGDB) was also developed using Pathway Tools, followed by an intensive manual curation. The manual curation filled or revised 68 pathway holes, deleted 36 metabolic pathways, and added 23 metabolic pathways. Consequently, the curated cattle PGDB contains 304 metabolic pathways, 2,460 reactions including 2,371 enzymatic reactions, and 4,012 enzymes. Furthermore, this study identified eight duplicated genes in 12 metabolic pathways in the cattle genome compared to human and mouse. Some of these duplicated genes are related with specific hormone biosynthesis and detoxifications. The updated genome-scale metabolic reconstruction is a useful tool for understanding biology and metabolic characteristics in cattle. There has been significant improvements in the quality of cattle genome annotations and the MetaCyc database. The duplicated metabolic genes in the cattle genome compared to human and mouse implies evolutionary changes in the cattle genome and provides a useful information for further research on understanding metabolic adaptations of cattle. PMID

  11. Link to paper

    Data.gov (United States)

    U.S. Environmental Protection Agency — Link to the paper. This dataset is associated with the following publication: Naile, J., A.W. Garrison, J. Avants, and J. Washington. Isomers/enantiomers of...

  12. CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cells

    International Nuclear Information System (INIS)

    Androutsopoulos, Vasilis P.; Ruparelia, Ketan; Arroo, Randolph R.J.; Tsatsakis, Aristidis M.; Spandidos, Demetrios A.

    2009-01-01

    Among the different mechanisms proposed to explain the cancer-protecting effect of dietary flavonoids, substrate-like interactions with cytochrome P450 CYP1 enzymes have recently been explored. In the present study, the metabolism of the flavonoids chrysin, baicalein, scutellarein, sinensetin and genkwanin by recombinant CYP1A1, CYP1B1 and CYP1A2 enzymes, as well as their antiproliferative activity in MDA-MB-468 human breast adenocarcinoma and MCF-10A normal breast cell lines, were investigated. Baicalein and 6-hydroxyluteolin were the only conversion products of chrysin and scutellarein metabolism by CYP1 family enzymes, respectively, while baicalein itself was not metabolized further. Sinensetin and genkwanin produced a greater number of metabolites and were shown to inhibit strongly in vitro proliferation of MDA-MB-468 cells at submicromolar and micromolar concentrations, respectively, without essentially affecting the viability of MCF-10A cells. Cotreatment of the CYP1 family inhibitor acacetin reversed the antiproliferative activity noticed for the two flavones in MDA-MB-468 cells to 13 and 14 μM respectively. In contrast chrysin, baicalein and scutellarein inhibited proliferation of MDA-MB-468 cells to a lesser extent than sinensetin and genkwanin. The metabolism of genkwanin to apigenin and of chrysin to baicalein was favored by CYP1B1 and CYP1A1, respectively. Taken together the data suggests that CYP1 family enzymes enhance the antiproliferative activity of dietary flavonoids in breast cancer cells, through bioconversion to more active products.

  13. Comprehensive metabolic characterization of serum osteocalcin action in a large non-diabetic sample

    DEFF Research Database (Denmark)

    Entenmann, Lukas; Pietzner, Maik; Artati, Anna

    2017-01-01

    to kynurenine points towards a pro-inflammatory state with increasing OCN. Inverse relations with intermediates of branch-chained amino acid metabolism suggest a link to energy metabolism. Finally, urinary surrogate markers of smoking highlight its adverse effect on OCN metabolism. In conclusion, the present...

  14. The Missing Link

    DEFF Research Database (Denmark)

    Schultz, Laura Luise

    2014-01-01

    Paper presented at A Valentine to Gertrude Stein. The Reception of Gertrude Stein in the Arts and Humanities, held at the University of Copenhagen 8. - 10. May 2014, in collaboration with the universities of Ghent and Linköping......Paper presented at A Valentine to Gertrude Stein. The Reception of Gertrude Stein in the Arts and Humanities, held at the University of Copenhagen 8. - 10. May 2014, in collaboration with the universities of Ghent and Linköping...

  15. Metabolism and virulence in Neisseria meningitidis

    Directory of Open Access Journals (Sweden)

    Christoph eSchoen

    2014-08-01

    Full Text Available A longstanding question in infection biology addresses the genetic basis for invasive behaviour in commensal pathogens. A prime example for such a pathogen is Neisseria meningitidis. On the one hand it is a harmless commensal bacterium exquisitely adapted to humans, and on the other hand it sometimes behaves like a ferocious pathogen causing potentially lethal disease such as sepsis and acute bacterial meningitis. Despite the lack of a classical repertoire of virulence genes in N. meningitidis separating commensal from invasive strains, molecular epidemiology suggests that carriage and invasive strains belong to genetically distinct populations. In recent years, it has become increasingly clear that metabolic adaptation enables meningococci to exploit host resources, supporting the concept of nutritional virulence as a crucial determinant of invasive capability. Here, we discuss the contribution of core metabolic pathways in the context of colonization and invasion with special emphasis on results from genome-wide surveys. The metabolism of lactate, the oxidative stress response, and, in particular, glutathione metabolism as well as the denitrification pathway provide examples of how meningococcal metabolism is intimately linked to pathogenesis. We further discuss evidence from genome-wide approaches regarding potential metabolic differences between strains from hyperinvasive and carriage lineages and present new data assessing in vitro growth differences of strains from these two populations. We hypothesize that strains from carriage and hyperinvasive lineages differ in the expression of regulatory genes involved particularly in stress responses and amino acid metabolism under infection conditions.

  16. Curcumin Implants, not Curcumin Diet Inhibits Estrogen-Induced Mammary Carcinogenesis in ACI Rats

    Science.gov (United States)

    Bansal, Shyam S.; kausar, Hina; Vadhanam, Manicka V.; Ravoori, Srivani; Pan, Jianmin; Rai, Shesh N.; Gupta, Ramesh C.

    2014-01-01

    Curcumin is widely known for its anti-oxidant, anti-inflammatory and anti-proliferative activities in cell culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvents oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female ACI rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2-cm; 200 mg each; 20% drug load) 4 days prior to grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Implants were changed after 4½ months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2±1 vs 5±3; p=0.001) and tumor volume (184±198 mm3 vs 280±141 mm3; p=0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in presence of E2. Since CYP1A and 3A4 metabolize most of the E2 to its non-carcinogenic 2-OH metabolite and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by HPLC showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered. PMID:24501322

  17. Linked Ocean Data

    Science.gov (United States)

    Leadbetter, Adam; Arko, Robert; Chandler, Cynthia; Shepherd, Adam

    2014-05-01

    "Linked Data" is a term used in Computer Science to encapsulate a methodology for publishing data and metadata in a structured format so that links may be created and exploited between objects. Berners-Lee (2006) outlines the following four design principles of a Linked Data system: Use Uniform Resource Identifiers (URIs) as names for things. Use HyperText Transfer Protocol (HTTP) URIs so that people can look up those names. When someone looks up a URI, provide useful information, using the standards (Resource Description Framework [RDF] and the RDF query language [SPARQL]). Include links to other URIs so that they can discover more things. In 2010, Berners-Lee revisited his original design plan for Linked Data to encourage data owners along a path to "good Linked Data". This revision involved the creation of a five star rating system for Linked Data outlined below. One star: Available on the web (in any format). Two stars: Available as machine-readable structured data (e.g. An Excel spreadsheet instead of an image scan of a table). Three stars: As two stars plus the use of a non-proprietary format (e.g. Comma Separated Values instead of Excel). Four stars: As three stars plus the use of open standards from the World Wide Web Commission (W3C) (i.e. RDF and SPARQL) to identify things, so that people can point to your data and metadata. Five stars: All the above plus link your data to other people's data to provide context Here we present work building on the SeaDataNet common vocabularies served by the NERC Vocabulary Server, connecting projects such as the Rolling Deck to Repository (R2R) and the Biological and Chemical Oceanography Data Management Office (BCO-DMO) and other vocabularies such as the Marine Metadata Interoperability Ontology Register and Repository and the NASA Global Change Master Directory to create a Linked Ocean Data cloud. Publishing the vocabularies and metadata in standard RDF XML and exposing SPARQL endpoints renders them five-star Linked

  18. Metabolism and disease

    National Research Council Canada - National Science Library

    Grodzicker, Terri; Stewart, David J; Stillman, Bruce

    2011-01-01

    ...), cellular, organ system (cardiovascular, bone), and organismal (timing and life span) scales. Diseases impacted by metabolic imbalance or dysregulation that were covered in detail included diabetes, obesity, metabolic syndrome, and cancer...

  19. Comprehensive metabolic characterization of serum osteocalcin action in a large non-diabetic sample.

    Directory of Open Access Journals (Sweden)

    Lukas Entenmann

    Full Text Available Recent research suggested a metabolic implication of osteocalcin (OCN in e.g. insulin sensitivity or steroid production. We used an untargeted metabolomics approach by analyzing plasma and urine samples of 931 participants using mass spectrometry to reveal further metabolic actions of OCN. Several detected relations between OCN and metabolites were strongly linked to renal function, however, a number of associations remained significant after adjustment for renal function. Intermediates of proline catabolism were associated with OCN reflecting the implication in bone metabolism. The association to kynurenine points towards a pro-inflammatory state with increasing OCN. Inverse relations with intermediates of branch-chained amino acid metabolism suggest a link to energy metabolism. Finally, urinary surrogate markers of smoking highlight its adverse effect on OCN metabolism. In conclusion, the present study provides a read-out of metabolic actions of OCN. However, most of the associations were weak arguing for a limited role of OCN in whole-body metabolism.

  20. Comprehensive metabolic characterization of serum osteocalcin action in a large non-diabetic sample.

    Science.gov (United States)

    Entenmann, Lukas; Pietzner, Maik; Artati, Anna; Hannemann, Anke; Henning, Ann-Kristin; Kastenmüller, Gabi; Völzke, Henry; Nauck, Matthias; Adamski, Jerzy; Wallaschofski, Henri; Friedrich, Nele

    2017-01-01

    Recent research suggested a metabolic implication of osteocalcin (OCN) in e.g. insulin sensitivity or steroid production. We used an untargeted metabolomics approach by analyzing plasma and urine samples of 931 participants using mass spectrometry to reveal further metabolic actions of OCN. Several detected relations between OCN and metabolites were strongly linked to renal function, however, a number of associations remained significant after adjustment for renal function. Intermediates of proline catabolism were associated with OCN reflecting the implication in bone metabolism. The association to kynurenine points towards a pro-inflammatory state with increasing OCN. Inverse relations with intermediates of branch-chained amino acid metabolism suggest a link to energy metabolism. Finally, urinary surrogate markers of smoking highlight its adverse effect on OCN metabolism. In conclusion, the present study provides a read-out of metabolic actions of OCN. However, most of the associations were weak arguing for a limited role of OCN in whole-body metabolism.

  1. Metabolic Engineering X Conference

    Energy Technology Data Exchange (ETDEWEB)

    Flach, Evan [American Institute of Chemical Engineers

    2015-05-07

    The International Metabolic Engineering Society (IMES) and the Society for Biological Engineering (SBE), both technological communities of the American Institute of Chemical Engineers (AIChE), hosted the Metabolic Engineering X Conference (ME-X) on June 15-19, 2014 at the Westin Bayshore in Vancouver, British Columbia. It attracted 395 metabolic engineers from academia, industry and government from around the globe.

  2. Link til hjemmesider

    DEFF Research Database (Denmark)

    Bervild, Charlotte

    2015-01-01

    Link til læringsobjekter/undervisningsportalhttp://videoportal.ucc.dk/channel/10492641/charlotte-bervilds-undervisninghttp://videoportal.ucc.dk/video/8248508/3d-printer-v-lektor-charlotte-bervildFotoblog:http://charlottebervild.blogspot.dk/2008/10/fotocollager-af-charlotte-bervild.html......Link til læringsobjekter/undervisningsportalhttp://videoportal.ucc.dk/channel/10492641/charlotte-bervilds-undervisninghttp://videoportal.ucc.dk/video/8248508/3d-printer-v-lektor-charlotte-bervildFotoblog:http://charlottebervild.blogspot.dk/2008/10/fotocollager-af-charlotte-bervild.html...

  3. Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

    OpenAIRE

    Wang, Jing; Long, Cheng; Zhang, Haijun; Zhang, Yanan; Wang, Hao; Yue, Hongyuan; Wang, Xiaocui; Wu, Shugeng; Qi, Guanghai

    2016-01-01

    Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and die...

  4. Basal metabolism in tropical birds: Latitude, altitude, and the 'pace of life'

    OpenAIRE

    Londoño, GA; Chappell, MA; Castañeda, MDR; Jankowski, JE; Robinson, SK

    2015-01-01

    © 2014 The Authors. Life history varies across latitudes, with the 'pace of life' being 'slower' in tropical regions. Because life history is coupled to energy metabolism via allocation tradeoffs and links between performance capacity and energy use, low metabolic intensity is expected in tropical animals. Low metabolism has been reported for lowland tropical birds, but it is unclear if this is due to 'slow' life history or to a warm, stable environment. We measured basal metabolic rates (BMR...

  5. Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging

    OpenAIRE

    Palmer, Clovis S.; Palchaudhuri, Riya; Albargy, Hassan; Abdel-Mohsen, Mohamed; Crowe, Suzanne M.

    2018-01-01

    An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impa...

  6. Linking Microbiota to Human Diseases

    DEFF Research Database (Denmark)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, F

    2015-01-01

    The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2...

  7. 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/

  8. Engineering Cellular Metabolism

    DEFF Research Database (Denmark)

    Nielsen, Jens; Keasling, Jay

    2016-01-01

    Metabolic engineering is the science of rewiring the metabolism of cells to enhance production of native metabolites or to endow cells with the ability to produce new products. The potential applications of such efforts are wide ranging, including the generation of fuels, chemicals, foods, feeds...... of metabolic engineering and will discuss how new technologies can enable metabolic engineering to be scaled up to the industrial level, either by cutting off the lines of control for endogenous metabolism or by infiltrating the system with disruptive, heterologous pathways that overcome cellular regulation....

  9. Helically linked mirror arrangement

    International Nuclear Information System (INIS)

    Ranjan, P.

    1986-08-01

    A scheme is described for helical linking of mirror sections, which endeavors to combine the better features of toroidal and mirror devices by eliminating the longitudinal loss of mirror machines, having moderately high average β and steady state operation. This scheme is aimed at a device, with closed magnetic surfaces having rotational transform for equilibrium, one or more axisymmetric straight sections for reduced radial loss, a simple geometrical axis for the links and an overall positive magnetic well depth for stability. We start by describing several other attempts at linking of mirror sections, made both in the past and the present. Then a description of our helically linked mirror scheme is given. This example has three identical straight sections connected by three sections having helical geometric axes. A theoretical analysis of the magnetic field and single-particle orbits in them leads to the conclusion that most of the passing particles would be confined in the device and they would have orbits independent of pitch angle under certain conditions. Numerical results are presented, which agree well with the theoretical results as far as passing particle orbits are concerned

  10. Analysis of Aspergillus nidulans metabolism at the genome-scale

    DEFF Research Database (Denmark)

    David, Helga; Ozcelik, İlknur Ş; Hofmann, Gerald

    2008-01-01

    of relevant secondary metabolites, was reconstructed based on detailed metabolic reconstructions available for A. niger and Saccharomyces cerevisiae, and information on the genetics, biochemistry and physiology of A. nidulans. Thereby, it was possible to identify metabolic functions without a gene associated...... a function. Results: In this work, we have manually assigned functions to 472 orphan genes in the metabolism of A. nidulans, by using a pathway-driven approach and by employing comparative genomics tools based on sequence similarity. The central metabolism of A. nidulans, as well as biosynthetic pathways......, in an objective and systematic manner. The functional assignments served as a basis to develop a mathematical model, linking 666 genes (both previously and newly annotated) to metabolic roles. The model was used to simulate metabolic behavior and additionally to integrate, analyze and interpret large-scale gene...

  11. Metabolic changes in cancer: beyond the Warburg effect

    Institute of Scientific and Technical Information of China (English)

    Weihua Wu; Shimin Zhao

    2013-01-01

    Altered metabolism is one of the hallmarks of cancer cells.The best-known metabolic abnormality in cancer cells is the Warburg effect,which demonstrates an increased glycolysis even in the presence of oxygen.However,tumor-related metabolic abnormalities are not limited to altered balance between glucose fermentation and oxidative phosphorylation.Key tumor genes such as p53 and c-myc are found to be master regulators of metabolism.Metabolic enzymes such as succinate dehydrogenase,fumarate hydratase,pyruvate kinase,and isocitrate dehydrogenase mutations or expressing level alterations are all linked to tumorigenesis.In this review,we introduce some of the cancer-associated metabolic disorders and current understanding of their molecular tumorigenic mechanisms.

