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Sample records for metabolic pathways hormonal

  1. Dietary modification of metabolic pathways via nuclear hormone receptors.

    PubMed

    Caiozzi, Gianella; Wong, Brian S; Ricketts, Marie-Louise

    2012-10-01

    Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in the control of whole body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bind ligand with lower affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By binding to these NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors that have been shown to be activated by dietary components. The physiological consequences of such receptor activation by these dietary components will then be discussed in more detail.

  2. Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma

    PubMed Central

    Hyland, Paula L.

    2013-01-01

    In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations. PMID:23358850

  3. [Growth hormone signaling pathways].

    PubMed

    Zych, Sławomir; Szatkowska, Iwona; Czerniawska-Piatkowska, Ewa

    2006-01-01

    The substantial improvement in the studies on a very complicated mechanism-- growth hormone signaling in a cell, has been noted in last decade. GH-induced signaling is characterized by activation of several pathways, including extracellular signal-regulated kinase (ERK), the signal transducer and activator of transcription and phosphatidylinositol-3 kinase (PI3) pathways. This review shows a current model of the growth hormone receptor dimerization, rotation of subunits and JAK2 kinase activation as the initial steps in the cascade of events. In the next stages of the signaling process, the GH-(GHR)2-(JAK2)2 complex may activate signaling molecules such as Stat, IRS-1 and IRS-2, and particularly all cascade proteins that activate MAP kinase. These pathways regulate basal cellular functions including target gene transcription, enzymatic activity and metabolite transport. Therefore growth hormone is considered as a major regulator of postnatal growth and metabolism, probably for mammary gland growth and development too.

  4. Possible role of the aromatase-independent steroid metabolism pathways in hormone responsive primary breast cancers.

    PubMed

    Hanamura, Toru; Niwa, Toshifumi; Gohno, Tatsuyuki; Kurosumi, Masafumi; Takei, Hiroyuki; Yamaguchi, Yuri; Ito, Ken-ichi; Hayashi, Shin-ichi

    2014-01-01

    Aromatase inhibitors (AIs) exert antiproliferative effects by reducing local estrogen production from androgens in postmenopausal women with hormone-responsive breast cancer. Previous reports have shown that androgen metabolites generated by the aromatase-independent enzymes, 5α-androstane-3β, 17β-diol (3β-diol), androst-5-ene-3β, and 17β-diol (A-diol), also activate estrogen receptor (ER) α. Estradiol (E2) can also reportedly be generated from estrone sulfate (E1S) pooled in the plasma. Estrogenic steroid-producing aromatase-independent pathways have thus been proposed as a mechanism of AI resistance. However, it is unclear whether these pathways are functional in clinical breast cancer. To investigate this issue, we assessed the transcriptional activities of ER in 45 ER-positive human breast cancers using the adenovirus estrogen-response element-green fluorescent protein assay and mRNA expression levels of the ER target gene, progesterone receptor, as indicators of ex vivo and in vivo ER activity, respectively. We also determined mRNA expression levels of 5α-reductase type 1 (SRD5A1) and 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD type 1; HSD3B1), which produce 3β-diol from androgens, and of steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1; HSD17B1), which produce E2 or A-diol from E1S or dehydroepiandrosterone sulfate. SRD5A1 and HSD3B1 expression levels were positively correlated with ex vivo and in vivo ER activities. STS and HSD17B1 expression levels were positively correlated with in vivo ER activity alone. Elevated expression levels of these steroid-metabolizing enzymes in association with high in vivo ER activity were particularly notable in postmenopausal patients. Analysis of the expression levels of steroid-metabolizing enzymes revealed positive correlations between SRD5A1 and HSD3B1, and STS and HSD17B1. These findings suggest that the SRD5A1-HSD3B1 as well as the STS-HSD17B pathways, could contributes

  5. Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways.

    PubMed

    Lafontan, Max

    2012-01-15

    For many years, there was little interest in the biochemistry or physiology of adipose tissue. It is now well recognized that adipocytes play an important dynamic role in metabolic regulation. They are able to sense metabolic states via their ability to perceive a large number of nervous and hormonal signals. They are also able to produce hormones, called adipokines, that affect nutrient intake, metabolism and energy expenditure. The report by Rodbell in 1964 that intact fat cells can be obtained by collagenase digestion of adipose tissue revolutionized studies on the hormonal regulation and metabolism of the fat cell. In the context of the advent of systems biology in the field of cell biology, the present seems an appropriate time to look back at the global contribution of the fat cell to cell biology knowledge. This review focuses on the very early approaches that used the fat cell as a tool to discover and understand various cellular mechanisms. Attention essentially focuses on the early investigations revealing the major contribution of mature fat cells and also fat cells originating from adipose cell lines to the discovery of major events related to hormone action (hormone receptors and transduction pathways involved in hormonal signaling) and mechanisms involved in metabolite processing (hexose uptake and uptake, storage, and efflux of fatty acids). Dormant preadipocytes exist in the stroma-vascular fraction of the adipose tissue of rodents and humans; cell culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells. Finally, more recent insights into adipocyte secretion, a completely new role with major metabolic impact, are also briefly summarized.