  12. Metabolic markers in sports medicine.

    Science.gov (United States)

    Banfi, Giuseppe; Colombini, Alessandra; Lombardi, Giovanni; Lubkowska, Anna

    2012-01-01

    Physical exercise induces adaptations in metabolism considered beneficial for health. Athletic performance is linked to adaptations, training, and correct nutrition in individuals with genetic traits that can facilitate such adaptations. Intense and continuous exercise, training, and competitions, however, can induce changes in the serum concentrations of numerous laboratory parameters. When these modifications, especially elevated laboratory levels, result outside the reference range, further examinations are ordered or participation in training and competition is discontinued or sports practice loses its appeal. In order to correctly interpret commonly used laboratory data, laboratory professionals and sport physicians need to know the behavior of laboratory parameters during and after practice and competition. We reviewed the literature on liver, kidney, muscle, heart, energy, and bone parameters in athletes with a view to increase the knowledge about clinical chemistry applied to sport and to stimulate studies in this field. In liver metabolism, the interpretation of serum aminotransferases concentration in athletes should consider the release of aspartate aminotransferase (AST) from muscle and of alanine aminotransferase (ALT) mainly from the liver, when bilirubin can be elevated because of continuous hemolysis, which is typical of exercise. Muscle metabolism parameters such as creatine kinase (CK) are typically increased after exercise. This parameter can be used to interpret the physiological release of CK from muscle, its altered release due to rhabdomyolysis, or incomplete recovery due to overreaching or trauma. Cardiac markers are released during exercise, and especially endurance training. Increases in these markers should not simply be interpreted as a signal of cardiac damage or wall stress but rather as a sign of regulation of myocardial adaptation. Renal function can be followed in athletes by measuring serum creatinine concentration, but it should

  13. Cardiorenal metabolic syndrome in the African diaspora: rationale for including chronic kidney disease in the metabolic syndrome definition.

    Science.gov (United States)

    Lea, Janice P; Greene, Eddie L; Nicholas, Susanne B; Agodoa, Lawrence; Norris, Keith C

    2009-01-01

    Chronic kidney disease (CKD) is more likely to progress to end-stage renal disease (ESRD) in African Americans while the reasons for this are unclear. The metabolic syndrome is a risk factor for the development of diabetes, cardiovascular disease, and has been recently linked to incident CKD. Historically, fewer African Americans meet criteria for the definition of metabolic syndrome, despite having higher rates of cardiovascular mortality than Caucasians. The presence of microalbuminuria portends increased cardiovascular risks and has been shown to cluster with the metabolic syndrome. We recently reported that proteinuria is a predictor of CKD progression in African American hypertensives with metabolic syndrome. In this review we explore the potential value of including CKD markers--microalbuminuria/proteinuria or low glomerular filtration rate (GFR)-in refining the cluster of factors defined as metabolic syndrome, ie, "cardiorenal metabolic syndrome."

  14. Metabolic Diet App Suite for inborn errors of amino acid metabolism.

    Science.gov (United States)

    Ho, Gloria; Ueda, Keiko; Houben, Roderick F A; Joa, Jeff; Giezen, Alette; Cheng, Barbara; van Karnebeek, Clara D M

    2016-03-01

    An increasing number of rare inborn errors of metabolism (IEMs) are amenable to targeted metabolic nutrition therapy. Daily adherence is important to attain metabolic control and prevent organ damage. This is challenging however, given the lack of information of disorder specific nutrient content of foods, the limited availability and cost of specialty products as well as difficulties in reliable calculation and tracking of dietary intake and targets. To develop apps for all inborn errors of amino acid metabolism for which the mainstay of treatment is a medical diet, and obtain patient and family feedback throughout the process to incorporate this into subsequent versions. The Metabolic Diet App Suite was created with input from health care professionals as a free, user-friendly, online tool for both mobile devices and desktop computers (http://www.metabolicdietapp.org) for 15 different IEMs. General information is provided for each IEM with links to useful online resources. Nutrient information is based on the MetabolicPro™, a North American food database compiled by the Genetic Metabolic Dietitians International (GMDI) Technology committee. After user registration, a personalized dashboard and management plan including specific nutrient goals are created. Each Diet App has a user-friendly interface and the functions include: nutrient intake counts, adding your own foods and homemade recipes and, managing a daily food diary. Patient and family feedback was overall positive and specific suggestions were used to further improve the App Suite. The Metabolic Diet App Suite aids individuals affected by IEMs to track and plan their meals. Future research should evaluate its impact on patient adherence, metabolic control, quality of life and health-related outcomes. The Suite will be updated and expanded to Apps for other categories of IEMs. Finally, this Suite is a support tool only, and does not replace medical/metabolic nutrition professional advice. Copyright

  15. Transcriptional and metabolic effects of glucose on Streptococcus pneumoniae sugar metabolism

    Directory of Open Access Journals (Sweden)

    Laura ePaixão

    2015-10-01

    Full Text Available Streptococcus pneumoniae is a strictly fermentative human pathogen that relies on carbohydrate metabolism to generate energy for growth. The nasopharynx colonised by the bacterium is poor in free sugars, but mucosa lining glycans can provide a source of sugar. In blood and inflamed tissues glucose is the prevailing sugar. As a result during progression from colonisation to disease S. pneumoniae has to cope with a pronounced shift in carbohydrate nature and availability. Thus, we set out to assess the pneumococcal response to sugars found in glycans and the influence of glucose (Glc on this response at the transcriptional, physiological and metabolic levels. Galactose (Gal, N-acetylglucosamine (GlcNAc and mannose (Man affected the expression of 8 to 14% of the genes covering cellular functions including central carbon metabolism and virulence. The pattern of end-products as monitored by in vivo 13C-NMR is in good agreement with the fermentation profiles during growth, while the pools of phosphorylated metabolites are consistent with the type of fermentation observed (homolactic vs. mixed and regulation at the metabolic level. Furthermore, the accumulation of α-Gal6P and Man6P indicate metabolic bottlenecks in the metabolism of Gal and Man, respectively. Glc added to cells actively metabolizing other sugar(s was readily consumed and elicited a metabolic shift towards a homolactic profile. The transcriptional response to Glc was large (over 5% of the genome. In central carbon metabolism (most represented category, Glc exerted mostly negative regulation. The smallest response to Glc was observed on a sugar mix, suggesting that exposure to varied sugars improves the fitness of S. pneumoniae. The expression of virulence factors was negatively controlled by Glc in a sugar-dependent manner. Overall, our results shed new light on the link between carbohydrate metabolism, adaptation to host niches and virulence.

  16. Transcriptional and metabolic effects of glucose on Streptococcus pneumoniae sugar metabolism.

    Science.gov (United States)

    Paixão, Laura; Caldas, José; Kloosterman, Tomas G; Kuipers, Oscar P; Vinga, Susana; Neves, Ana R

    2015-01-01

    Streptococcus pneumoniae is a strictly fermentative human pathogen that relies on carbohydrate metabolism to generate energy for growth. The nasopharynx colonized by the bacterium is poor in free sugars, but mucosa lining glycans can provide a source of sugar. In blood and inflamed tissues glucose is the prevailing sugar. As a result during progression from colonization to disease S. pneumoniae has to cope with a pronounced shift in carbohydrate nature and availability. Thus, we set out to assess the pneumococcal response to sugars found in glycans and the influence of glucose (Glc) on this response at the transcriptional, physiological, and metabolic levels. Galactose (Gal), N-acetylglucosamine (GlcNAc), and mannose (Man) affected the expression of 8 to 14% of the genes covering cellular functions including central carbon metabolism and virulence. The pattern of end-products as monitored by in vivo (13)C-NMR is in good agreement with the fermentation profiles during growth, while the pools of phosphorylated metabolites are consistent with the type of fermentation observed (homolactic vs. mixed) and regulation at the metabolic level. Furthermore, the accumulation of α-Gal6P and Man6P indicate metabolic bottlenecks in the metabolism of Gal and Man, respectively. Glc added to cells actively metabolizing other sugar(s) was readily consumed and elicited a metabolic shift toward a homolactic profile. The transcriptional response to Glc was large (over 5% of the genome). In central carbon metabolism (most represented category), Glc exerted mostly negative regulation. The smallest response to Glc was observed on a sugar mix, suggesting that exposure to varied sugars improves the fitness of S. pneumoniae. The expression of virulence factors was negatively controlled by Glc in a sugar-dependent manner. Overall, our results shed new light on the link between carbohydrate metabolism, adaptation to host niches and virulence.

  17. Website Policies / Important Links | DOepatents

    Science.gov (United States)

    Links Website Policies / Important Links Javascript Not Enabled OSTI Security Website Policies and first) Publication Date (oldest first) Close Clear All Find DOepatents Website Policies / Important Important Links Some links on this page may take you to non-federal websites. Their policies may differ from

  18. Social Metabolism and Environmental Conflicts in India

    OpenAIRE

    Martínez Alier, Joan

    2014-01-01

    This paper explains the methods for counting the energy and material flows in the economy, and gives the main results of the Material Flows for the economy of India between 1961 and 2008 as researched by Simron Singh et al (2012). Drawing on work done in the EJOLT project, some illustrations are given of the links between the changing social metabolism and ecological distribution conflicts, looking at responses in Odisha to bauxite mining, at conflicts on sand mining, at disputes on waste man...

  19. Social Metabolism and Environmental Conflicts in India

    OpenAIRE

    Martinez-Alier, Joan; Temper, Leah; Demaria, Federico

    2014-01-01

    This paper explains the methods for counting the energy and material flows in the economy, and gives the main results of the Material Flows for the economy of India between 1961 and 2008 as researched by Simron Singh et al (2012). Drawing on work done in the EJOLT project, some illustrations are given of the links between the changing social metabolism and ecological distribution conflicts, looking at responses in Odisha to bauxite mining, at conflicts on sand mining, at disputes on waste ma...

  20. Social Metabolism and Environmental Conflicts in India

    OpenAIRE

    Joan Martinez-Alier; Leah Temper; Federico Demaria

    2014-01-01

    This paper explains the methods for counting the energy and material flows in the economy, and gives the main results of the Material Flows for the economy of India between 1961 and 2008 as researched by Simron Singh et al (2012). Drawing on work done in the EJOLT project, some illustrations are given of the links between the changing social metabolism and ecological distribution conflicts, looking at responses in Odisha to bauxite mining, at conflicts on sand mining, at disputes on waste ...

  1. Metabolic disturbances connecting obesity and depression

    Directory of Open Access Journals (Sweden)

    Cecile eHryhorczuk

    2013-10-01

    Full Text Available Obesity markedly increases the odds of developing depression. Depressed mood not only impairs motivation, quality of life and overall functioning but also increases the risks of obesity complications. Abdominal obesity is a better predictor of depression and anxiety risk than overall adipose mass. A growing amount of research suggests that metabolic abnormalities stemming from central obesity that lead to metabolic disease may also responsible for the increased incidence of depression in obesity. As reviewed here, a higher mass of dysfunctional adipose tissue is associated with several metabolic disturbances that are either directly or indirectly implicated in the control of emotions and mood. To better comprehend the development of depression in obesity, this review pulls together select findings addressing the link between adiposity, diet and negative emotional states and discusses the evidence that alterations in glucocorticoids, adipose-derived hormones and inflammatory signalling that are characteristic of central obesity may be involved.

  2. Gastric emptying, glucose metabolism and gut hormones

    DEFF Research Database (Denmark)

    Vermeulen, Mechteld A R; Richir, Milan C; Garretsen, Martijn K

    2011-01-01

    To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant and carb......To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant...... and carbohydrate content. However, gastric emptying of fluids is influenced by its nutrient composition; hence, safety of preoperative carbohydrate loading should be confirmed. Because gut hormones link carbohydrate metabolism and gastric emptying, hormonal responses were studied....

  3. Melatonin, mitochondria, and the metabolic syndrome.

    Science.gov (United States)

    Cardinali, Daniel P; Vigo, Daniel E

    2017-11-01

    A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.

  4. Bottom-linked innovation

    DEFF Research Database (Denmark)

    Kristensen, Catharina Juul

    2018-01-01

    hitherto been paid little explicit attention, namely collaboration between middle managers and employees in innovation processes. In contrast to most studies, middle managers and employees are here both subjects of explicit investigation. The collaboration processes explored in this article are termed...... ‘bottom-linked innovation’. The empirical analysis is based on an in-depth qualitative study of bottom-linked innovation in a public frontline institution in Denmark. By combining research on employee-driven innovation and middle management, the article offers new insights into such collaborative......Employee-driven innovation is gaining ground as a strategy for developing sustainable organisations in the public and private sector. This type of innovation is characterised by active employee participation, and the bottom-up perspective is often emphasised. This article explores an issue that has...

  5. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling

    International Nuclear Information System (INIS)

    Lo, Sheng-Nan; Chang, Yu-Ping; Tsai, Keng-Chang; Chang, Chia-Yu; Wu, Tian-Shung; Ueng, Yune-Fang

    2013-01-01

    Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least K i value of 44 ± 16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC 50 values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different. - Highlights: • Berberine preferentially inhibited CYP1B1 activity. • Berberine caused similar inhibitory effects on CYP1B1.1, CYP1B1.3 and CYP1B1.4. • Asn228 in CYP1B1 was an

  6. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lo, Sheng-Nan [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Chang, Yu-Ping; Tsai, Keng-Chang [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Chang, Chia-Yu [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China); Wu, Tian-Shung [Department of Chemistry, National Chung-Kung University, Tainan 701, Taiwan, ROC (China); Ueng, Yune-Fang, E-mail: ueng@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China)

    2013-11-01

    Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least K{sub i} value of 44 ± 16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC{sub 50} values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different. - Highlights: • Berberine preferentially inhibited CYP1B1 activity. • Berberine caused similar inhibitory effects on CYP1B1.1, CYP1B1.3 and CYP1B1.4. • Asn228 in CYP

  7. Thermodynamics of interactions between mammalian cytochromes P450 and b5.

    Science.gov (United States)

    Yablokov, Evgeny; Florinskaya, Anna; Medvedev, Alexei; Sergeev, Gennady; Strushkevich, Natallia; Luschik, Alexander; Shkel, Tatsiana; Haidukevich, Irina; Gilep, Andrei; Usanov, Sergey; Ivanov, Alexis

    2017-04-01

    Cytochromes P450 (CYPs) play an important role in the metabolism of xenobiotics and various endogenous substrates. Being a crucial component of the microsomal monooxygenase system, CYPs are involved in numerous protein-protein interactions. However, mechanisms underlying molecular interactions between components of the monooxygenase system still need better characterization. In this study thermodynamic parameters of paired interactions between mammalian CYPs and cytochromes b5 (CYB5) have been evaluated using a Surface Plasmon Resonance (SPR) based biosensor Biacore 3000. Analysis of 18 pairs of CYB5-CYP complexes formed by nine different isoforms of mammalian CYPs and two isoforms of human CYB5 has shown that thermodynamically these complexes can be subdivided into enthalpy-driven and entropy-driven groups. Formation of the enthalpy-driven complexes was observed in the case of microsomal CYPs allosterically regulated by CYB5 (CYB5A-CYP3A4, CYB5A-CYP3A5, CYB5A-CYP17A1). The entropy-driven complexes were formed when CYB5 had no effect on the CYP activity (CYB5A-CYP51A1, CYB5A-CYP1B1, CYB5B-CYP11A1). Results of this study suggest that such interactions determining protein clustering are indirectly linked to the monooxygenase functioning. Positive ΔH values typical for such interactions may be associated with displacement of the solvation shells of proteins upon clustering. CYB5-CYP complex formation accompanied by allosteric regulation of CYP activity by CYB5 is enthalpy-dependent. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Influence of high carbohydrate versus high fat diet in ozone induced pulmonary injury and systemic metabolic impairment in a Brown Norway (BN) rat model of healthy aging

    Science.gov (United States)

    Rationale: Air pollution has been recently linked to the increased prevalence of metabolic syndrome. It has been postulated that dietary risk factors might exacerbate air pollution-induced metabolic impairment. We have recently reported that ozone exposure induces acute systemic ...

  9. [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.

  10. Metabolic syndrome and menopause

    OpenAIRE

    Jouyandeh, Zahra; Nayebzadeh, Farnaz; Qorbani, Mostafa; Asadi, Mojgan

    2013-01-01

    Abstract Background The metabolic syndrome is defined as an assemblage of risk factors for cardiovascular diseases, and menopause is associated with an increase in metabolic syndrome prevalence. The aim of this study was to assess the prevalence of metabolic syndrome and its components among postmenopausal women in Tehran, Iran. Methods In this cross-sectional study in menopause clinic in Tehran, 118 postmenopausal women were investigated. We used the adult treatment panel 3 (ATP3) criteria t...

  11. [Metabolic functions and sport].

    Science.gov (United States)

    Riviere, Daniel

    2004-01-01

    Current epidemiological studies emphasize the increased of metabolic diseases of the adults, such as obesity, type-2 diabetes and metabolic syndromes. Even more worrying is the rising prevalence of obesity in children. It is due more to sedentariness, caused more by inactivity (television, video, games, etc.) than by overeating. Many studies have shown that regular physical activities benefit various bodily functions including metabolism. After dealing with the major benefits of physical exercise on some adult metabolic disorders, we focus on the prime role played by physical activity in combating the public health problem of childhood obesity.

  12. Mathematical modelling of metabolism

    DEFF Research Database (Denmark)

    Gombert, Andreas Karoly; Nielsen, Jens

    2000-01-01

    Mathematical models of the cellular metabolism have a special interest within biotechnology. Many different kinds of commercially important products are derived from the cell factory, and metabolic engineering can be applied to improve existing production processes, as well as to make new processes...... availability of genomic information and powerful analytical techniques, mathematical models also serve as a tool for understanding the cellular metabolism and physiology....... available. Both stoichiometric and kinetic models have been used to investigate the metabolism, which has resulted in defining the optimal fermentation conditions, as well as in directing the genetic changes to be introduced in order to obtain a good producer strain or cell line. With the increasing...

  13. Fluoroacetylcarnitine: metabolism and metabolic effects in mitochondria

    Energy Technology Data Exchange (ETDEWEB)

    Bremer, J; Davis, E J

    1973-01-01

    The metabolism and metabolic effects of fluoroacetylcarnitine have been investigated. Carnitineacetyltransferase transfers the fluoro-acetyl group of fluoroacetylcarnitine nearly as rapidly to CoA as the acetyl group of acetylcarnitine. Fluorocitrate is then formed by citrate synthase, but this second reaction is relatively slow. The fluorocitrate formed intramitochondrially inhibits the metabolism of citrate. In heart and skeletal muscle mitochondria the accumulated citrate inhibits citrate synthesis and the ..beta..-oxidation of fatty acids. Free acetate is formed, presumably because accumulated acetyl-CoA is hydrolyzed. In liver mitochondria the accumulation of citrate leads to a relatively increased rate of ketogenesis. Increased ketogenesis is obtained also upon the addition of citrate to the reaction mixture.

  14. Linking consumer experiences

    DEFF Research Database (Denmark)

    Smed, Karina Madsen

    become part of the individual self, worldview, and behaviour. This paper seeks to explore links between consumer experiences through the exploration of narrative sequences in travel blogs. Findings indicate that non-consumption is a central element to the bloggers and also indicative of a community......Consumers consume products in various ways serving a number of purposes. Much attention has been paid to experiences attached to consumption, sometimes very explicitly, e.g. in tourism, the essence of which is experiences of various sorts, but often also implicitly as internalised experiences...

  15. Knots and links

    CERN Document Server

    Rolfsen, Dale

    2003-01-01

    Rolfsen's beautiful book on knots and links can be read by anyone, from beginner to expert, who wants to learn about knot theory. Beginners with a basic background find an inviting introduction to the elements of topology, emphasizing the tools needed for understanding knots, the fundamental group and van Kampen's theorem, for example, which are then applied to concrete problems, such as computing knot groups. For experts, Rolfsen explains advanced topics, such as the connections between knot theory and surgery and how they are useful to understanding three-manifolds. Besides providing a guide

  16. Fatty acid metabolism: target for metabolic syndrome

    OpenAIRE

    Wakil, Salih J.; Abu-Elheiga, Lutfi A.

    2009-01-01

    Fatty acids are a major energy source and important constituents of membrane lipids, and they serve as cellular signaling molecules that play an important role in the etiology of the metabolic syndrome. Acetyl-CoA carboxylases 1 and 2 (ACC1 and ACC2) catalyze the synthesis of malonyl-CoA, the substrate for fatty acid synthesis and the regulator of fatty acid oxidation. They are highly regulated and play important roles in the energy metabolism of fatty acids in animals, including humans. They...

  17. Sodium signaling and astrocyte energy metabolism

    KAUST Repository

    Chatton, Jean-Yves; Magistretti, Pierre J.; Barros, L. Felipe

    2016-01-01

    The Na+ gradient across the plasma membrane is constantly exploited by astrocytes as a secondary energy source to regulate the intracellular and extracellular milieu, and discard waste products. One of the most prominent roles of astrocytes in the brain is the Na+-dependent clearance of glutamate released by neurons during synaptic transmission. The intracellular Na+ load collectively generated by these processes converges at the Na,K-ATPase pump, responsible for Na+ extrusion from the cell, which is achieved at the expense of cellular ATP. These processes represent pivotal mechanisms enabling astrocytes to increase the local availability of metabolic substrates in response to neuronal activity. This review presents basic principles linking the intracellular handling of Na+ following activity-related transmembrane fluxes in astrocytes and the energy metabolic pathways involved. We propose a role of Na+ as an energy currency and as a mediator of metabolic signals in the context of neuron-glia interactions. We further discuss the possible impact of the astrocytic syncytium for the distribution and coordination of the metabolic response, and the compartmentation of these processes in cellular microdomains and subcellular organelles. Finally, we illustrate future avenues of investigation into signaling mechanisms aimed at bridging the gap between Na+ and the metabolic machinery. © 2016 Wiley Periodicals, Inc.

  18. Metabolic aspects of obstructive sleep apnoea syndrome

    Directory of Open Access Journals (Sweden)

    M. R. Bonsignore

    2009-06-01

    Full Text Available Insulin resistance is often associated with obstructive sleep apnoea syndrome (OSAS and could contribute to cardiovascular risk in OSAS. Sleep loss and intermittent hypoxia could contribute to the pathogenesis of the metabolic alterations associated with obesity, a common feature of OSAS. The biology of the adipocyte is being increasingly studied, and it has been found that hypoxia negatively affects adipocyte function. In November 2007, the European Respiratory Society and two EU COST Actions (Cardiovascular risk in OSAS (B26 and Adipose tissue and the metabolic syndrome (BM0602, held a Research Seminar in Düsseldorf, Germany, to discuss the following: 1 the effects of hypoxia on glucose metabolism and adipocyte function; 2 the role of inflammatory activation in OSAS and obesity; 3 the alarming rates of obesity and OSAS in children; 4 the harmful effects of the metabolic syndrome in OSAS; 5 the effects of OSAS treatment on metabolic variables; and 6 the relationship between daytime sleepiness and hormonal and inflammatory responses. Insulin resistance in skeletal muscle, the role of the endocannabinoid system and novel pharmacological approaches to treat insulin resistance were also discussed. As obesity and hypoxia could be the basic links between OSAS and adipocyte dysfunction, further research is needed to translate these new data into clinical practice.

  19. Sodium signaling and astrocyte energy metabolism

    KAUST Repository

    Chatton, Jean-Yves

    2016-03-31

    The Na+ gradient across the plasma membrane is constantly exploited by astrocytes as a secondary energy source to regulate the intracellular and extracellular milieu, and discard waste products. One of the most prominent roles of astrocytes in the brain is the Na+-dependent clearance of glutamate released by neurons during synaptic transmission. The intracellular Na+ load collectively generated by these processes converges at the Na,K-ATPase pump, responsible for Na+ extrusion from the cell, which is achieved at the expense of cellular ATP. These processes represent pivotal mechanisms enabling astrocytes to increase the local availability of metabolic substrates in response to neuronal activity. This review presents basic principles linking the intracellular handling of Na+ following activity-related transmembrane fluxes in astrocytes and the energy metabolic pathways involved. We propose a role of Na+ as an energy currency and as a mediator of metabolic signals in the context of neuron-glia interactions. We further discuss the possible impact of the astrocytic syncytium for the distribution and coordination of the metabolic response, and the compartmentation of these processes in cellular microdomains and subcellular organelles. Finally, we illustrate future avenues of investigation into signaling mechanisms aimed at bridging the gap between Na+ and the metabolic machinery. © 2016 Wiley Periodicals, Inc.

  20. Modular co-evolution of metabolic networks

    Directory of Open Access Journals (Sweden)

    Yu Zhong-Hao

    2007-08-01

    Full Text Available Abstract Background The architecture of biological networks has been reported to exhibit high level of modularity, and to some extent, topological modules of networks overlap with known functional modules. However, how the modular topology of the molecular network affects the evolution of its member proteins remains unclear. Results In this work, the functional and evolutionary modularity of Homo sapiens (H. sapiens metabolic network were investigated from a topological point of view. Network decomposition shows that the metabolic network is organized in a highly modular core-periphery way, in which the core modules are tightly linked together and perform basic metabolism functions, whereas the periphery modules only interact with few modules and accomplish relatively independent and specialized functions. Moreover, over half of the modules exhibit co-evolutionary feature and belong to specific evolutionary ages. Peripheral modules tend to evolve more cohesively and faster than core modules do. Conclusion The correlation between functional, evolutionary and topological modularity suggests that the evolutionary history and functional requirements of metabolic systems have been imprinted in the architecture of metabolic networks. Such systems level analysis could demonstrate how the evolution of genes may be placed in a genome-scale network context, giving a novel perspective on molecular evolution.

  1. Linking tumor glycolysis and immune evasion in cancer: Emerging concepts and therapeutic opportunities.

    Science.gov (United States)

    Ganapathy-Kanniappan, Shanmugasundaram

    2017-08-01

    Metabolic reprogramming and immune evasion are two hallmarks of cancer. Metabolic reprogramming is exemplified by cancer's propensity to utilize glucose at an exponential rate which in turn is linked with "aerobic glycolysis", popularly known as the "Warburg effect". Tumor glycolysis is pivotal for the efficient management of cellular bioenergetics and uninterrupted cancer growth. Mounting evidence suggests that tumor glycolysis also plays a key role in instigating immunosuppressive networks that are critical for cancer cells to escape immune surveillance ("immune evasion"). Recent data show that induction of cellular stress or metabolic dysregulation sensitize cancer cells to antitumor immune cells implying that metabolic reprogramming and immune evasion harmonize during cancer progression. However, the molecular link between these two hallmarks of cancer remains obscure. In this review the molecular intricacies of tumor glycolysis that facilitate immune evasion has been discussed in the light of recent research to explore immunotherapeutic potential of targeting cancer metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Metabolic regulation of inflammation.

    Science.gov (United States)

    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.

  3. Metabolic syndrome and menopause

    Directory of Open Access Journals (Sweden)

    Jouyandeh Zahra

    2013-01-01

    Full Text Available Abstract Background The metabolic syndrome is defined as an assemblage of risk factors for cardiovascular diseases, and menopause is associated with an increase in metabolic syndrome prevalence. The aim of this study was to assess the prevalence of metabolic syndrome and its components among postmenopausal women in Tehran, Iran. Methods In this cross-sectional study in menopause clinic in Tehran, 118 postmenopausal women were investigated. We used the adult treatment panel 3 (ATP3 criteria to classify subjects as having metabolic syndrome. Results Total prevalence of metabolic syndrome among our subjects was 30.1%. Waist circumference, HDL-cholesterol, fasting blood glucose, diastolic blood pressure ,Systolic blood pressure, and triglyceride were significantly higher among women with metabolic syndrome (P-value Conclusions Our study shows that postmenopausal status is associated with an increased risk of metabolic syndrome. Therefore, to prevent cardiovascular disease there is a need to evaluate metabolic syndrome and its components from the time of the menopause.

  4. Hepatic diseases related to triglyceride metabolism.

    Science.gov (United States)

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

  5. Drug metabolism in birds

    Science.gov (United States)

    Pan, Huo Ping; Fouts, James R.

    1979-01-01

    Papers published over 100 years since the beginning of the scientific study of drug metabolism in birds were reviewed. Birds were found to be able to accomplish more than 20 general biotransformation reactions in both functionalization and conjugation. Chickens were the primary subject of study but over 30 species of birds were used. Large species differences in drug metabolism exist between birds and mammals as well as between various birds, these differences were mostly quantitative. Qualitative differences were rare. On the whole, drug metabolism studies in birds have been neglected as compared with similar studies on insects and mammals. The uniqueness of birds and the advantages of using birds in drug metabolism studies are discussed. Possible future studies of drug metabolism in birds are recommended.

  6. Metabolic imaging using SPECT

    International Nuclear Information System (INIS)

    Taki, Junichi; Matsunari, Ichiro

    2007-01-01

    In normal condition, the heart obtains more than two-thirds of its energy from the oxidative metabolism of long chain fatty acids, although a wide variety of substrates such as glucose, lactate, ketone bodies and amino acids are also utilised. In ischaemic myocardium, on the other hand, oxidative metabolism of free fatty acid is suppressed and anaerobic glucose metabolism plays a major role in residual oxidative metabolism. Therefore, metabolic imaging can be an important technique for the assessment of various cardiac diseases and conditions. In SPECT, several iodinated fatty acid traces have been introduced and studied. Of these, 123 I-labelled 15-(p-iodophenyl)3-R, S-methylpentadecanoic acid (BMIPP) has been the most commonly used tracer in clinical studies, especially in some of the European countries and Japan. In this review article, several fatty acid tracers for SPECT are characterised, and the mechanism of uptake and clinical utility of BMIPP are discussed in detail. (orig.)

  7. Mycobacterium tuberculosis Metabolism

    Science.gov (United States)

    Warner, Digby F.

    2015-01-01

    Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances—in particular, the development of systems biology tools such as metabolomics—have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host–pathogen interaction through modulation of metabolic functions. PMID:25502746

  8. Metabolic Engineering VII Conference

    Energy Technology Data Exchange (ETDEWEB)

    Kevin Korpics

    2012-12-04

    The aims of this Metabolic Engineering conference are to provide a forum for academic and industrial researchers in the field; to bring together the different scientific disciplines that contribute to the design, analysis and optimization of metabolic pathways; and to explore the role of Metabolic Engineering in the areas of health and sustainability. Presentations, both written and oral, panel discussions, and workshops will focus on both applications and techniques used for pathway engineering. Various applications including bioenergy, industrial chemicals and materials, drug targets, health, agriculture, and nutrition will be discussed. Workshops focused on technology development for mathematical and experimental techniques important for metabolic engineering applications will be held for more in depth discussion. This 2008 meeting will celebrate our conference tradition of high quality and relevance to both industrial and academic participants, with topics ranging from the frontiers of fundamental science to the practical aspects of metabolic engineering.

  9. Metabolic imaging using PET

    International Nuclear Information System (INIS)

    Kudo, Takashi

    2007-01-01

    There is growing evidence that myocardial metabolism plays a key role not only in ischaemic heart disease but also in a variety of diseases which involve myocardium globally, such as heart failure and diabetes mellitus. Understanding myocardial metabolism in such diseases helps to elucidate the pathophysiology and assists in making therapeutic decisions. As well as providing information on regional changes, PET can deliver quantitative information about both regional and global changes in metabolism. This capability of quantitative measurement is one of the major advantages of PET along with physiological positron tracers, especially relevant in evaluating diseases which involve the whole myocardium. This review discusses major PET tracers for metabolic imaging and their clinical applications and contributions to research regarding ischaemic heart disease and other diseases such as heart failure and diabetic heart disease. Future applications of positron metabolic tracers for the detection of vulnerable plaque are also highlighted briefly. (orig.)

  10. Astrocytes and energy metabolism.

    Science.gov (United States)

    Prebil, Mateja; Jensen, Jørgen; Zorec, Robert; Kreft, Marko

    2011-05-01

    Astrocytes are glial cells, which play a significant role in a number of processes, including the brain energy metabolism. Their anatomical position between blood vessels and neurons make them an interface for effective glucose uptake from blood. After entering astrocytes, glucose can be involved in different metabolic pathways, e.g. in glycogen production. Glycogen in the brain is localized mainly in astrocytes and is an important energy source in hypoxic conditions and normal brain functioning. The portion of glucose metabolized into glycogen molecules in astrocytes is as high as 40%. It is thought that the release of gliotransmitters (such as glutamate, neuroactive peptides and ATP) into the extracellular space by regulated exocytosis supports a significant part of communication between astrocytes and neurons. On the other hand, neurotransmitter action on astrocytes has a significant role in brain energy metabolism. Therefore, understanding the astrocytes energy metabolism may help understanding neuron-astrocyte interactions.

  11. Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders

    Directory of Open Access Journals (Sweden)

    Rinki Murphy

    2013-01-01

    Full Text Available Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1 severe, non-syndromic obesity, (2 pancreatic beta cell forms of early-onset diabetes, and (3 severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted.

  12. [Genomic research of traditional Chinese medicines in vivo metabolism].

    Science.gov (United States)

    Xiao, Shui-Ming; Bai, Rui; Zhang, Xiao-Yan

    2016-11-01

    Gene is the base of in vivo metabolism and effectiveness for traditional Chinese medicines (TCM), and the gene expression, regulation and modification are used as the research directions to perform the TCM multi-component, multi-link and multi-target in vivo metabolism studies, which will improve the research on TCM metabolic proecess, effect target and molecular mechanism. Humans are superorganisms with 1% genes inherited from parents and 99% genes from various parts of the human body, mainly coming from the microorganisms in intestinal flora. These indicate that genetically inherited human genome and "second genome" could affect the TCM in vivo metabolism from inheritance and "environmental" aspects respectively. In the present paper, typical case study was used to discuss related TCM in vivo metabolic genomics research, mainly including TCM genomics research and gut metagenomics research, as well as the personalized medicine evoked from the individual difference of above genomics (metagenomics). Copyright© by the Chinese Pharmaceutical Association.