  6. Endocrine and Metabolic Pathways Linked to Keratoconus: Implications for the Role of Hormones in the Stromal Microenvironment

    PubMed Central

    McKay, Tina B; Hjortdal, Jesper; Sejersen, Henrik; Asara, John M; Wu, Jennifer; Karamichos, Dimitrios

    2016-01-01

    Hormones play a critical role in regulating tissue function by promoting cell survival, proliferation, and differentiation. Our study explores the influence of endocrine function in regulating metabolism and inflammatory pathways in Keratoconus (KC), which is a corneal thinning disease associated with reduced stromal deposition. KC is known to be a multifactorial disease with an elusive pathogenesis. We utilized a cross-sectional study analyzing clinical features and saliva samples from sixty-four KC patients and fourteen healthy controls. In order to determine if endocrine function varied between healthy controls and KC, we measured hormone levels in saliva and found significantly increased dehydroepiandrosterone sulfate (DHEA-S) and reduced estrone levels in KC patients compared to healthy controls. We measured significant variations in metabolites associated with pro-inflammatory processes, including myoinositol and 1-methyl-histidine, by targeted mass spectrometry. We also measured significantly increased IL-16 and stem cell factor in KC saliva samples compared to healthy controls, with higher expression of these pro-inflammatory proteins correlating with increased KC clinical grade, corneal curvature, and stromal thinning. Our results identify a novel mechanism linking KC and pro-inflammatory markers and suggest that altered hormone levels modulate metabolism, cytokine, and growth factor expression leading to increased severity of the KC condition. PMID:27157003

  7. The association of polymorphisms in hormone metabolism pathway genes, menopausal hormone therapy, and breast cancer risk: a nested case-control study in the California Teachers Study cohort

    PubMed Central

    2011-01-01

    Introduction The female sex steroids estrogen and progesterone are important in breast cancer etiology. It therefore seems plausible that variation in genes involved in metabolism of these hormones may affect breast cancer risk, and that these associations may vary depending on menopausal status and use of hormone therapy. Methods We conducted a nested case-control study of breast cancer in the California Teachers Study cohort. We analyzed 317 tagging single nucleotide polymorphisms (SNPs) in 24 hormone pathway genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by fitting conditional logistic regression models using all women or subgroups of women defined by menopausal status and hormone therapy use. P values were adjusted for multiple correlated tests (PACT). Results The strongest associations were observed for SNPs in SLCO1B1, a solute carrier organic anion transporter gene, which transports estradiol-17β-glucuronide and estrone-3-sulfate from the blood into hepatocytes. Ten of 38 tagging SNPs of SLCO1B1 showed significant associations with postmenopausal breast cancer risk; 5 SNPs (rs11045777, rs11045773, rs16923519, rs4149057, rs11045884) remained statistically significant after adjusting for multiple testing within this gene (PACT = 0.019-0.046). In postmenopausal women who were using combined estrogen-progestin therapy (EPT) at cohort enrollment, the OR of breast cancer was 2.31 (95% CI = 1.47-3.62) per minor allele of rs4149013 in SLCO1B1 (P = 0.0003; within-gene PACT = 0.002; overall PACT = 0.023). SNPs in other hormone pathway genes evaluated in this study were not associated with breast cancer risk in premenopausal or postmenopausal women. Conclusions We found evidence that genetic variation in SLCO1B1 is associated with breast cancer risk in postmenopausal women, particularly among those using EPT. PMID:21457551

  8. Thyroid Hormone Regulation of Metabolism

    PubMed Central

    Mullur, Rashmi; Liu, Yan-Yun

    2014-01-01

    Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. PMID:24692351

  9. Pathways and genes involved in steroid hormone metabolism in male pigs: a review and update.

    PubMed

    Robic, Annie; Faraut, Thomas; Prunier, Armelle

    2014-03-01

    This paper reviews state-of-the-art knowledge on steroid biosynthesis pathways in the pig and provides an updated characterization of the porcine genes involved in these pathways with particular focus on androgens, estrogens, and 16-androstenes. At least 21 different enzymes appear to be involved in these pathways in porcine tissues together with at least five cofactors. Until now, data on several porcine genes were scarce or confusing. We characterized the complete genomic and transcript sequences of the single porcine CYP11B gene. We analyzed the porcine AKR1 gene cluster and identified four AKR1C, one AKR1C like genes and one AKR1E2 gene. We provide evidence that porcine AKR1C genes are not orthologous to human AKR1C. A new nomenclature is thus needed for this gene family in the pig. Thirty-two genes are now described: transcript (30+2 characterized in this study) and genomic (complete: 18+1 and partial: 12+1) sequences are identified. However, despite increasing knowledge on steroid metabolism in the pig, there is still no explanation of why porcine testes can produce androstenone and epiandrosterone, but not dihydrotestosterone (DHT), which is also a reduced steroid.