  13. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the Link - Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors ... GA: CDC, DHHS. Retrieved November 2017. How are Drug Misuse and HIV Related? Drug misuse and addiction ...

  14. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the link between drug misuse and HIV infection. It contains information for young people, parents and teachers, ... present time. The virus (HIV) and the disease it causes (AIDS) are often linked and referred to ...

  15. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... teens and young adults have never known a world without it. NIDA’s "Learn the Link" campaign continues ... for HIV infection through risky sexual behaviors. NIDA researchers have studied and continue to study the links ...

  16. The HANDSS-55 Linking Equipment

    International Nuclear Information System (INIS)

    Crosby, S.

    2001-01-01

    The Bucket Translation Unit (BTU) and the Drum Handler are two of the HANDSS-55 subsystems identified as linking components. Both subsystems link other modules together by moving material to or from another module

  17. Phosphorylation of human link proteins

    International Nuclear Information System (INIS)

    Oester, D.A.; Caterson, B.; Schwartz, E.R.

    1986-01-01

    Three link proteins of 48, 44 and 40 kDa were purified from human articular cartilage and identified with monoclonal anti-link protein antibody 8-A-4. Two sets of lower molecular weight proteins of 30-31 kDa and 24-26 kDa also contained link protein epitopes recognized by the monoclonal antibody and were most likely degradative products of the intact link proteins. The link proteins of 48 and 40 kDa were identified as phosphoproteins while the 44 kDa link protein did not contain 32 P. The phosphorylated 48 and 40 kDa link proteins contained approximately 2 moles PO 4 /mole link protein

  18. Metabolism as an Integral Cog in the Mammalian Circadian Clockwork

    Science.gov (United States)

    Gamble, Karen L.; Young, Martin E.

    2013-01-01

    Circadian rhythms are an integral part of life. These rhythms are apparent in virtually all biological processes studies to date, ranging from the individual cell (e.g., DNA synthesis) to the whole organism (e.g., behaviors such as physical activity). Oscillations in metabolism have been characterized extensively in various organisms, including mammals. These metabolic rhythms often parallel behaviors such as sleep/wake and fasting/feeding cycles that occur on a daily basis. What has become increasingly clear over the past several decades is that many metabolic oscillations are driven by cell autonomous circadian clocks, which orchestrate metabolic processes in a temporally appropriate manner. During the process of identifying the mechanisms by which clocks influence metabolism, molecular-based studies have revealed that metabolism should be considered an integral circadian clock component. The implications of such an interrelationship include the establishment of a vicious cycle during cardiometabolic disease states, wherein metabolism-induced perturbations in the circadian clock exacerbate metabolic dysfunction. The purpose of this review is therefore to highlight recent insights gained regarding links between cell autonomous circadian clocks and metabolism, and the implications of clock dysfunction in the pathogenesis of cardiometabolic diseases. PMID:23594144

  19. Metabolic Syndrome in Schizophrenia: A Non‑systematic Review

    Directory of Open Access Journals (Sweden)

    Marta Nascimento

    2012-12-01

    Full Text Available Background: The link between mental illness and metabolic disturbances has been recognized since the beginning of the last century. The debate concerning medical morbidity in schizophrenia intensified during the last twenty years, especially after the introduction of atypical antipsychotics. Aims: To highlight some features of the metabolic syndrome in this population, specifically epidemiological data, underlying mechanisms and antipsychotic therapy. Methods: Non‑systematic review of literature. Results and Conclusions: Despite the different criteria used for the definition of metabolic syndrome, it is clear today that the schizophrenic population has the highest rate of metabolic syndrome. Additionally, the prevalence of the metabolic syndrome in this population demonstrates a geographical distribution similar to the general population. Although it hasn’t been recognized for years, schizophrenic patients’ vulnerability to develop metabolic disturbances isn’t entirely related to antipsychotic therapy. Actually, it results from an interaction of multiple factors, including hereditary, genetic, biochemical and environmental ones (which include antipsychotic therapy. Moreover, they are not exclusively explained by weight gain. Metabolic disturbances are one of the main concerns related to general psychopharmacology. The differences between typical and atypical antipsychotics in terms of metabolic syndrome are not completely established. However, clozapine and olanzapine are recognized to have the worst metabolic profile, amongst all atypical antipsychotics.

  20. Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zachary Freyberg

    2017-07-01

    Full Text Available For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs which on their own are also strongly associated with metabolic side effects. The combination of APD-induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naïve patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control.

  1. Metabolic Syndrome in Schizophrenia: A Non‑systematic Review

    Directory of Open Access Journals (Sweden)

    Marta Nascimento

    2013-11-01

    Full Text Available Background: The link between mental illness and metabolic disturbances has been recognized since the beginning of the last century. The debate concerning medical morbidity in schizophrenia intensified during the last twenty years, especially after the introduction of atypical antipsychotics. Aims: To highlight some features of the metabolic syndrome in this population, specifically epidemiological data, underlying mechanisms and antipsychotic therapy. Methods: Non‑systematic review of literature. Results and Conclusions: Despite the different criteria used for the definition of metabolic syndrome, it is clear today that the schizophrenic population has the highest rate of metabolic syndrome. Additionally, the prevalence of the metabolic syndrome in this population demonstrates a geographical distribution similar to the general population. Although it hasn’t been recognized for years, schizophrenic patients’ vulnerability to develop metabolic disturbances isn’t entirely related to antipsychotic therapy. Actually, it results from an interaction of multiple factors, including hereditary, genetic, biochemical and environmental ones (which include antipsychotic therapy. Moreover, they are not exclusively explained by weight gain. Metabolic disturbances are one of the main concerns related to general psychopharmacology. The differences between typical and atypical antipsychotics in terms of metabolic syndrome are not completely established. However, clozapine and olanzapine are recognized to have the worst metabolic profile, amongst all atypical antipsychotics.

  2. Defining Molecular Sensors to Assess Long-Term Effects of Pesticides on Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Fanny L'Héritier

    2014-09-01

    Full Text Available The abundance of dioxins and dioxin-like pollutants has massively increased in the environment due to human activity. These chemicals are particularly persistent and accumulate in the food chain, which raises major concerns regarding long-term exposure to human health. Most dioxin-like pollutants activate the aryl hydrocarbon receptor (AhR transcription factor, which regulates xenobiotic metabolism enzymes that belong to the cytochrome P450 1A family (that includes CYP1A1 and CYP1B1. Importantly, a crosstalk exists between estrogen receptor α (ERα and AhR. More specifically, ERα represses the expression of the CYP1A1 gene, which encodes an enzyme that converts 17β-estradiol into 2-hydroxyestradiol. However, (ERα does not repress the CYP1B1 gene, which encodes an enzyme that converts 17β-estradiol into 4-hydroxyestradiol, one of the most genotoxic estrogen metabolites. In this review, we discuss how chronic exposure to xenobiotic chemicals, such as pesticides, might affect the expression of genes regulated by the AhR–ERα crosstalk. Here, we focus on recent advances in the understanding of molecular mechanisms that mediate this crosstalk repression, and particularly on how ERα represses the AhR target gene CYP1A1, and could subsequently promote breast cancer. Finally, we propose that genes implicated in this crosstalk could constitute important biomarkers to assess long-term effects of pesticides on human health.

  3. 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.

  4. ITK optical links backup document

    CERN Document Server

    Huffman, B T; The ATLAS collaboration; Flick, T; Ye, J

    2013-01-01

    This document describes the proposed optical links to be used for the ITK in the phase II upgrade. The current R&D for optical links pursued in the Versatile Link group is reviewed. In particular the results demonstrating the radiation tolerance of all the on-detector components are documented. The bandwidth requirements and the resulting numerology are given.

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... for young people, parents and teachers, and the media with links to our latest research findings and news updates. Read on to Learn the Link between ... to this site at: http://www.drugabuse.gov/news-events/public-education-projects/learn-link-drugs-hiv . ... Social Media Send the message to young people and to ...

  6. Seismic link at plate boundary

    Indian Academy of Sciences (India)

    time series to determine the causality and related orientation. The resulting link ... Triggering causes changes in the Coulomb stress on a specified fault, which is ... work link shows that the alignment of the links is parallel to the Honshu Trench ...

  7. Fermions and link invariants

    International Nuclear Information System (INIS)

    Kauffman, L.; Saleur, H.

    1991-01-01

    Various aspects of knot theory are discussed when fermionic degrees of freedom are taken into account in the braid group representations and in the state models. It is discussed how the R matrix for the Alexander polynomial arises from the Fox differential calculus, and how it is related to the quantum group U q gl(1,1). New families of solutions of the Yang Baxter equation obtained from ''linear'' representations of the braid group and exterior algebra are investigated. State models associated with U q sl(n,m), and in the case n=m=1 a state model for the multivariable Alexander polynomial are studied. Invariants of links in solid handlebodies are considered and it is shown how the non trivial topology lifts the boson fermion degeneracy is present in S 3 . (author) 36 refs

  8. Multilevel DC link inverter

    Science.gov (United States)

    Su, Gui-Jia

    2003-06-10

    A multilevel DC link inverter and method for improving torque response and current regulation in permanent magnet motors and switched reluctance motors having a low inductance includes a plurality of voltage controlled cells connected in series for applying a resulting dc voltage comprised of one or more incremental dc voltages. The cells are provided with switches for increasing the resulting applied dc voltage as speed and back EMF increase, while limiting the voltage that is applied to the commutation switches to perform PWM or dc voltage stepping functions, so as to limit current ripple in the stator windings below an acceptable level, typically 5%. Several embodiments are disclosed including inverters using IGBT's, inverters using thyristors. All of the inverters are operable in both motoring and regenerating modes.

  9. Linking Wayfinding and Wayfaring

    DEFF Research Database (Denmark)

    Lanng, Ditte Bendix; Jensen, Ole B.

    2016-01-01

    In this chapter we propose to expand and enhance the understanding of wayfi nding beyond the strictly “instrumental” (i.e., getting from point A to point B), to include the qualities and multi-sensorial inputs that inform and shape people’s movement through space. We take as a point of departure...... of environmental information , which includes the embodied, multi-sensorial experience of moving through physical space. We base our examination in part on the classic positions of the wayfi nding literature—for example, Lynch’s seminal study, The Image of the City ( 1960 ). However, we also examine the so......-called mobilities turn in which mobility is viewed as a complex, multilayered process that entails much more than simply getting from point A to point B (see Cresswell 2006 ; Jensen 2013 ; Urry 2007 ).The structure of the chapter is simple: We fi rst introduce the concepts that are key to linking wayfi nding...

  10. LinkLights

    DEFF Research Database (Denmark)

    Grönvall, Erik; Kramp, Gunnar

    2011-01-01

    The project described in this paper aims to provide assistive tools to support elderly people affected by vestibular dysfunction (i.e. a form of balance disorder leading to dizziness and nausea) in their home-based rehabilitation activities. Challenges emerge as the rehabilitation moves from...... a supervised hospital setting to private homes. Our studies have shown that the elderly people are less motivated to perform the training at home. This paper presents a tangible, portable, two dimensional modular platform called LinkLights that has been developed to sustain the home-based rehabilitation......, giving clear guidelines what to do, adding motivational cues and elements of variation and surprise in the activity. Furthermore, a set of challenges for successful translocation of the therapeutic regimen from a supervised, hospital setting to an unsupervised home-based setting together with some early...

  11. Named Entity Linking Algorithm

    Directory of Open Access Journals (Sweden)

    M. F. Panteleev

    2017-01-01

    Full Text Available In the tasks of processing text in natural language, Named Entity Linking (NEL represents the task to define and link some entity, which is found in the text, with some entity in the knowledge base (for example, Dbpedia. Currently, there is a diversity of approaches to solve this problem, but two main classes can be identified: graph-based approaches and machine learning-based ones. Graph and Machine Learning approaches-based algorithm is proposed accordingly to the stated assumptions about the interrelations of named entities in a sentence and in general.In the case of graph-based approaches, it is necessary to solve the problem of identifying an optimal set of the related entities according to some metric that characterizes the distance between these entities in a graph built on some knowledge base. Due to limitations in processing power, to solve this task directly is impossible. Therefore, its modification is proposed. Based on the algorithms of machine learning, an independent solution cannot be built due to small volumes of training datasets relevant to NEL task. However, their use can contribute to improving the quality of the algorithm. The adaptation of the Latent Dirichlet Allocation model is proposed in order to obtain a measure of the compatibility of attributes of various entities encountered in one context.The efficiency of the proposed algorithm was experimentally tested. A test dataset was independently generated. On its basis the performance of the model was compared using the proposed algorithm with the open source product DBpedia Spotlight, which solves the NEL problem.The mockup, based on the proposed algorithm, showed a low speed as compared to DBpedia Spotlight. However, the fact that it has shown higher accuracy, stipulates the prospects for work in this direction.The main directions of development were proposed in order to increase the accuracy of the system and its productivity.

  12. Metabolic disorders in menopause

    Directory of Open Access Journals (Sweden)

    Grzegorz Stachowiak

    2015-04-01

    Full Text Available Metabolic disorders occurring in menopause, including dyslipidemia, disorders of carbohydrate metabolism (impaired glucose tolerance – IGT, type 2 diabetes mellitus – T2DM or components of metabolic syndrome, constitute risk factors for cardiovascular disease in women. A key role could be played here by hyperinsulinemia, insulin resistance and visceral obesity, all contributing to dyslipidemia, oxidative stress, inflammation, alter coagulation and atherosclerosis observed during the menopausal period. Undiagnosed and untreated, metabolic disorders may adversely affect the length and quality of women’s life. Prevention and treatment preceded by early diagnosis should be the main goal for the physicians involved in menopausal care. This article represents a short review of the current knowledge concerning metabolic disorders (e.g. obesity, polycystic ovary syndrome or thyroid diseases in menopause, including the role of a tailored menopausal hormone therapy (HT. According to current data, HT is not recommend as a preventive strategy for metabolic disorders in menopause. Nevertheless, as part of a comprehensive strategy to prevent chronic diseases after menopause, menopausal hormone therapy, particularly estrogen therapy may be considered (after balancing benefits/risks and excluding women with absolute contraindications to this therapy. Life-style modifications, with moderate physical activity and healthy diet at the forefront, should be still the first choice recommendation for all patients with menopausal metabolic abnormalities.

  13. Impact of stoichiometry representation on simulation of genotype-phenotype relationships in metabolic networks

    DEFF Research Database (Denmark)

    Brochado, Ana Rita; Andrejev, Sergej; Maranas, Costas D.

    2012-01-01

    the formulation of the desired objective functions, by casting objective functions using metabolite turnovers rather than fluxes. By simulating perturbed metabolic networks, we demonstrate that the use of stoichiometry representation independent algorithms is fundamental for unambiguously linking modeling results...

  14. Calcium and Bone Metabolism Indices.

    Science.gov (United States)

    Song, Lu

    2017-01-01

    Calcium and inorganic phosphate are of critical importance for many body functions, thus the regulations of their plasma concentrations are tightly controlled by the concerted actions of reabsorption/excretion in the kidney, absorption in the intestines, and exchange from bone, the major reservoir for calcium and phosphate in the body. Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH) 2 D) control calcium homeostasis, whereas PTH, 1,25(OH) 2 D, and bone-derived fibroblast growth factor 23 (FGF 23) control phosphate homeostasis. Hypoparathyroidism can cause hypocalcemia and hyperphosphatemia, whereas deficient vitamin D actions can cause osteomalacia in adults and rickets in children. Hyperparathyroidism, alternatively, can cause hypercalcemia and hypophosphatemia. Laboratory tests of calcium, phosphate, PTH, and 25-hydroxyvitamin D are very useful in the diagnosis of abnormalities associated with calcium and/or phosphate metabolisms. Bone is constantly remodeled throughout life in response to mechanical stress and a need for calcium in extracellular fluids. Metabolic bone diseases such as osteoporosis, osteomalacia in adults or rickets in children, and renal osteodystrophy develop when bone resorption exceeds bone formation. Bone turnover markers (BTM) such as serum N-terminal propeptide of type I procollagen (P1NP) and C-terminal collagen cross-link (CTX) may be useful in predicting future fracture risk or monitoring the response to anti-resorptive therapy. There is a need to standardize sample collection protocols because certain BTMs exhibit large circadian variations and tend to be influenced by food intakes. In the United States, a project to standardize BTM sample collection protocols and to establish the reference intervals for serum P1NP and serum CTX is ongoing. We anticipate the outcome of this project to shine lights on the standardization of BTM assays, sample collection protocols, reference intervals in relation to age, sex, and ethnic

  15. VRML metabolic network visualizer.

    Science.gov (United States)

    Rojdestvenski, Igor

    2003-03-01

    A successful date collection visualization should satisfy a set of many requirements: unification of diverse data formats, support for serendipity research, support of hierarchical structures, algorithmizability, vast information density, Internet-readiness, and other. Recently, virtual reality has made significant progress in engineering, architectural design, entertainment and communication. We experiment with the possibility of using the immersive abstract three-dimensional visualizations of the metabolic networks. We present the trial Metabolic Network Visualizer software, which produces graphical representation of a metabolic network as a VRML world from a formal description written in a simple SGML-type scripting language.