  10. Food restriction in young Japanese quails: effects on growth, metabolism, plasma thyroid hormones and mRNA species in the thyroid hormone signalling pathway.

    PubMed

    Rønning, Bernt; Mortensen, Anne S; Moe, Børge; Chastel, Olivier; Arukwe, Augustine; Bech, Claus

    2009-10-01

    Young birds, in their post-natal growth period, may reduce their growth and metabolism when facing a food shortage. To examine how such responses can be mediated by endocrine-related factors, we exposed Japanese quail chicks to food restriction for either 2 days (age 6-8 days) or 5 days (age 6-11 days). We then measured growth and resting metabolic rate (RMR), and circulating 3,3',5-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4) levels as well as expression patterns of genes involved in growth (insulin-like growth factor-I: IGF-I) and thyroid hormone signalling (thyroid-stimulating hormone-beta: TSHbeta, type II iodothyronine deiodinase: D2, thyroid hormone receptors isoforms: TRalpha and TRbeta). The food-restricted chicks receiving a weight-maintenance diet showed reductions in structural growth and RMR. Plasma levels of both T3 and T4 were reduced in the food-restricted birds, and within the 5 days food-restricted group there was a positive correlation between RMR and T3. IGF-I mRNA showed significantly higher abundance in the liver of ad libitum fed birds at day 8 compared with food-restricted birds. In the brain, TSHbeta mRNA level tended to be lower in food-restricted quails on day 8 compared with controls. Furthermore, TRalpha expression was lower in the brain of food-restricted birds at day 8 compared with birds fed ad libitum. Interestingly, brain D2 mRNA was negatively correlated with plasma T3 levels, tending to increase with the length of food restriction. Overall, our results show that food restriction produced significant effects on circulating thyroid hormones and differentially affected mRNA species in the thyroid hormone signalling pathway. Thus, we conclude that the effects of food restriction observed on growth and metabolism were partly mediated by changes in the endocrine-related factors investigated.

  11. Sex Hormones and Macronutrient Metabolism

    PubMed Central

    Comitato, Raffaella; Saba, Anna; Turrini, Aida; Arganini, Claudia; Virgili, Fabio

    2015-01-01

    The biological differences between males and females are determined by a different set of genes and by a different reactivity to environmental stimuli, including the diet, in general. These differences are further emphasized and driven by the exposure to a different hormone flux throughout the life. These differences have not been taken into appropriate consideration by the scientific community. Nutritional sciences are not immune from this “bias” and when nutritional needs are concerned, females are considered only when pregnant, lactating or when their hormonal profile is returning back to “normal,” i.e., to the male-like profile. The authors highlight some of the most evident differences in aspects of biology that are associated with nutrition. This review presents and describes available data addressing differences and similarities of the “reference man” vs. the “reference woman” in term of metabolic activity and nutritional needs. According to this assumption, available evidences of sex-associated differences of specific biochemical pathways involved in substrate metabolism are reported and discussed. The modulation by sexual hormones affecting glucose, amino acid and protein metabolism and the metabolization of nutritional fats and the distribution of fat depots, is considered targeting a tentative starting up background for a gender concerned nutritional science. PMID:24915409

  12. Growth hormone signaling pathways.

    PubMed

    Carter-Su, Christin; Schwartz, Jessica; Argetsinger, Lawrence S

    2016-06-01

    Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight.

  13. Thyroid hormone signaling in energy homeostasis and energy metabolism

    PubMed Central

    McAninch, Elizabeth A.; Bianco, Antonio C.

    2014-01-01

    The thyroid hormone plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. Thyroid hormone signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the thyroid hormone exerts its effects after concerted mechanisms facilitate binding to the thyroid hormone receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma thyroid hormone at the appropriate level to preserve energy homeostasis. At the tissue level, thyroid hormone actions on metabolism are controlled by transmembrane transporters, deiodinases, and thyroid hormone receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and thus understanding the contribution of the thyroid hormone to cellular and organism metabolism is increasingly relevant. PMID:24697152

  14. Hypothalamic Hormones and Metabolism

    PubMed Central

    Thio, Liu Lin

    2011-01-01

    Summary The ketogenic diet is an effective treatment for medically intractable epilepsy and may have antiepileptogenic, neuroprotective, and antitumor properties. While on a ketogenic diet, the body obtains most of its calories from fat rather than carbohydrates. This dramatic change in caloric composition results in a unique metabolic state. In turn, these changes in caloric composition and metabolism alter some of the neurohormones that participate in the complex neuronal network regulating energy homeostasis. Two observed changes are an increase in serum leptin and a decrease in serum insulin. These opposing changes in leptin and insulin are unique compared to other metabolic stimuli and may modify the activity of several cell signaling cascades including phosphoinositidyl-3 kinase (PI3K), adenosine monophosphate activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR). These cell signaling pathways may mediate the anticonvulsant and other beneficial effects of the diet, though the neurohormonal changes induced by the ketogenic diet and the physiological consequences of these changes remain poorly characterized. PMID:21856125

  15. Hypothalamic effects of thyroid hormones on metabolism.

    PubMed

    Martínez-Sánchez, Noelia; Alvarez, Clara V; Fernø, Johan; Nogueiras, Rubén; Diéguez, Carlos; López, Miguel

    2014-10-01

    Over the past few decades, obesity and its related metabolic disorders have increased at an epidemic rate in the developed and developing world. New signals and factors involved in the modulation of energy balance and metabolism are continuously being discovered, providing potential novel drug targets for the treatment of metabolic disease. A parallel strategy is to better understand how hormonal signals, with an already established role in energy metabolism, work, and how manipulation of the pathways involved may lead to amelioration of metabolic dysfunction. The thyroid hormones belong to the latter category, with dysregulation of the thyroid axis leading to marked alterations in energy balance. The potential of thyroid hormones in the treatment of obesity has been known for decades, but their therapeutic use has been hampered because of side-effects. Data gleaned over the past few years, however, have uncovered new features at the mechanisms of action involved in thyroid hormones. Sophisticated neurobiological approaches have allowed the identification of specific energy sensors, such as AMP-activated protein kinase and mechanistic target of rapamycin, acting in specific groups of hypothalamic neurons, mediating many of the effects of thyroid hormones on food intake, energy expenditure, glucose, lipid metabolism, and cardiovascular function. More extensive knowledge about these molecular mechanisms will be of great relevance for the treatment of obesity and metabolic syndrome.

  16. Metabolic analysis reveals changes in the mevalonate and juvenile hormone synthesis pathways linked to the mosquito reproductive physiology.

    PubMed

    Rivera-Perez, Crisalejandra; Nouzova, Marcela; Lamboglia, Ivanna; Noriega, Fernando G

    2014-08-01

    Juvenile hormone (JH) regulates reproductive maturation in insects; therefore interruption of JH biosynthesis has been considered as a strategy for the development of target-specific insecticides. The corpora allata (CA) from mosquitoes is highly specialized to supply variable levels of JH, which are linked to ovarian developmental stages and influenced by nutritional signals. However, very little is known about how changes in JH synthesis relate to reproductive physiology and how JH synthesis regulation is translated into changes in the CA machinery. With the advent of new methods that facilitate the analysis of transcripts, enzymes and metabolites in the minuscule CA, we were able to provide comprehensive descriptions of the mevalonic (MVA) and JH synthesis pathways by integrating information on changes in the basic components of those pathways. Our results revealed remarkable dynamic changes in JH synthesis and exposed part of a complex mechanism that regulates CA activity. Principal component (PC) analyses validated that both pathways (MVAP and JH-branch) are transcriptionally co-regulated as a single unit, and catalytic activities for the enzymes of the MVAP and JH-branch also changed in a coordinate fashion. Metabolite studies showed that global fluctuations in the intermediate pool sizes in the MVAP and JH-branch were often inversely related. PC analyses suggest that in female mosquitoes, there are at least 4 developmental switches that alter JH synthesis by modulating the flux at distinctive points in both pathways.

  17. Identifying Branched Metabolic Pathways by Merging Linear Metabolic Pathways

    NASA Astrophysics Data System (ADS)

    Heath, Allison P.; Bennett, George N.; Kavraki, Lydia E.

    This paper presents a graph-based algorithm for identifying complex metabolic pathways in multi-genome scale metabolic data. These complex pathways are called branched pathways because they can arrive at a target compound through combinations of pathways that split compounds into smaller ones, work in parallel with many compounds, and join compounds into larger ones. While most previous work has focused on identifying linear metabolic pathways, branched metabolic pathways predominate in metabolic networks. Automatic identification of branched pathways has a number of important applications in areas that require deeper understanding of metabolism, such as metabolic engineering and drug target identification. Our algorithm utilizes explicit atom tracking to identify linear metabolic pathways and then merges them together into branched metabolic pathways. We provide results on two well-characterized metabolic pathways that demonstrate that this new merging approach can efficiently find biologically relevant branched metabolic pathways with complex structures.

  18. Hormone metabolism genes and mammographic density in Singapore Chinese women

    PubMed Central

    Lee, Eunjung; Su, Yu-Chen; Lewinger, Juan Pablo; Hsu, Chris; Van den Berg, David; Ursin, Giske; Koh, Woon-Puay; Yuan, Jian-Min; Stram, Daniel O.; Yu, Mimi C.; Wu, Anna H.