  16. Human Body Exergy Metabolism

    OpenAIRE

    Mady, Carlos Eduardo Keutenedjian

    2013-01-01

    The exergy analysis of the human body is a tool that can provide indicators of health and life quality. To perform the exergy balance it is necessary to calculate the metabolism on an exergy basis, or metabolic exergy, although there is not yet consensus in its calculation procedure. Hence, the aim of this work is to provide a general method to evaluate this physical quantity for human body based on indirect calorimetry data. To calculate the metabolism on an exergy basis it is necessary to d...

  17. Too Many Links in the Horizon; What is Next? Linked Views and Linked History

    NARCIS (Netherlands)

    E. Liarou (Erietta); S. Idreos (Stratos)

    2011-01-01

    textabstractThe trend for more online linked data becomes stronger. Foreseeing a future where ``everything" will be online and linked, we ask the critical question; what is next? We envision that managing, querying and storing large amounts of links and data is far from yet another query

  18. Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging [version 1; referees: 4 approved

    OpenAIRE

    Clovis S. Palmer; Riya Palchaudhuri; Hassan Albargy; Mohamed Abdel-Mohsen; Suzanne M. Crowe

    2018-01-01

    An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impa...

  19. Evidence for a Role of Proline and Hypothalamic Astrocytes in the Regulation of Glucose Metabolism in Rats

    OpenAIRE

    Arrieta-Cruz, Isabel; Su, Ya; Knight, Colette M.; Lam, Tony K.T.; Gutiérrez-Juárez, Roger

    2013-01-01

    The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyte-neuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our result...

  20. Cellular Links between Neuronal Activity and Energy Homeostasis

    OpenAIRE

    Shetty, Pavan K.; Galeffi, Francesca; Turner, Dennis A.

    2012-01-01

    Neuronal activity, astrocytic responses to this activity, and energy homeostasis are linked together during baseline, conscious conditions, and short-term rapid activation (as occurs with sensory or motor function). Nervous system energy homeostasis also varies during long-term physiological conditions (i.e., development and aging) and with adaptation to pathological conditions, such as ischemia or low glucose. Neuronal activation requires increased metabolism (i.e., ATP generation) which lea...

  1. The origin of modern metabolic networks inferred from phylogenomic analysis of protein architecture.

    Science.gov (United States)

    Caetano-Anollés, Gustavo; Kim, Hee Shin; Mittenthal, Jay E

    2007-05-29

    Metabolism represents a complex collection of enzymatic reactions and transport processes that convert metabolites into molecules capable of supporting cellular life. Here we explore the origins and evolution of modern metabolism. Using phylogenomic information linked to the structure of metabolic enzymes, we sort out recruitment processes and discover that most enzymatic activities were associated with the nine most ancient and widely distributed protein fold architectures. An analysis of newly discovered functions showed enzymatic diversification occurred early, during the onset of the modern protein world. Most importantly, phylogenetic reconstruction exercises and other evidence suggest strongly that metabolism originated in enzymes with the P-loop hydrolase fold in nucleotide metabolism, probably in pathways linked to the purine metabolic subnetwork. Consequently, the first enzymatic takeover of an ancient biochemistry or prebiotic chemistry was related to the synthesis of nucleotides for the RNA world.

  2. Genetic response to metabolic fluctuations: correlation between central carbon metabolism and DNA replication in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Szalewska-Pałasz Agnieszka

    2011-03-01

    Full Text Available Abstract Background Until now, the direct link between central carbon metabolism and DNA replication has been demonstrated only in Bacillus. subtilis. Therefore, we asked if this is a specific phenomenon, characteristic for this bacterium and perhaps for its close relatives, or a more general biological rule. Results We found that temperature-sensitivity of mutants in particular genes coding for replication proteins could be suppressed by deletions of certain genes coding for enzymes of the central carbon metabolism. Namely, the effects of dnaA46(ts mutation could be suppressed by dysfunction of pta or ackA, effects of dnaB(ts by dysfunction of pgi or pta, effects of dnaE486(ts by dysfunction of tktB, effects of dnaG(ts by dysfunction of gpmA, pta or ackA, and effects of dnaN159(ts by dysfunction of pta or ackA. The observed suppression effects were not caused by a decrease in bacterial growth rate. Conclusions The genetic correlation exists between central carbon metabolism and DNA replication in the model Gram-negative bacterium, E. coli. This link exists at the steps of initiation and elongation of DNA replication, indicating the important global correlation between metabolic status of the cell and the events leading to cell reproduction.

  3. Deploying Linked Open Vocabulary (LOV to Enhance Library Linked Data

    Directory of Open Access Journals (Sweden)

    Oh, Sam Gyun

    2015-06-01

    Full Text Available Since the advent of Linked Data (LD as a method for building webs of data, there have been many attempts to apply and implement LD in various settings. Efforts have been made to convert bibliographic data in libraries into Linked Data, thereby generating Library Linked Data (LLD. However, when memory institutions have tried to link their data with external sources based on principles suggested by Tim Berners-Lee, identifying appropriate vocabularies for use in describing their bibliographic data has proved challenging. The objective of this paper is to discuss the potential role of Linked Open Vocabularies (LOV in providing better access to various open datasets and facilitating effective linking. The paper will also examine the ways in which memory institutions can utilize LOV to enhance the quality of LLD and LLD-based ontology design.

  4. What is Nutrition & Metabolism?

    Directory of Open Access Journals (Sweden)

    Feinman Richard D

    2004-08-01

    Full Text Available Abstract A new Open Access journal, Nutrition & Metabolism (N&M will publish articles that integrate nutrition with biochemistry and molecular biology. The open access process is chosen to provide rapid and accessible dissemination of new results and perspectives in a field that is of great current interest. Manuscripts in all areas of nutritional biochemistry will be considered but three areas of particular interest are lipoprotein metabolism, amino acids as metabolic signals, and the effect of macronutrient composition of diet on health. The need for the journal is identified in the epidemic of obesity, diabetes, dyslipidemias and related diseases, and a sudden increase in popular diets, as well as renewed interest in intermediary metabolism.

  5. Epigenetics and Cellular Metabolism

    Directory of Open Access Journals (Sweden)

    Wenyi Xu

    2016-01-01

    Full Text Available Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc. is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

  6. Amino Acid Metabolism Disorders

    Science.gov (United States)

    ... this process. One group of these disorders is amino acid metabolism disorders. They include phenylketonuria (PKU) and maple syrup urine disease. Amino acids are "building blocks" that join together to form ...

  7. The metabolic radiotherapy

    International Nuclear Information System (INIS)

    Begon, F.; Gaci, M.

    1993-01-01

    In this article, the authors recall the principles of the metabolic radiotherapy and present these main applications in the treatment of thyroid cancers, hyperthyroidism, polycythemia, arthritis, bone metastases, adrenergic neoplasms. They also present the radioimmunotherapy

  8. Engineering of metabolic control

    Science.gov (United States)

    Liao, James C.

    2004-03-16

    The invention features a method of producing heterologous molecules in cells under the regulatory control of a metabolite and metabolic flux. The method can enhance the synthesis of heterologous polypeptides and metabolites.

  9. Purines and Neuronal Excitability: Links to the Ketogenic Diet

    Science.gov (United States)

    Masino, SA; Kawamura, M; Ruskin, DN; Geiger, JD; Boison, D

    2011-01-01

    ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A1 receptor (A1R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A1Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A1R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A1Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A1Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms. PMID:21880467

  10. Link for Injured Kids

    Science.gov (United States)

    Ramirez, Marizen; Toussaint, Maisha; Woods-Jaeger, Briana; Harland, Karisa; Wetjen, Kristel; Wilgenbusch, Tammy; Pitcher, Graeme; Jennissen, Charles

    2017-01-01

    Objective Injury, the most common type of pediatric trauma, can lead to a number of adverse psychosocial outcomes, including posttraumatic stress disorder. Currently, few evidence-based parent programs exist to support children hospitalized after a traumatic injury. Using methods in evaluation and intervention research, we completed a formative research study to develop a new program of psychological first aid, Link for Injured Kids, aimed to educate parents in supporting their children after a severe traumatic injury. Methods Using qualitative methods, we held focus groups with parents and pediatric trauma providers of children hospitalized at a Level I Children's Hospital because of an injury in 2012. We asked focus group participants to describe reactions to trauma and review drafts of our intervention materials. Results Health professionals and caregivers reported a broad spectrum of emotional responses by their children or patients; however, difficulties were experienced during recovery at home and upon returning to school. All parents and health professionals recommended that interventions be offered to parents either in the emergency department or close to discharge among admissions. Conclusions Results from this study strongly indicate a need for posttrauma interventions, particularly in rural settings, to support families of children to address the psychosocial outcomes in the aftermath of an injury. Findings presented here describe the process of intervention development that responds to the needs of an affected population. PMID:26428077

  11. The CMS link system

    International Nuclear Information System (INIS)

    Vila, I.

    1999-01-01

    The Compact Muon Solenoid (CMS) is a multi-purpose detector that is going to be installed in the future Large Hadron Collider (LHC) at CERN. Muons are one of the main physical signatures of the expected new physics. The muons are going to be detected by the Central Tracker (CT) and the Muon Spectrometer (MS). Both, the CT and MS can provide an independent muon momentum measurement, but for all η and momentum values the highest precision for muon momentum measurement is achieved when the muon tracks are reconstructed using both tracking detectors. The calorimeters and the solenoid volumes separate about three meters the CT and the MS. It has been shown that the alignment of the CT with respect to the MS can not be guaranteed by a software alignment in a reasonable time scale. Therefore, an opto-mechanical system (the multipoint link system) have been designed to monitor, on-line, the relative position of both sub-detectors providing a common reference frame for both of them. The local alignment of the muon barrel spectrometer determines the relative position of the muon chambers with respect to themselves and also with respect to a carbon fiber rigid structure called MAB (Module for the Alignment of the Barrel). There are a total of 36 MABs distributed in the boundary planes of each muon spectrometer sector. This paper describes all the equipment and presents the principle of measurement. (author)

  12. Diabetes and dementia links

    Directory of Open Access Journals (Sweden)

    Paula Jankowska

    2018-06-01

    Full Text Available Introduction The number of patients suffering from diabetes mellitus is growing globally. It is expected to observe 253.4 million sufferers in geriatric population in 2045. In this time, also 131.5 million of people is going to have dementia and other cognitive problems. In people aged over 65 these two diseases are concomitant quite often. What are the connections in the area of etiology and treatment? Aim The purpose of this study is to present links between dementia and diabetes are depicted in professional literature. Results Diabetes and dementia are associated on many levels. These conditions have common risk factors. Diabetes may contribute to cognitive impairment in many ways, promoting development of atherosclerosis, brain vessel damage and vascular dementia. Alzheimer disease may be promoted by hyperglycemia and hyperinsulinemia. On contrary also hypoglycaemia, often met in elderly diabetic patients has negative impact on cognitive function. Dementia seriously affects treatment of diabetes. The main problems are not satisfying adherence and diabetes self-management. Conclusions Prevention of diabetes and dementia risk factors can be performed simultaneously as the are common for both diseases. Enhancing physical activity, reducing saturated fats consumption, levels of cholesterol and body mass are considered to be beneficial in the context of described conditions. Furthermore, treatment of diabetes is strongly affected by cognitive dysfunction. Management of dementive diabetics requires individualization and using long-acting drugs. It is crucial to reduce risk of life-threatening hypoglycaemias and to create wide team to take care of these patients.

  13. Hierarchical Linked Views

    Energy Technology Data Exchange (ETDEWEB)

    Erbacher, Robert; Frincke, Deb

    2007-07-02

    Coordinated views have proven critical to the development of effective visualization environments. This results from the fact that a single view or representation of the data cannot show all of the intricacies of a given data set. Additionally, users will often need to correlate more data parameters than can effectively be integrated into a single visual display. Typically, development of multiple-linked views results in an adhoc configuration of views and associated interactions. The hierarchical model we are proposing is geared towards more effective organization of such environments and the views they encompass. At the same time, this model can effectively integrate much of the prior work on interactive and visual frameworks. Additionally, we expand the concept of views to incorporate perceptual views. This is related to the fact that visual displays can have information encoded at various levels of focus. Thus, a global view of the display provides overall trends of the data while focusing in on individual elements provides detailed specifics. By integrating interaction and perception into a single model, we show how one impacts the other. Typically, interaction and perception are considered separately, however, when interaction is being considered at a fundamental level and allowed to direct/modify the visualization directly we must consider them simultaneously and how they impact one another.

  14. Linking to the Future

    Science.gov (United States)

    Moore, John W.

    1999-09-01

    of JCE in the mail each month, and I expect you do too. I can glance at the cover to get an overview of an issue's content, and I usually am enticed inside by intriguing cover art. I can scan the table of contents to find articles I want to read, or I can just browse through the issue to see what looks interesting. Usually the editors have juxtaposed related articles so that I often find a small treasure trove. The printed Journal is quite portable and can be read in a car or airplane. It will last a long time, and until the paper deteriorates, I will never have a problem reading back issues. I have almost every issue from the first day I subscribed and have even added some older ones from collections of retired colleagues who no longer had shelf space for them. I certainly would not want to give up my printed copies, and I want to keep getting them. I find that JCE Online provides a different kind of resource that is equally valuable. It contains more information, and information that is more appropriate in electronic form. It links related ideas into a much more complex web of information than is possible in print. And it opens pathways to lots of information that is not part of JCE but resides elsewhere. Using this issue as an example, let's take a tour of what JCE Online can do. Point your Web browser to http://jchemed.chem.wisc.edu Click on Journal and then on Current Issue (unless September 1999 is no longer the current issue, in which case you will find it in Past Issues). In the table of contents, find the article "UV Catalysis, Cyanotype Photography, and Sunscreens". Click on the title. When the abstract appears, click on Full Text (PDF) to see the article, just as it appears on page 1199 in this issue. When you are prompted, enter the name and subscriber number from your address label. At the end of the article you will find that supplementary materials are available (including a procedure for testing sunscreens) and you can click on the link to view them

  15. Object linking in repositories

    Science.gov (United States)

    Eichmann, David (Editor); Beck, Jon; Atkins, John; Bailey, Bill

    1992-01-01

    This topic is covered in three sections. The first section explores some of the architectural ramifications of extending the Eichmann/Atkins lattice-based classification scheme to encompass the assets of the full life cycle of software development. A model is considered that provides explicit links between objects in addition to the edges connecting classification vertices in the standard lattice. The second section gives a description of the efforts to implement the repository architecture using a commercially available object-oriented database management system. Some of the features of this implementation are described, and some of the next steps to be taken to produce a working prototype of the repository are pointed out. In the final section, it is argued that design and instantiation of reusable components have competing criteria (design-for-reuse strives for generality, design-with-reuse strives for specificity) and that providing mechanisms for each can be complementary rather than antagonistic. In particular, it is demonstrated how program slicing techniques can be applied to customization of reusable components.

  16. Oxidative metabolism in muscle.

    OpenAIRE

    Ferrari, M; Binzoni, T; Quaresima, V

    1997-01-01

    Oxidative metabolism is the dominant source of energy for skeletal muscle. Near-infrared spectroscopy allows the non-invasive measurement of local oxygenation, blood flow and oxygen consumption. Although several muscle studies have been made using various near-infrared optical techniques, it is still difficult to interpret the local muscle metabolism properly. The main findings of near-infrared spectroscopy muscle studies in human physiology and clinical medicine are summarized. The advantage...

  17. Tumor Macroenvironment and Metabolism

    OpenAIRE

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

    2014-01-01

    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 organ...

  18. Liver fat content in type 2 diabetes: relationship with hepatic perfusion and substrate metabolism

    NARCIS (Netherlands)

    Rijzewijk, Luuk J.; van der Meer, Rutger W.; Lubberink, Mark; Lamb, Hildo J.; Romijn, Johannes A.; de Roos, Albert; Twisk, Jos W.; Heine, Robert J.; Lammertsma, Adriaan A.; Smit, Johannes W. A.; Diamant, Michaela

    2010-01-01

    Hepatic steatosis is common in type 2 diabetes. It is causally linked to the features of the metabolic syndrome, liver cirrhosis, and cardiovascular disease. Experimental data have indicated that increased liver fat may impair hepatic perfusion and metabolism. The aim of the current study was to

  19. Specific gut microbiota features and metabolic markers in postmenopausal women with obesity

    DEFF Research Database (Denmark)

    Brahe, Lena Kirchner; Le Chatelier, E; Prifti, E

    2015-01-01

    BACKGROUND: Gut microbial gene richness and specific bacterial species are associated with metabolic risk markers in humans, but the impact of host physiology and dietary habits on the link between the gut microbiota and metabolic markers remain unclear. The objective of this study was to identify...