    2014-01-01

    Background Female steroid hormone levels and exogenous hormone use influence breast cancer risk. We investigated the association between genetic variation in the hormone metabolism and signaling pathway and mammographic density (MD), a strong predictor of breast cancer risk. Methods We genotyped 161 SNPs in 15 hormone metabolism pathway gene regions and evaluated MD in 2,038 Singapore Chinese women. Linear regression analysis was used to investigate SNP-MD association. An overall pathway summary was obtained using the adaptive ranked truncated product test. Results We did not find any of the individually tested SNPs to be associated with MD after a multiple testing correction. There was no evidence of an overall effect on MD of genetic variation in the hormone metabolism pathway. Conclusions In this cross-sectional study, genetic variation in hormone metabolism pathway was not associated with MD in Singapore Chinese women. Impact Consistent with existing data from Caucasian populations, polymorphisms in hormone pathway genes are not likely to be strong predictors of MD in Asian women. PMID:23429186

  19. Metabolic hormones, dopamine circuits, and feeding

    PubMed Central

    Narayanan, Nandakumar S.; Guarnieri, Douglas J.; DiLeone, Ralph J.

    2009-01-01

    Recent evidence has emerged demonstrating that metabolic hormones such as ghrelin and leptin can act on ventral tegmental area (VTA) midbrain dopamine neurons to influence feeding. The VTA is the origin of mesolimbic dopamine neurons that project to the nucleus accumbens (NAc) to influence behavior. While blockade of dopamine via systemic antagonists or targeted gene delete can impair food intake, local NAc dopamine manipulations have little effect on food intake. Notably, non-dopaminergic manipulations in the VTA and NAc produce more consistent effects on feeding and food choice. More recent genetic evidence supports a role for the substantia nigra-striatal dopamine pathways in food intake, while the VTA-NAc circuit is more likely involved in higher-order aspects of food acquisition, such as motivation and cue associations. This rich and complex literature should be considered in models of how peripheral hormones influence feeding behavior via action on the midbrain circuits. PMID:19836414

  20. Thyroid hormone signaling in energy homeostasis and energy metabolism.

    PubMed

    McAninch, Elizabeth A; Bianco, Antonio C

    2014-04-01

    The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.

  1. Thyroid Hormones, Metabolic Syndrome and Its Components.

    PubMed

    Delitala, Alessandro P; Fanciulli, Giuseppe; Pes, Giovanni M; Maioli, Margherita; Delitala, Giuseppe

    2017-03-20

    Metabolic syndrome is a clustering of various metabolic parameters, which included diabetes, low high-density lipoprotein cholesterol, elevated triglycerides, abdominal obesity, and hypertension. It has merged as a worldwide epidemic and a major public health care concern. However, due to the different criteria used for the assessment, the frequency of metabolic syndrome in the general population is variable but it more common in the older people. Metabolic syndrome is closely linked to cardiovascular risk and increases cardiovascular outcomes and all-cause mortality. Recent evidences showed that alterations of the thyroid function could have an impact on the components of the metabolic syndrome, suggesting that thyroid hormones have a variety of effects on energy homeostasis, lipid and glucose metabolism, and blood pressure. In this review we summarize available data on the action of thyroid hormone on the components of metabolic syndrome.

  2. Selenium and the control of thyroid hormone metabolism.

    PubMed

    Köhrle, Josef

    2005-08-01

    Thyroid hormone synthesis, metabolism and action require adequate availability of the essential trace elements iodine and selenium, which affect homeostasis of thyroid hormone-dependent metabolic pathways. The three selenocysteine-containing iodothyronine deiodinases constitute a novel gene family. Selenium is retained and deiodinase expression is maintained at almost normal levels in the thyroid gland, the brain and several other endocrine tissues during selenium deficiency, thus guaranteeing adequate local and systemic levels of the active thyroid hormone T(3). Due to their low tissue concentrations and their mRNA SECIS elements deiodinases rank high in the cellular and tissue-specific hierarchy of selenium distribution among various selenoproteins. While systemic selenium status and expression of abundant selenoproteins (glutathione peroxidase or selenoprotein P) is already impaired in patients with cancer, disturbed gastrointestinal resorption, unbalanced nutrition or patients requiring intensive care treatment, selenium-dependent deiodinase function might still be adequate. However, disease-associated alterations in proinflammatory cytokines, growth factors, hormones and pharmaceuticals modulate deiodinase isoenzyme expression independent from altered selenium status and might thus pretend causal relationships between systemic selenium status and altered thyroid hormone metabolism. Limited or inadequate supply of both trace elements, iodine and selenium, leads to complex rearrangements of thyroid hormone metabolism enabling adaptation to unfavorable conditions.

  3. MPW : the metabolic pathways database.

    SciTech Connect

    Selkov, E., Jr.; Grechkin, Y.; Mikhailova, N.; Selkov, E.; Mathematics and Computer Science; Russian Academy of Sciences

    1998-01-01

    The Metabolic Pathways Database (MPW) (www.biobase.com/emphome.html/homepage. html.pags/pathways.html) a derivative of EMP (www.biobase.com/EMP) plays a fundamental role in the technology of metabolic reconstructions from sequenced genomes under the PUMA (www.mcs.anl.gov/home/compbio/PUMA/Production/ ReconstructedMetabolism/reconstruction.html), WIT (www.mcs.anl.gov/home/compbio/WIT/wit.html ) and WIT2 (beauty.isdn.msc.anl.gov/WIT2.pub/CGI/user.cgi) systems. In October 1997, it included some 2800 pathway diagrams covering primary and secondary metabolism, membrane transport, signal transduction pathways, intracellular traffic, translation and transcription. In the current public release of MPW (beauty.isdn.mcs.anl.gov/MPW), the encoding is based on the logical structure of the pathways and is represented by the objects commonly used in electronic circuit design. This facilitates drawing and editing the diagrams and makes possible automation of the basic simulation operations such as deriving stoichiometric matrices, rate laws, and, ultimately, dynamic models of metabolic pathways. Individual pathway diagrams, automatically derived from the original ASCII records, are stored as SGML instances supplemented by relational indices. An auxiliary database of compound names and structures, encoded in the SMILES format, is maintained to unambiguously connect the pathways to the chemical structures of their intermediates.

  4. Hormone signaling pathways under stress combinations.

    PubMed

    Suzuki, Nobuhiro

    2016-11-01

    As sessile organisms, plants are continuously exposed to various environmental stresses. In contrast to the controlled conditions employed in many researches, more than one or more abiotic and/or biotic stresses simultaneously occur and highly impact growth of plants and crops in the field environments. Therefore, an urgent need to generate crops with enhanced tolerance to stress combinations exists. Researchers, however, focused on the mechanisms underlying acclimation of plants to combined stresses only in recent studies. Plant hormones might be a key regulator of the tailored responses of plants to different stress combinations. Co-ordination between different hormone signaling, or hormone signaling and other pathways such as ROS regulatory mechanisms could be flexible, being altered by timing and types of stresses, and could be different depending on plant species under the stress combinations. In this review, update on recent studies focusing on complex-mode of hormone signaling under stress combinations will be provided.

  5. Metabolic hormones in saliva: origins and functions

    PubMed Central

    Zolotukhin, S.

    2012-01-01

    The salivary proteome consists of thousands of proteins, which include, among others, hormonal modulators of energy intake and output. Although the functions of this prominent category of hormones in whole body energy metabolism are well characterized, their functions in the oral cavity, whether as a salivary component, or when expressed in taste cells, are less studied and poorly understood. The respective receptors for the majority of salivary metabolic hormones have been also shown to be expressed in salivary glands, taste cells, or other cells in the oral mucosa. This review provides a comprehensive account of the gastrointestinal hormones, adipokines, and neuropeptides identified in saliva, salivary glands, or lingual epithelium, as well as their respective cognate receptors expressed in the oral cavity. Surprisingly, few functions are assigned to salivary metabolic hormones, and these functions are mostly associated with the modulation of taste perception. Because of the well-characterized correlation between impaired oral nutrient sensing and increased energy intake and body mass index, a conceptually provocative point of view is introduced, whereupon it is argued that targeted changes in the composition of saliva could affect whole body metabolism in response to the activation of cognate receptors expressed locally in the oral mucosa. PMID:22994880

  6. Hormonal control of the metabolic machinery of hepatocellular carcinoma.

    PubMed

    Wong, Carmen Chak-Lui; Wong, Chun-Ming; Ng, Irene Oi-Lin

    2016-06-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect.

  7. Representations of metabolic knowledge: Pathways

    SciTech Connect

    Karp, P.D.; Paley, S.M.

    1994-12-31

    The automatic generation of drawings of metabolic pathways is a challenging problem that depends intimately on exactly what information has been recorded for each pathway, and on how that information is encoded. The chief contributions of the paper are a minimized representation for biochemical pathways called the predecessor list, and inference procedures for converting the predecessor list into a pathway-graph representation that can serve as input to a pathway-drawing algorithm. The predecessor list has several advantages over the pathway graph, including its compactness and its lack of redundancy. The conversion between the two representations can be formulated as both a constraint-satisfaction problem and a logical inference problem, whose goal is to assign directions to reactions, and to determine which are the main chemical compounds in the reaction. We describe a set of production rules that solves this inference problem. We also present heuristics for inferring whether the exterior compounds that are substrates of reactions at the periphery of a pathway are side or main compounds. These techniques were evaluated on 18 metabolic pathways from the EcoCyc knowledge base.

  8. The plasticizer benzyl butyl phthalate (BBP) alters the ecdysone hormone pathway, the cellular response to stress, the energy metabolism, and several detoxication mechanisms in Chironomus riparius larvae.