  20. The Relationship Between Shift Work and Metabolic Risk Factors : A Systematic Review of Longitudinal Studies

    NARCIS (Netherlands)

    Proper, Karin I; van de Langenberg, Daniëlla|info:eu-repo/dai/nl/374886970; Rodenburg, Wendy; Vermeulen, Roel C H|info:eu-repo/dai/nl/216532620; van der Beek, Allard J; van Steeg, Harry; van Kerkhof, Linda W M

    2016-01-01

    CONTEXT: Although the metabolic health effects of shift work have been extensively studied, a systematic synthesis of the available research is lacking. This review aimed to systematically summarize the available evidence of longitudinal studies linking shift work with metabolic risk factors.

  1. The interplay between sulphur and selenium metabolism influences the intracellular redox balance in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Mapelli, Valeria; Hillestrøm, Peter René; Patil, Kalpesh

    2012-01-01

    oxidative stress response is active when yeast actively metabolizes Se, and this response is linked to the generation of intracellular redox imbalance. The redox imbalance derives from a disproportionate ratio between the reduced and oxidized forms of glutathione and also from the influence of Se metabolism...

  2. Plasma apolipoprotein M is reduced in metabolic syndrome but does not predict intima media thickness

    DEFF Research Database (Denmark)

    Dullaart, Robin P F; Plomgaard, Peter; de Vries, Rindert

    2009-01-01

    BACKGROUND: Apolipoprotein (apo) M may exert anti-atherogenic properties in experimental studies. Its hepatic gene expression may be linked to glucose and lipid metabolism. Plasma apoM is decreased in obese mouse models. We hypothesized that plasma apoM is lower in metabolic syndrome (Met...

  3. Circulating adipocyte fatty acid-binding protein, juvenile obesity, and metabolic syndrome

    NARCIS (Netherlands)

    Krzystek-Korpacka, Malgorzata; Patryn, Eliza; Bednarz-Misa, Iwona; Mierzchala, Magdalena; Hotowy, Katarzyna; Czapinska, Elzbieta; Kustrzeba-Wojcicka, Irena; Gamian, Andrzej; Noczynska, Anna

    2011-01-01

    Adipocyte fatty acid-binding protein (A-FABP) links obesity and metabolic syndrome (MetS) and might be targeted in future therapies. Its utility as a MetS biomarker has been suggested in adults but has not been examined in children/adolescents. Our objectives were to identify metabolic parameters

  4. 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.

  5. Ca-48 metabolism studies

    International Nuclear Information System (INIS)

    Van der Merwe, D.G.

    1987-03-01

    Calcium metabolism has been studied in depth physiologically and is a relatively well-understood element in biochemistry and medicine. There is still only restricted knowledge of the metabolic fate of calcium in normal and abnormal paediatric subjects. The latter is partially owing to inadequate techniques for tracing and modelling calcium pathways in children. The advent of radioactive tracers has unquestionably enhanced medical research and improved the quality of many metabolic studies. The present study was aimed at the development, promotion and justification of a new tracer technique using the stable isotope, calcium-48. The obvious advantages of such a technique are its harmlessness tothe subject, its applicability to both short- and long-term studies as well as its usefulness to the study for which it was originally motivated, viz research defining the actual relationship between a calcium-deficient diet and the occurrence of rickets in rural Black children in South Africa. Exploratory instrumental analyses were performed specifically with serum samples. This proved successful enough to develop a less specific pre-concentration technique which improved the sensitivity and reduces the cost of doing calcium-48 metabolism studies. The results of a simple metabolic study are presented whereby the scope of the technique is demonstrated in a real situation. The possibilities and limitations of double-isotope metabolic studies are discussed, particularly with regard to strontium as the second tracer

  6. Cellular Metabolic Rate Is Influenced by Life-History Traits in Tropical and Temperate Birds

    OpenAIRE

    Jimenez, Ana Gabriela; Van Brocklyn, James; Wortman, Matthew; Williams, Joseph B.

    2014-01-01

    In general, tropical birds have a "slow pace of life," lower rates of whole-animal metabolism and higher survival rates, than temperate species. A fundamental challenge facing physiological ecologists is the understanding of how variation in life-history at the whole-organism level might be linked to cellular function. Because tropical birds have lower rates of whole-animal metabolism, we hypothesized that cells from tropical species would also have lower rates of cellular metabolism than cel...

  7. Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors

    OpenAIRE

    Montgomery, David C.; Sorum, Alexander W.; Guasch, Laura; Nicklaus, Marc C.; Meier, Jordan L.

    2015-01-01

    The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the met...

  8. NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus

    Science.gov (United States)

    Cantó, Carles; Menzies, Keir; Auwerx, Johan

    2015-01-01

    NAD+ has emerged as a vital cofactor that can rewire metabolism, activate sirtuins and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD+ metabolism revived interest in NAD+ boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD+ metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited. PMID:26118927

  9. How doth the little busy bee: unexpected metabolism.

    Science.gov (United States)

    Barros, L Felipe; Sierralta, Jimena; Weber, Bruno

    2015-01-01

    Brain energy metabolism powers information processing and behavior, much as electricity powers a computer. However, a recent study in insects suggests that this relationship is more interesting, causally linking aggressive behavior to energetics. These findings may also shed new light on aerobic glycolysis, a long-standing riddle of human brain physiology. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Malaria Parasite Metabolic Pathways (MPMP) Upgraded with Targeted Chemical Compounds

    KAUST Repository

    Ginsburg, Hagai

    2015-10-31

    Malaria Parasite Metabolic Pathways (MPMP) is the website for the functional genomics of intraerythrocytic Plasmodium falciparum. All the published information about targeted chemical compounds has now been added. Users can find the drug target and publication details linked to a drug database for further information about the medicinal properties of each compound.

  11. Metabolism related toxicity of diclofenac in yeast as model system

    NARCIS (Netherlands)

    van Leeuwen, J.S.; Vredenburg, G.; Dragovic, S.; Tjong, T.F.; Vos, J.C.; Vermeulen, N.P.E.

    2010-01-01

    Diclofenac is a widely used drug that can cause serious hepatotoxicity, which has been linked to metabolism by cytochrome P450s (P450). To investigate the role of oxidative metabolites in diclofenac toxicity, a model for P450-related toxicity was set up in Saccharomyces cerevisiae. We expressed a

  12. Malaria Parasite Metabolic Pathways (MPMP) Upgraded with Targeted Chemical Compounds

    KAUST Repository

    Ginsburg, Hagai; Abdel-Haleem, Alyaa M.

    2015-01-01

    Malaria Parasite Metabolic Pathways (MPMP) is the website for the functional genomics of intraerythrocytic Plasmodium falciparum. All the published information about targeted chemical compounds has now been added. Users can find the drug target and publication details linked to a drug database for further information about the medicinal properties of each compound.

  13. Malaria Parasite Metabolic Pathways (MPMP) Upgraded with Targeted Chemical Compounds.

    Science.gov (United States)

    Ginsburg, Hagai; Abdel-Haleem, Alyaa M

    2016-01-01

    Malaria Parasite Metabolic Pathways (MPMP) is the website for the functional genomics of intraerythrocytic Plasmodium falciparum. All the published information about targeted chemical compounds has now been added. Users can find the drug target and publication details linked to a drug database for further information about the medicinal properties of each compound. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Marko Kostovski

    2018-03-01

    CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.

  15. Three good reasons for heart surgeons to understand cardiac metabolism.

    Science.gov (United States)

    Doenst, Torsten; Bugger, Heiko; Schwarzer, Michael; Faerber, Gloria; Borger, Michael A; Mohr, Friedrich W

    2008-05-01

    It is the principal goal of cardiac surgeons to improve or reinstate contractile function with, through or after a surgical procedure on the heart. Uninterrupted contractile function of the heart is irrevocably linked to the uninterrupted supply of energy in the form of ATP. Thus, it would appear natural that clinicians interested in myocardial contractile function are interested in the way the heart generates ATP, i.e. the processes generally referred to as energy metabolism. Yet, it may appear that the relevance of energy metabolism in cardiac surgery is limited to the area of cardioplegia, which is a declining research interest. It is the goal of this review to change this trend and to illustrate the role and the therapeutic potential of metabolism and metabolic interventions for management. We present three compelling reasons why cardiac metabolism is of direct, practical interest to the cardiac surgeon and why a better understanding of energy metabolism might indeed result in improved surgical outcomes: (1) To understand cardioplegic arrest, ischemia and reperfusion, one needs a working knowledge of metabolism; (2) hyperglycemia is an underestimated and modifiable risk factor; (3) acute metabolic interventions can be effective in patients undergoing cardiac surgery.

  16. Bactericidal antibiotics induce programmed metabolic toxicity

    Directory of Open Access Journals (Sweden)

    Aislinn D. Rowan

    2016-03-01

    Full Text Available The misuse of antibiotics has led to the development and spread of antibiotic resistance in clinically important pathogens. These resistant infections are having a significant impact on treatment outcomes and contribute to approximately 25,000 deaths in the U.S. annually. If additional therapeutic options are not identified, the number of annual deaths is predicted to rise to 317,000 in North America and 10,000,000 worldwide by 2050. Identifying therapeutic methodologies that utilize our antibiotic arsenal more effectively is one potential way to extend the useful lifespan of our current antibiotics. Recent studies have indicated that modulating metabolic activity is one possible strategy that can impact the efficacy of antibiotic therapy. In this review, we will address recent advances in our knowledge about the impacts of bacterial metabolism on antibiotic effectiveness and the impacts of antibiotics on bacterial metabolism. We will particularly focus on two studies, Lobritz, et al. (PNAS, 112(27: 8173-8180 and Belenky et al. (Cell Reports, 13(5: 968–980 that together demonstrate that bactericidal antibiotics induce metabolic perturbations that are linked to and required for bactericidal antibiotic toxicity.

  17. Dietary fatty acid metabolism in prediabetes.

    Science.gov (United States)

    Noll, Christophe; Carpentier, André C

    2017-02-01

    Experimental evidences are strong for a role of long-chain saturated fatty acids in the development of insulin resistance and type 2 diabetes. Ectopic accretion of triglycerides in lean organs is a characteristic of prediabetes and type 2 diabetes and has been linked to end-organ complications. The contribution of disordered dietary fatty acid (DFA) metabolism to lean organ overexposure and lipotoxicity is still unclear, however. DFA metabolism is very complex and very difficult to study in vivo in humans. We have recently developed a novel imaging method using PET with oral administration of 14-R,S-F-fluoro-6-thia-heptadecanoic acid (FTHA) to quantify organ-specific DFA partitioning. Our studies thus far confirmed impaired storage of DFA per volume of fat mass in abdominal adipose tissues of individuals with prediabetes. They also highlighted the increased channeling of DFA toward the heart, associated with subclinical reduction in cardiac systolic and diastolic function in individuals with prediabetes. In the present review, we summarize previous work on DFA metabolism in healthy and prediabetic states and discuss these in the light of our novel findings using PET imaging of DFA metabolism. We herein provide an integrated view of abnormal organ-specific DFA partitioning in prediabetes in humans.

  18. The Mediator Complex and Lipid Metabolism.

    Science.gov (United States)

    Zhang, Yi; Xiaoli; Zhao, Xiaoping; Yang, Fajun

    2013-03-01

    The precise control of gene expression is essential for all biological processes. In addition to DNA-binding transcription factors, numerous transcription cofactors contribute another layer of regulation of gene transcription in eukaryotic cells. One of such transcription cofactors is the highly conserved Mediator complex, which has multiple subunits and is involved in various biological processes through directly interacting with relevant transcription factors. Although the current understanding on the biological functions of Mediator remains incomplete, research in the past decade has revealed an important role of Mediator in regulating lipid metabolism. Such function of Mediator is dependent on specific transcription factors, including peroxisome proliferator-activated receptor-gamma (PPARγ) and sterol regulatory element-binding proteins (SREBPs), which represent the master regulators of lipid metabolism. The medical significance of these findings is apparent, as aberrant lipid metabolism is intimately linked to major human diseases, such as type 2 diabetes and cardiovascular disease. Here, we briefly review the functions and molecular mechanisms of Mediator in regulation of lipid metabolism.

  19. Dissecting the insect metabolic machinery using twin ion mass spectrometry: a single P450 enzyme metabolizing the insecticide imidacloprid in vivo.

    Science.gov (United States)

    Hoi, Kin Kuan; Daborn, Phillip J; Battlay, Paul; Robin, Charles; Batterham, Philip; O'Hair, Richard A J; Donald, William A

    2014-04-01

    Insecticide resistance is one of the most prevalent examples of anthropogenic genetic change, yet our understanding of metabolic-based resistance remains limited by the analytical challenges associated with rapidly tracking the in vivo metabolites of insecticides at nonlethal doses. Here, using twin ion mass spectrometry analysis of the extracts of whole Drosophila larvae and excreta, we show that (i) eight metabolites of the neonicotinoid insecticide, imidacloprid, can be detected when formed by susceptible larval genotypes and (ii) the specific overtranscription of a single gene product, Cyp6g1, associated with the metabolic resistance to neonicotinoids, results in a significant increase in the formation of three imidacloprid metabolites that are formed in C-H bond activation reactions; that is, Cyp6g1 is directly linked to the enhanced metabolism of imidacloprid in vivo. These results establish a rapid and sensitive method for dissecting the metabolic machinery of insects by directly linking single gene products to insecticide metabolism.

  20. Interdependence of nutrient metabolism and the circadian clock system: Importance for metabolic health

    Science.gov (United States)

    Ribas-Latre, Aleix; Eckel-Mahan, Kristin

    2016-01-01

    Background While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. Scope of review This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively

  1. Metabolic interactions between cysteamine and epigallocatechin gallate.

    Science.gov (United States)

    Izzo, Valentina; Pietrocola, Federico; Sica, Valentina; Durand, Sylvère; Lachkar, Sylvie; Enot, David; Bravo-San Pedro, José Manuel; Chery, Alexis; Esposito, Speranza; Raia, Valeria; Maiuri, Luigi; Maiuri, Maria Chiara; Kroemer, Guido

    2017-02-01

    Phase II clinical trials indicate that the combination of cysteamine plus epigallocatechin gallate (EGCG) is effective against cystic fibrosis in patients bearing the most frequent etiological mutation (CFTRΔF508). Here, we investigated the interaction between both agents on cultured respiratory epithelia cells from normal and CFTRΔF508-mutated donors. We observed that the combination of both agents affected metabolic circuits (and in particular the tricarboxylic acid cycle) in a unique way and that cysteamine plus EGCG reduced cytoplasmic protein acetylation more than each of the 2 components alone. In a cell-free system, protein cross-linking activity of EGCG was suppressed by cysteamine. Finally, EGCG was able to enhance the conversion of cysteamine into taurine in metabolic flux experiments. Altogether, these results indicate that multiple pharmacological interactions occur between cysteamine and EGCG, suggesting that they contribute to the unique synergy of both agents in restoring the function of mutated CFTRΔF508.

  2. Social Metabolism and Environmental Conflicts in India

    Directory of Open Access Journals (Sweden)

    Joan Martinez-Alier

    2014-04-01

    Full Text Available This paper explains the methods for counting the energy and material flows in the economy, and gives the main results of the Material Flows for the economy of India between 1961 and 2008 as researched by Simron Singh et al (2012. Drawing on work done in the EJOLT project, some illustrations are given of the links between the changing social metabolism and ecological distribution conflicts, looking at responses in Odisha to bauxite mining, at conflicts on sand mining, at disputes on waste management options in Delhi and at ship dismantling in Alang, Gujarat. The aim is to show how a history of social metabolism, of socio-environmental conflicts, and of the changing valuation languages deployed by various social actors in such conflicts, could be written in a common framework.

  3. Vertigo and metabolic disorders.

    Science.gov (United States)

    Santos, Maruska D' Aparecida; Bittar, Roseli Saraiva Moreira

    2012-01-01

    Metabolic disorders are accepted by many authors as being responsible for balance disorders. Because of the importance of metabolic disorders in the field of labyrinthine dysfunction, we decided to assess the prevalence of carbohydrates, lipids and thyroid hormones disorders in our patients with vestibular diseases. The study evaluates the metabolic profile of 325 patients with vertigo who sought the Otolaryngology Department of the University of São Paulo in the Hospital das Clínicas da Universidade de São Paulo. The laboratory tests ordered according to the classical research protocol were: low-density lipoprotein cholesterol fraction, TSH, T3, T4 and fasting blood sugar level. The metabolic disorders found and the ones that were observed in the general population were compared. The high level of low-density lipoprotein cholesterol, the altered levels of thyroid hormones, the higher prevalence of diabetes mellitus were the most significant changes found in the group of study. The higher amount of metabolic disorders in patients with vertigo disease reinforces the hypothesis of its influence on the etiopathogenesis of cochleovestibular symptoms.

  4. Metabolic surgery: quo vadis?

    Science.gov (United States)

    Ramos-Leví, Ana M; Rubio Herrera, Miguel A

    2014-01-01

    The impact of bariatric surgery beyond its effect on weight loss has entailed a change in the way of regarding it. The term metabolic surgery has become more popular to designate those interventions that aim at resolving diseases that have been traditionally considered as of exclusive medical management, such as type 2 diabetes mellitus (T2D). Recommendations for metabolic surgery have been largely addressed and discussed in worldwide meetings, but no definitive consensus has been reached yet. Rates of diabetes remission after metabolic surgery have been one of the most debated hot topics, with heterogeneity being a current concern. This review aims to identify and clarify controversies regarding metabolic surgery, by focusing on a critical analysis of T2D remission rates achieved with different bariatric procedures, and using different criteria for its definition. Indications for metabolic surgery for patients with T2D who are not morbidly obese are also discussed. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

  5. Role of myokines in exercise and metabolism

    DEFF Research Database (Denmark)

    Pedersen, Bente Klarlund; Åkerström, Thorbjörn; Nielsen, Anders R.

    2007-01-01

    of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an "exercise factor," which could mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We suggest that cytokines and other peptides...... the capacity to express several myokines. To date the list includes IL-6, IL-8, and IL-15, and contractile activity plays a role in regulating the expression of these cytokines in skeletal muscle. The present review focuses on muscle-derived cytokines, their regulation by exercise, and their possible roles...

  6. Normal Roles for Dietary Fructose in Carbohydrate Metabolism

    Directory of Open Access Journals (Sweden)

    Maren R. Laughlin

    2014-08-01

    Full Text Available Although there are many well-documented metabolic effects linked to the fructose component of a very high sugar diet, a healthy diet is also likely to contain appreciable fructose, even if confined to that found in fruits and vegetables. These normal levels of fructose are metabolized in specialized pathways that synergize with glucose at several metabolic steps. Glucose potentiates fructose absorption from the gut, while fructose catalyzes glucose uptake and storage in the liver. Fructose accelerates carbohydrate oxidation after a meal. In addition, emerging evidence suggests that fructose may also play a role in the secretion of insulin and GLP-1, and in the maturation of preadipocytes to increase fat storage capacity. Therefore, fructose undergoing its normal metabolism has the interesting property of potentiating the disposal of a dietary carbohydrate load through several routes.

  7. The metabolic effects of diuron in the rat liver.

    Science.gov (United States)

    da Silva Simões, Mellina; Bracht, Lívia; Parizotto, Angela Valderrama; Comar, Jurandir Fernando; Peralta, Rosane Marina; Bracht, Adelar

    2017-09-01

    A systematic study on the effects of diuron on the hepatic metabolism was conducted with emphasis on parameters linked to energy metabolism. The experimental system was the isolated perfused rat liver. The results demonstrate that diuron inhibited biosynthesis (gluconeogenesis) and ammonia detoxification, which are dependent of ATP generated within the mitochondria. Conversely, it stimulated glycolysis and fructolysis, which are compensatory phenomena for an inhibited mitochondrial ATP generation. Furthermore, diuron diminished the cellular ATP content under conditions where the mitochondrial respiratory chain was the only source of this compound. Besides the lack of circulating glucose due to gluconeogenesis inhibition, one can expect metabolic acidosis due to excess lactate production, impairment of ammonia detoxification and cell damage due to a deficient maintenance of its homeostasis. Some of the general signs of toxicity that were observed in diuron-treated rats can be attributed, partly at least, to the effects of the herbicide on energy metabolism. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... link between drug misuse and HIV. http://1.usa.gov/1z20ww6 How many of us think about ... can’t ignore. Learn the Link: http://1.usa.gov/1uSUAI3 Think you’re not at risk? ...

  9. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... at: http://www.drugabuse.gov/news-events/public-education-projects/learn-link-drugs-hiv . 120x90 460x80 486x60 Social Media Send the message to young people and to parents, teachers, and the media about the link between drug misuse and HIV. Post on Facebook or Twitter ; add photos to your Flickr , ...

  10. Decouplink: Dynamic Links for Java

    DEFF Research Database (Denmark)

    Jensen, Martin Lykke Rytter; Jørgensen, Bo Nørregaard

    2011-01-01

    of dimensions of extension that can be exploited without performing modification of existing types. Thus, dynamic links make it possible to enforce the open/closed principle in situations where it would otherwise not be possible. We present Decouplink – a library-based implementation of dynamic links for Java...

  11. [Sex-linked juvenile retinoschisis].

    Science.gov (United States)

    François, P; Turut, P; Soltysik, C; Hache, J C

    1976-02-01

    About 13 observations of sexe linked juvenile retinoschisis, the authors describe the ophthalmoscopic, fluorographic and functional aspects of the disease whose caracteristics are:--its sexe linked recessive heredity; --its clinical characterestics associating: a microcystic macular degeneration, peripheral retinal lesions, vitreous body alterations, --an electroretinogram of the negative type.

  12. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Learn the Link campaign uses TV, print, and Web public service announcements (PSAs), as well as posters, e-cards, ... to misuse drugs. The Learn the Link public service campaign is just one ... site. Sincerely, Nora D. Volkow, M.D. Director ...

  13. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Link Need ideas for posts? We’ve provided sample Facebook status updates that you can easily copy ... LearntheLink. Need ideas for tweets? We’ve provided sample tweets that you can easily copy and paste ...

  14. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... projects/learn-link-drugs-hiv . 120x90 460x80 486x60 Social Media Send the message to young people and ... HIV/AIDS and the discovery of promising treatment interventions for breaking the harmful links between them, we ...

  15. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... at: http://www.drugabuse.gov/news-events/public-education-projects/learn-link-drugs-hiv . 120x90 460x80 486x60 Social Media Send the message to young people and to parents, teachers, and the media about the link between drug ...

  16. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse ... Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with drug misuse are ...

  17. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... HIV. Post on Facebook About Learn the Link Need ideas for posts? We’ve provided sample Facebook ... HIV, be sure to use the hashtag #LearntheLink. Need ideas for tweets? We’ve provided sample tweets ...

  18. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse Commonly Abused Drugs Charts Emerging ... Badges Other Resources Strategic Plan Search Share Print Home » News & Events » Public Education Projects » Learn the Link - ...

  19. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... site. Please link these banners back to this site at: http://www.drugabuse.gov/news-events/public-education-projects/learn-link-drugs-hiv . 120x90 460x80 486x60 Social Media Send the message to young people and to ...

  20. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs ... HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with drug misuse ...

  1. Epstein–Barr Virus-Induced Metabolic Rearrangements in Human B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Pier P. Piccaluga

    2018-06-01

    Full Text Available Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect. More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein–Barr virus (EBV was the first virus linked with cancer in humans when Burkitt lymphoma (BL was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas.

  2. Metabolism of phencyclidine

    International Nuclear Information System (INIS)

    Hoag, M.K.P.

    1987-01-01

    Phencyclidine (PCP) is a drug of abuse which may produce, in some users, a persistent schizophreniform psychosis. The possibility that long term effects of PCP are mediated by metabolic activation of the parent compound to reactive species is consistent with the demonstration of metabolism-dependent covalent binding of radiolabeled PCP in vivo and in vitro to macromolecules in rodent lung, liver, and kidney. Formation of the electrophilic iminium ion metabolite of PCP is believed to be critical for covalent binding since binding was inhibited by cyanide ion at concentrations which did not inhibit metabolism of PCP but did trap the iminium ion to form the corresponding alpha-aminonitrile. The present studies were designed to characterize further the biological fate of PCP by identifying possible macromolecular targets of the reactive metabolite(s)

  3. A mapping of drug space from the viewpoint of small molecule metabolism.

    Directory of Open Access Journals (Sweden)

    James Corey Adams

    2009-08-01

    Full Text Available Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the "effect space" comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.

  4. A mapping of drug space from the viewpoint of small molecule metabolism.

    Science.gov (United States)

    Adams, James Corey; Keiser, Michael J; Basuino, Li; Chambers, Henry F; Lee, Deok-Sun; Wiest, Olaf G; Babbitt, Patricia C

    2009-08-01

    Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the "effect space" comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.

  5. Metabolic changes in malnutrition.

    Science.gov (United States)

    Emery, P W

    2005-10-01

    This paper is concerned with malnutrition caused by inadequate intake of all the major nutrients rather than deficiency diseases relating to a single micronutrient. Three common situations are recognised: young children in third world countries with protein-energy malnutrition; adults in the same countries who are chronically adapted to subsisting on marginally inadequate diets; and patients who become malnourished as a result of chronic diseases. In all these situations infectious diseases are often also present, and this complicates the interpretation of biochemical and physiological observations. The metabolic response to starvation is primarily concerned with maintaining a supply of water-soluble substrates to supply energy to the brain. Thus there is an initial rise in metabolic rate, reflecting gluconeogenic activity. As fasting progresses, gluconeogenesis is suppressed to minimise muscle protein breakdown and ketones become the main fuel for the brain. With chronic underfeeding the basal metabolic rate per cell appears to fall, but the mechanistic basis for this is not clear. The main adaptation to chronic energy deficiency is slow growth and low adult body size, although the reduction in energy requirement achieved by this is partially offset by the preservation of the more metabolically active organs at the expense of muscle, which has a lower metabolic rate. The interaction between malnutrition and the metabolic response to trauma has been studied using an animal model. The rise in energy expenditure and urinary nitrogen excretion following surgery were significantly attenuated in malnourished rats, suggesting that malnutrition impairs the ability of the body to mobilise substrates to support inflammatory and reparative processes. However, the healing process in wounded muscle remained unimpaired in malnutrition, suggesting that this process has a high biological priority.

  6. Urea metabolism in plants.

    Science.gov (United States)

    Witte, Claus-Peter

    2011-03-01

    Urea is a plant metabolite derived either from root uptake or from catabolism of arginine by arginase. In agriculture, urea is intensively used as a nitrogen fertilizer. Urea nitrogen enters the plant either directly, or in the form of ammonium or nitrate after urea degradation by soil microbes. In recent years various molecular players of plant urea metabolism have been investigated: active and passive urea transporters, the nickel metalloenzyme urease catalyzing the hydrolysis of urea, and three urease accessory proteins involved in the complex activation of urease. The degradation of ureides derived from purine breakdown has long been discussed as a possible additional metabolic source for urea, but an enzymatic route for the complete hydrolysis of ureides without a urea intermediate has recently been described for Arabidopsis thaliana. This review focuses on the proteins involved in plant urea metabolism and the metabolic sources of urea but also addresses open questions regarding plant urea metabolism in a physiological and agricultural context. The contribution of plant urea uptake and metabolism to fertilizer urea usage in crop production is still not investigated although globally more than half of all nitrogen fertilizer is applied to crops in the form of urea. Nitrogen use efficiency in crop production is generally well below 50% resulting in economical losses and creating ecological problems like groundwater pollution and emission of nitric oxides that can damage the ozone layer and function as greenhouse gasses. Biotechnological approaches to improve fertilizer urea usage bear the potential to increase crop nitrogen use efficiency. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  7. Nitrile Metabolizing Yeasts

    Science.gov (United States)

    Bhalla, Tek Chand; Sharma, Monica; Sharma, Nitya Nand

    Nitriles and amides are widely distributed in the biotic and abiotic components of our ecosystem. Nitrile form an important group of organic compounds which find their applications in the synthesis of a large number of compounds used as/in pharmaceutical, cosmetics, plastics, dyes, etc>. Nitriles are mainly hydro-lyzed to corresponding amide/acid in organic chemistry. Industrial and agricultural activities have also lead to release of nitriles and amides into the environment and some of them pose threat to human health. Biocatalysis and biotransformations are increasingly replacing chemical routes of synthesis in organic chemistry as a part of ‘green chemistry’. Nitrile metabolizing organisms or enzymes thus has assumed greater significance in all these years to convert nitriles to amides/ acids. The nitrile metabolizing enzymes are widely present in bacteria, fungi and yeasts. Yeasts metabolize nitriles through nitrilase and/or nitrile hydratase and amidase enzymes. Only few yeasts have been reported to possess aldoxime dehydratase. More than sixty nitrile metabolizing yeast strains have been hither to isolated from cyanide treatment bioreactor, fermented foods and soil. Most of the yeasts contain nitrile hydratase-amidase system for metabolizing nitriles. Transformations of nitriles to amides/acids have been carried out with free and immobilized yeast cells. The nitrilases of Torulopsis candida>and Exophiala oligosperma>R1 are enantioselec-tive and regiospecific respectively. Geotrichum>sp. JR1 grows in the presence of 2M acetonitrile and may have potential for application in bioremediation of nitrile contaminated soil/water. The nitrilase of E. oligosperma>R1 being active at low pH (3-6) has shown promise for the hydroxy acids. Immobilized yeast cells hydrolyze some additional nitriles in comparison to free cells. It is expected that more focus in future will be on purification, characterization, cloning, expression and immobilization of nitrile metabolizing

  8. Hypothyroidism in metabolic syndrome

    Directory of Open Access Journals (Sweden)

    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

  9. Prokaryote metabolism activity

    OpenAIRE

    Biederman, Lori

    2017-01-01

    I wrote this activity to emphasize that prokaryotic organisms can carry out 6 different types of metabolisms (as presented in Freeman’s Biological Science textbook) and this contrasts to eukaryotes, which can only use 2 metabolism pathways (photoautotroph and heterotroph).    For in class materials I remove the  red box (upper right corner) and print slides 3-10, place them back-to-back and laminate them.  The students get a key (slide 2) and a two-sided organism sheet...

  10. LinkMind: Link Optimization in Swarming Mobile Sensor Networks

    DEFF Research Database (Denmark)

    Ngo, Trung Dung

    2012-01-01

    of the most advantageous properties of the swarming wireless sensor network is that mobile nodes can work cooperatively to organize an ad-hoc network and optimize the network link capacity to maximize the transmission of gathered data from a source to a target. This paper describes a new method of link...... optimization of swarming mobile sensor networks. The new method is based on combination of the artificial potential force guaranteeing connectivities of the mobile sensor nodes and the max-flow min-cut theorem of graph theory ensuring optimization of the network link capacity. The developed algorithm...

  11. 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.

  12. Interactions between host metabolism, immune regulation, and the gut microbiota in diet-associated obesity and metabolic dysfunction

    DEFF Research Database (Denmark)

    Andersen, Daniel

    The increase in the prevalence of obesity and obesity-associated complications such as the metabolic syndrome is becoming a global challenge. Dietary habits and nutrient consumption modulates host homeostasis, which manifests in various diet-induced complications marked by changes in host...... metabolism and immune regulation, which are intricately linked. In addition, diet effectively shapes the gut microbiota composition and activity, which in turn interacts with the host to modulate host metabolism and immune regulation. In the three studies included in this PhD thesis, we have explored...... the impact of specific dietary components on host metabolic function, immune regulation and gut microbiota composition and activity. In the first study, we have characterized the effect of a combined high-fat and gliadin-rich diet, since dietary gliadin has been reported to be associated with intestinal...

  13. Association of Metabolic Syndrome and Its Components with Knee Osteoarthritis

    Directory of Open Access Journals (Sweden)

    Shahpoor Maddah

    2015-12-01

    Full Text Available The association of obesity and other metabolic conditions with osteoarthritis is under debate; however, a strong link between metabolic disturbances is suggested to contribute to increased incidences and progression of osteoarthritis. We examined the association of metabolic syndrome and its components with the incidence of knee osteoarthritis in Iranian population. A community-based study was conducted on a total of 625 Iranian volunteers with the complaint of knee pain. Weight-bearing and anteroposterior plain radiographs of both knees were taken on the day of admission. Metabolic syndrome was diagnosed using the modified Adult Treatment Panel III of the National Cholesterol Education Program criteria. Prevalence rates of metabolic syndrome were 22.5% in males and 11.6% in females (P=0.002. The prevalence rate of knee osteoarthritis was 20.0% in males and 43.8% of females (P<0.001. In both genders, osteoarthritis group had higher serum levels of triglyceride and systolic blood pressure in comparison with non-osteoarthritis group. Women with osteoarthritis had higher Body Mass Index (BMI, however, this association was not observed in men. In females, the presence of osteoarthritis was significantly associated with the presence of metabolic syndrome, with the risk of metabolic syndrome in the osteoarthritis group at 2.187 fold the risk in the non-osteoarthritis group. But, the presence of osteoarthritis was not associated with metabolic syndrome in males. Metabolic syndrome mainly through high BMI is associated with knee osteoarthritis in the Iranian women, but neither metabolic syndrome nor any related components are associated with knee osteoarthritis in men.

  14. Metabolic Plasticity of Stem Cells and Macrophages in Cancer

    Directory of Open Access Journals (Sweden)

    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.