    PubMed

    Herrero, Óscar; Planelló, Rosario; Morcillo, Gloria

    2015-06-01

    Butyl benzyl phthalate (BBP) has been extensively used worldwide as a plasticizer in the polyvinyl chloride (PVC) industry and the manufacturing of many other products, and its presence in the aquatic environment is expected for decades. In the present study, the toxicity of BBP was investigated in Chironomus riparius aquatic larvae. The effects of acute 24-h and 48-h exposures to a wide range of BBP doses were evaluated at the molecular level by analysing changes in genes related to the stress response, the endocrine system, the energy metabolism, and detoxication pathways, as well as in the enzyme activity of glutathione S-transferase. BBP caused a dose and time-dependent toxicity in most of the selected biomarkers. 24-h exposures to high doses affected larval survival and lead to a significant response of several heat-shock genes (hsp70, hsp40, and hsp27), and to a clear endocrine disrupting effect by upregulating the ecdysone receptor gene (EcR). Longer treatments with low doses triggered a general repression of transcription and GST activity. Furthermore, delayed toxicity studies were specially relevant, since they allowed us to detect unpredictable toxic effects, not immediately manifested after contact with the phthalate. This study provides novel and interesting results on the toxic effects of BBP in C. riparius and highlights the suitability of this organism for ecotoxicological risk assessment, especially in aquatic ecosystems.

  9. Identification of Metabolic Pathway Systems

    PubMed Central

    Dolatshahi, Sepideh; Voit, Eberhard O.

    2016-01-01

    The estimation of parameters in even moderately large biological systems is a significant challenge. This challenge is greatly exacerbated if the mathematical formats of appropriate process descriptions are unknown. To address this challenge, the method of dynamic flux estimation (DFE) was proposed for the analysis of metabolic time series data. Under ideal conditions, the first phase of DFE yields numerical representations of all fluxes within a metabolic pathway system, either as values at each time point or as plots against their substrates and modulators. However, this numerical result does not reveal the mathematical format of each flux. Thus, the second phase of DFE selects functional formats that are consistent with the numerical trends obtained from the first phase. While greatly facilitating metabolic data analysis, DFE is only directly applicable if the pathway system contains as many dependent variables as fluxes. Because most actual systems contain more fluxes than metabolite pools, this requirement is seldom satisfied. Auxiliary methods have been proposed to alleviate this issue, but they are not general. Here we propose strategies that extend DFE toward general, slightly underdetermined pathway systems. PMID:26904095

  10. Folate metabolic pathways in Leishmania.

    PubMed

    Vickers, Tim J; Beverley, Stephen M

    2011-01-01

    Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for 'repurposing' of compounds developed originally for treatment of human cancers or other infectious agents.

  11. Asparagine Metabolic Pathways in Arabidopsis.

    PubMed

    Gaufichon, Laure; Rothstein, Steven J; Suzuki, Akira

    2016-04-01

    Inorganic nitrogen in the form of ammonium is assimilated into asparagine via multiple steps involving glutamine synthetase (GS), glutamate synthase (GOGAT), aspartate aminotransferase (AspAT) and asparagine synthetase (AS) in Arabidopsis. The asparagine amide group is liberated by the reaction catalyzed by asparaginase (ASPG) and also the amino group of asparagine is released by asparagine aminotransferase (AsnAT) for use in the biosynthesis of amino acids. Asparagine plays a primary role in nitrogen recycling, storage and transport in developing and germinating seeds, as well as in vegetative and senescence organs. A small multigene family encodes isoenzymes of each step of asparagine metabolism in Arabidopsis, except for asparagine aminotransferase encoded by a single gene. The aim of this study is to highlight the structure of the genes and encoded enzyme proteins involved in asparagine metabolic pathways; the regulation and role of different isogenes; and kinetic and physiological properties of encoded enzymes in different tissues and developmental stages.

  12. From hormones to secondary metabolism: the emergence of metabolic gene clusters in plants.

    PubMed

    Chu, Hoi Yee; Wegel, Eva; Osbourn, Anne

    2011-04-01

    Gene clusters for the synthesis of secondary metabolites are a common feature of microbial genomes. Well-known examples include clusters for the synthesis of antibiotics in actinomycetes, and also for the synthesis of antibiotics and toxins in filamentous fungi. Until recently it was thought that genes for plant metabolic pathways were not clustered, and this is certainly true in many cases; however, five plant secondary metabolic gene clusters have now been discovered, all of them implicated in synthesis of defence compounds. An obvious assumption might be that these eukaryotic gene clusters have arisen by horizontal gene transfer from microbes, but there is compelling evidence to indicate that this is not the case. This raises intriguing questions about how widespread such clusters are, what the significance of clustering is, why genes for some metabolic pathways are clustered and those for others are not, and how these clusters form. In answering these questions we may hope to learn more about mechanisms of genome plasticity and adaptive evolution in plants. It is noteworthy that for the five plant secondary metabolic gene clusters reported so far, the enzymes for the first committed steps all appear to have been recruited directly or indirectly from primary metabolic pathways involved in hormone synthesis. This may or may not turn out to be a common feature of plant secondary metabolic gene clusters as new clusters emerge.