  15. Primary Metabolic Pathways and Metabolic Flux Analysis

    DEFF Research Database (Denmark)

    Villadsen, John

    2015-01-01

    his chapter introduces the metabolic flux analysis (MFA) or stoichiometry-based MFA, and describes the quantitative basis for MFA. It discusses the catabolic pathways in which free energy is produced to drive the cell-building anabolic pathways. An overview of these primary pathways provides...... the reader who is primarily trained in the engineering sciences with atleast a preliminary introduction to biochemistry and also shows how carbon is drained off the catabolic pathways to provide precursors for cell mass building and sometimes for important industrial products. The primary pathways...... to be examined in the following are: glycolysis, primarily by the EMP pathway, but other glycolytic pathways is also mentioned; fermentative pathways in which the redox generated in the glycolytic reactions are consumed; reactions in the tricarboxylic acid (TCA) cycle, which produce biomass precursors and redox...

  16. Sleep and Metabolism: An Overview

    Directory of Open Access Journals (Sweden)

    Sunil Sharma

    2010-01-01

    Full Text Available Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders may be altering human metabolism.

  17. Bystander signaling via oxidative metabolism.

    Science.gov (United States)

    Sawal, Humaira Aziz; Asghar, Kashif; Bureik, Matthias; Jalal, Nasir

    2017-01-01

    The radiation-induced bystander effect (RIBE) is the initiation of biological end points in cells (bystander cells) that are not directly traversed by an incident-radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS) act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to pursue this field of science.

  18. Metabolic syndrome: definitions and controversies

    Directory of Open Access Journals (Sweden)

    Kaltsas Gregory

    2011-05-01

    Full Text Available Abstract Metabolic syndrome (MetS is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. Currently, several different definitions of MetS exist, causing substantial confusion as to whether they identify the same individuals or represent a surrogate of risk factors. Recently, a number of other factors besides those traditionally used to define MetS that are also linked to the syndrome have been identified. In this review, we critically consider existing definitions and evolving information, and conclude that there is still a need to develop uniform criteria to define MetS, so as to enable comparisons between different studies and to better identify patients at risk. As the application of the MetS model has not been fully validated in children and adolescents as yet, and because of its alarmingly increasing prevalence in this population, we suggest that diagnosis, prevention and treatment in this age group should better focus on established risk factors rather than the diagnosis of MetS.

  19. Neonatal nutrition and metabolism

    National Research Council Canada - National Science Library

    Thureen, Patti J; Hay, William W

    2006-01-01

    ..., the volume highlights the important longterm effects of fetal and neonatal growth on health in later life. In addition, there are very practical chapters on methods and techniques for assessing nutritional status, body composition, and evaluating metabolic function. Written by an authoritative, international team of cont...

  20. Insect flight muscle metabolism

    NARCIS (Netherlands)

    Horst, D.J. van der; Beenakkers, A.M.Th.; Marrewijk, W.J.A. van

    1984-01-01

    The flight of an insect is of a very complicated and extremely energy-demanding nature. Wingbeat frequency may differ between various species but values up to 1000 Hz have been measured. Consequently metabolic activity may be very high during flight and the transition from rest to flight is

  1. Sleep and metabolic function.

    Science.gov (United States)

    Morselli, Lisa L; Guyon, Aurore; Spiegel, Karine

    2012-01-01

    Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health.

  2. Synthetic Metabolic Pathways

    DEFF Research Database (Denmark)

    topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and practical, Synthetic Metabolic Pathways: Methods and Protocols aims to ensure successful results in the further study...

  3. Metabolism of femoxetine

    International Nuclear Information System (INIS)

    Larsson, H.; Lund, J.

    1981-01-01

    The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two 14 C-femoxetine compounds with labelling in different positions. The metabolic pathways were oxidations (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N-oxide than monkey and man, while most of the radioactivity (60-100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N-CH 3 group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolic pattern. No dose dependency was observed in any of the three animal species investigated. (author)

  4. 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.

  5. Metabolic Diseases of Muscle

    Science.gov (United States)

    ... here and still get the great care and treatment I received in Michigan.” MDA Is Here to Help You T he Muscular Dystrophy Association offers a vast array of services to help you and your family deal with metabolic diseases of muscle. The staff at your local MDA office is ...

  6. The Kynurenine Pathway: a Proposed Mechanism Linking Diabetes and Periodontal Disease in Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Rishabh Kapila

    2011-07-01

    Full Text Available Introduction: Diabetes mellitus is a metabolic disease characte-rized by dysregulation of carbohydrate, protein and lipid metabolism. Diabetes could result, in part, in activation of tryptophan metabolism. Diabetic patients are more susceptible to gingivitis and periodontitis than healthy subjects. The salivary kynurenine derivatives are also implicated in the onset and development of periodontal dis-ease in humans.The hypothesis: We propose that the tryptophan metabolites via kynurenine pathway may lead to diabetes and an increased severity of periodontal disease in diabetic patients, thus linking both diabetes and periodontal disease.Evaluation of the hypothesis: Tryptophan has been found in significant amount in saliva in diabetic individuals in some studies, particularly tryptophan metabolites like kynurenine and anthranilic acid. Moreover, altered tryptophan metabolism has also been reported in the onset of periodontal disease. Thus, this correlation between diabetes mellitus, periodontal disease and salivary tryptophan metabolite levels could be related to the impaired kynurenine pathway metabolism of tryptophan.

  7. Basal metabolism in tropical birds: latitude, altitude, and the ‘pace of life’

    OpenAIRE

    Londoño, Gustavo Adolfo

    2015-01-01

    Life history varies across latitudes, with the ‘pace of life’ being ‘slower’ in tropical regions. Because life history is coupled to energy metabolism via allocation tradeoffs and links between performance capacity and energy use, low metabolic intensity is expected in tropical animals. Low metabolism has been reported for lowland tropical birds, but it is unclear if this is due to ‘slow’ life history or to a warm, stable environment. We measured basal metabolic rates (BMR) of 253 bird spe...

  8. Obesity and Cancer Progression: Is There a Role of Fatty Acid Metabolism?

    Directory of Open Access Journals (Sweden)

    Seher Balaban

    2015-01-01

    Full Text Available Currently, there is renewed interest in elucidating the metabolic characteristics of cancer and how these characteristics may be exploited as therapeutic targets. Much attention has centered on glucose, glutamine and de novo lipogenesis, yet the metabolism of fatty acids that arise from extracellular, as well as intracellular, stores as triacylglycerol has received much less attention. This review focuses on the key pathways of fatty acid metabolism, including uptake, esterification, lipolysis, and mitochondrial oxidation, and how the regulators of these pathways are altered in cancer. Additionally, we discuss the potential link that fatty acid metabolism may serve between obesity and changes in cancer progression.

  9. Cancer-specific Therapeutic Potential of Resveratrol: Metabolic Approach against Hallmarks of Cancer

    Directory of Open Access Journals (Sweden)

    Dong Hoon Suh

    2013-08-01

    Full Text Available ABSTRACTCancer hallmarks include evading apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis. Cancer cells undergo metabolic reprogramming and inevitably take advantage of glycolysis to meet the increased metabolic demand: rapid energy generation and macromolecular synthesis. Resveratrol, a polyphenolic phytoalexin, is known to exhibit pleiotropic anti-cancer effects most of which are linked to metabolic reprogramming in cancer cells. This review summarizes various anti-cancer effects of resveratrol in the context of cancer hallmarks in relation to metabolic reprogramming.

  10. Cerebral ketone body metabolism.

    Science.gov (United States)

    Morris, A A M

    2005-01-01

    Ketone bodies (KBs) are an important source of energy for the brain. During the neonatal period, they are also precursors for the synthesis of lipids (especially cholesterol) and amino acids. The rate of cerebral KB metabolism depends primarily on the concentration in blood; high concentrations occur during fasting and on a high-fat diet. Cerebral KB metabolism is also regulated by the permeability of the blood-brain barrier (BBB), which depends on the abundance of monocarboxylic acid transporters (MCT1). The BBB's permeability to KBs increases with fasting in humans. In rats, permeability increases during the suckling period, but human neonates have not been studied. Monocarboxylic acid transporters are also present in the plasma membranes of neurons and glia but their role in regulating KB metabolism is uncertain. Finally, the rate of cerebral KB metabolism depends on the activities of the relevant enzymes in brain. The activities vary with age in rats, but reliable results are not available for humans. Cerebral KB metabolism in humans differs from that in the rat in several respects. During fasting, for example, KBs supply more of the brain's energy in humans than in the rat. Conversely, KBs are probably used more extensively in the brain of suckling rats than in human neonates. These differences complicate the interpretation of rodent studies. Most patients with inborn errors of ketogenesis develop normally, suggesting that the only essential role for KBs is as an alternative fuel during illness or prolonged fasting. On the other hand, in HMG-CoA lyase deficiency, imaging generally shows asymptomatic white-matter abnormalities. The ability of KBs to act as an alternative fuel explains the effectiveness of the ketogenic diet in GLUT1 deficiency, but its effectiveness in epilepsy remains unexplained.

  11. A Metabolic Race

    Directory of Open Access Journals (Sweden)

    A.M.S. Costa et al.

    2017-07-01

    Full Text Available Metabolic Syndrome describes a set of metabolic risk factors that manifest in an individual and some aspects contribute to its appearance: genetic, overweight and the absence of physical activity. So, a board game was created to simulate the environment and routine experienced by UFF students that could contribute  to the development of Metabolic Syndrome. Players move along a simplified map of Niterói city, where places as Antônio Pedro Hospital (HUAP are pointed out. OBJECTIVES: This project aimed to develop an educational game to consolidate Metabolic Syndrome biochemical events. MATERIAL E METHODS: Each group receives a board, pins, dice, question, challenge and diagnostics cards. One student performs the family doctor function, responsable for delivering cards, reading activities and providing diagnosis to players when game is over.The scoring system is based on 3 criteria for Metabolic Syndrome diagnosis: glycemia, abdominal obesity and HDL cholesterol. At the end of game, it is possible to calculate the rates of each player and provide proportional diagnosis. The winner is the healthiest that first arrives at HUAP. RESULTS AND DISCUSSION: The game was applied to 50 students and only 10% classified the subject-matter as difficult. This finding highlight the need to establish new methods to enhance the teaching and learning process and decrease the students’ dificulties. Students evaluated the game as an important educational support and 85% of them agreed it complements  and consolidate the content discussed in classroom. Finally, the game was very highly rated by students according to their perception about their own performance while playing.  In addition, 95 % students pointed they would play again and 98% said they think games are able to optimize learning. CONCLUSIONS: It was possible not only to approximate biochemical phenomena to the students’ daily life, but also to solidify the theoretical concepts in a dynamic and fun

  12. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Notes Podcasts E-Newsletters Public Education Projects National Drug & Alcohol Facts Week NIDA TV PEERx Drugs & Health Blog ... Award for Addiction Science USA Science & Engineering Festival Drug & Alcohol Chat Day HBO Addiction Project Learn the Link ...

  13. Drugs + HIV, Learn the Link

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    Full Text Available ... she went to a party and under the influence of drugs and alcohol engaged in risky sexual ... the message to young people and to parents, teachers, and the media about the link between drug ...

  14. Drugs + HIV, Learn the Link

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    Full Text Available ... Drugs and HIV Learn the Link - Drugs and HIV Email Facebook Twitter 2005 –Ongoing Behaviors associated with ... Send the Message . Get the Facts What are HIV and AIDS? HIV (human immunodeficiency virus) is the ...

  15. Medicare and Medicaid Linked Files

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Medicare-Medicaid Linked Enrollee Analytic Data Source (MMLEADS) has been developed to allow for the examination of all Medicare and Medicaid enrollment and...

  16. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available Skip to main content En español Researchers Medical & Health Professionals Patients & Families Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu ...

  17. Drugs + HIV, Learn the Link

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    Full Text Available ... Link between drug use and HIV and to help us Send the Message . Get the Facts What ... and the public. Send the Message Overview Please help us send the message to young people and ...

  18. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... people on HAART (highly active antiretroviral therapy), for example, who continue to misuse drugs. The Learn the Link public service campaign is just one example of how NIDA continues to respond to the ...

  19. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... HIV Learn the Link - Drugs and HIV ... Drugs can change the way the brain works, disrupting the parts of the brain that people use to weigh risks and benefits when making decisions. ...

  20. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... HIV (human immunodeficiency virus) is the virus that causes AIDS (acquired immune deficiency syndrome). AIDS is a ... time. The virus (HIV) and the disease it causes (AIDS) are often linked and referred to as " ...

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... It contains information for young people, parents and teachers, and the media with links to our latest ... greater injury to cells in the brain and cognitive impairment among people who use methamphetamine than among ...

  2. Drugs + HIV, Learn the Link

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    Full Text Available ... of many drugs, which can alter judgment and inhibition and lead people to engage in impulsive and ... easily copy and paste to help show your support for Learn the Link . Be sure to check ...

  3. Front end data link processor

    International Nuclear Information System (INIS)

    Wallace, J.J.

    1988-01-01

    It is possible to expand the data acquisition capabilities of an existing process computer to include other dedicated computer based systems, provided each system has at least minimal data link capabilities. The following paper discusses the addition of three computer based acquisition systems to a Honeywell 4500C (also designated the 45000) running the SEER system. Only one data link port was required to support the link. Each of the three specialized systems implemented data link protocols used by their suppliers in previous projects: none of the three were compatible with Honeywell's protocol. Part one of the following provides a generic overview of the project and would be relevent to the operator of any process system interested in expansion. Part two provides specific details of this project and may serve to provide performance benchmarks to those who wish to consider a similar project

  4. EPA Linked Open Data (Collection)

    Data.gov (United States)

    U.S. Environmental Protection Agency — This is a collection item referencing the following EPA Linked Data resources: - EPA Facility Registry Service (FRS) - EPA Substance Registry Service (SRS) -...

  5. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA Donating to NIDA Frequently Asked Questions Contact Us Sharing Tools and Badges Other Resources Strategic Plan Search Share Print Home » News & Events » Public Education Projects » Learn the Link - Drugs and HIV Learn ...

  6. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... contracting or transmitting HIV/AIDS or other infectious diseases. Research Reports: HIV/AIDS : Explores the link between drug misuse and HIV/AIDS, populations most at risk, trends in HIV/AIDS, and ...

  7. Protein Linked to Atopic Dermatitis

    Science.gov (United States)

    ... Research Matters NIH Research Matters January 14, 2013 Protein Linked to Atopic Dermatitis Normal skin from a ... in mice suggests that lack of a certain protein may trigger atopic dermatitis, the most common type ...

  8. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Process Funding Priorities Research Training News & Events News Nora's Blog NIDA in the News NIDA Notes Podcasts ... of the National Institute on Drug Abuse, Dr. Nora D. Volkow. Message from the Director The Link ...

  9. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... their lives , but now their night out always will be associated with HIV/AIDS. The “d’cisions” ... for breaking the harmful links between them, we will continue to update this Web site. Sincerely, Nora ...

  10. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Link" campaign continues to raise awareness among this generation of the real risks of drug use for ... Resource Center (NWHRC) Mujeres Unidas Contra el SIDA New Mexico AIDS Services African Advocates Against AIDS The ...

  11. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... link between non-injection drug use and HIV. Television Networks: MunDos Azteca America ... and Families The American Academy of Child & Adolescent Psychiatry (AACAP) The United Negro College Fund, ...

  12. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... of people infected with HIV, drug misuse can interfere with an individual's likelihood of adhering to the ... HIV/AIDS and the discovery of promising treatment interventions for breaking the harmful links between them, we ...

  13. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... other organizations in your tweets to spread the word even further. Tweet About Learn the Link To ... other organizations in your tweets to spread the word even further. Share with Flickr, Pinterest or Instagram ...

  14. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... can affect anyone. Watch the “d’cisions” Videos Campaign Materials After the Party Posters: We have developed ... share on your social media accounts. About the Campaign Overview The Learn the Link campaign uses TV, ...

  15. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... the main factors in the spread of HIV infection in the United States. Drugs can change the ... about the link between drug misuse and HIV infection. It contains information for young people, parents and ...

  16. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... Parents & Educators Children & Teens Search Connect with NIDA : Facebook LinkedIn Twitter YouTube Flickr RSS Menu Home Drugs of Abuse Commonly Abused Drugs Charts Emerging Trends and Alerts ...

  17. Drugs + HIV, Learn the Link

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    Full Text Available ... En español Researchers Medical & Health Professionals Patients & Families Parents & Educators Children & Teens Search Connect with NIDA : Facebook ... HIV infection. It contains information for young people, parents and teachers, and the media with links to ...

  18. Analytic invariants of boundary links

    OpenAIRE

    Garoufalidis, Stavros; Levine, Jerome

    2001-01-01

    Using basic topology and linear algebra, we define a plethora of invariants of boundary links whose values are power series with noncommuting variables. These turn out to be useful and elementary reformulations of an invariant originally defined by M. Farber.

  19. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... that use text messaging as a means of communication. The "Text Message" PSA features two young girls ... about the link between drug misuse and HIV. Post on Facebook or Twitter ; add photos to your ...

  20. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... NIDA’s "Learn the Link" campaign continues to raise awareness among this generation of the real risks of ... Collaborators Thanks to Those Who Have Helped Raise Awareness of Our Campaign! NIDA acknowledges the following television ...