  13. Hormonal control of the metabolic machinery of hepatocellular carcinoma

    PubMed Central

    Wong, Carmen Chak-Lui; Wong, Chun-Ming

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most fatal malignancies worldwide. It is an aggressive cancer with low cure rate, frequent metastasis, and highly resistant to conventional chemotherapies. Better knowledge regarding the molecular and metabolic alterations in HCC will be instrumental to the development of novel therapeutic interventions against HCC. In the August 2015 issue of Hepatology, Nie et al. reports an important molecular pathway that contributes to the Warburg Effect in HCC. They have beautifully demonstrated that the loss of a component of a hormonal system, the mineralocorticoid receptor (MR), reprogrammed the metabolic machinery of HCC cells to aerobic glycolysis through the miR-338-3p-PKL/R axis. The implication could be that in addition to drugs that directly target the metabolic enzymes in cancer cells, more translational efforts could be focused on the development of drugs that involve the activation of the MR-aldosterone system or other hormonal systems to target the Warburg effect. PMID:27275458

  14. Minireview: Nuclear Receptor-Controlled Steroid Hormone Synthesis and Metabolism

    PubMed Central

    He, Jinhan; Cheng, Qiuqiong; Xie, Wen

    2010-01-01

    Steroid hormones are essential in normal physiology whereas disruptions in hormonal homeostasis represent an important etiological factor for many human diseases. Steroid hormones exert most of their functions through the binding and activation of nuclear hormone receptors (NRs or NHRs), a superfamily of DNA-binding and often ligand-dependent transcription factors. In recent years, accumulating evidence has suggested that NRs can also regulate the biosynthesis and metabolism of steroid hormones. This review will focus on the recent progress in our understanding of the regulatory role of NRs in hormonal homeostasis and the implications of this regulation in physiology and diseases. PMID:19762543

  15. Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression.

    PubMed

    Donepudi, Ajay C; Cheng, Qiuqiong; Lu, Zhenqiang James; Cherrington, Nathan J; Slitt, Angela L

    2016-04-01

    Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor- and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport.

  16. Parathyroid hormone - Secretion and metabolism in vivo.

    NASA Technical Reports Server (NTRS)

    Habener, J. F.; Powell, D.; Murray, T. M.; Mayer, G. P.; Potts, J. T., Jr.

    1971-01-01

    Gel filtration and radioimmunoassay were used to determine the molecular size and immunochemical reactivity of parathyroid hormone present in gland extracts, in the general peripheral circulation, and in parathyroid effluent blood from patients with hyperparathyroidism, as well as from calves and from cattle. It was found that parathyroid hormone secreted from the parathyroids in man and cattle is at least as large as the molecule extracted from normal bovine glands. However, once secreted into the circulation the hormone is cleaved, and one or more fragments, immunologically, dissimilar to the originally secreted hormone, constitute the dominant form of circulating immunoreactive hormone.

  17. Hormone-independent pathways of sexual differentiation.

    PubMed

    Renfree, Marilyn B; Chew, Keng Yih; Shaw, Geoffrey

    2014-01-01

    New observations over the last 25 years of hormone-independent sexual dimorphisms have gradually and unequivocally overturned the dogma, arising from Jost's elegant experiments in the mid-1900s, that all somatic sex dimorphisms in vertebrates arise from the action of gonadal hormones. Although we know that Sry, a Y-linked gene, is the primary gonadal sex determinant in mammals, more recent analysis in marsupials, mice, and finches has highlighted numerous sexual dimorphisms that are evident well before the differentiation of the testis and which cannot be explained by a sexually dimorphic hormonal environment. In marsupials, scrotal bulges and mammary primordia are visible before the testis has differentiated due to the expression of a gene(s) on the X chromosome. ZZ and ZW gynandromorph finches have brains that develop in a sexually dimorphic way dependent on their sex chromosome content. In genetically manipulated mice, it is the X chromosomes, not the gonads, that determine many characters including rate of early development, adiposity, and neural circuits. Even spotted hyenas have sexual dimorphisms that cannot be simply explained by hormonal exposure. This review discusses the recent findings that confirm that there are hormone-independent sexual dimorphisms well before the gonads begin to produce their hormones.

  18. MP-Align: alignment of metabolic pathways

    PubMed Central

    2014-01-01

    Background Comparing the metabolic pathways of different species is useful for understanding metabolic functions and can help in studying diseases and engineering drugs. Several comparison techniques for metabolic pathways have been introduced in the literature as a first attempt in this direction. The approaches are based on some simplified representation of metabolic pathways and on a related definition of a similarity score (or distance measure) between two pathways. More recent comparative research focuses on alignment techniques that can identify similar parts between pathways. Results We propose a methodology for the pairwise comparison and alignment of metabolic pathways that aims at providing the largest conserved substructure of the pathways under consideration. The proposed methodology has been implemented in a tool called MP-Align, which has been used to perform several validation tests. The results showed that our similarity score makes it possible to discriminate between different domains and to reconstruct a meaningful phylogeny from metabolic data. The results further demonstrate that our alignment algorithm correctly identifies subpathways sharing a common biological function. Conclusion The results of the validation tests performed with MP-Align are encouraging. A comparison with another proposal in the literature showed that our alignment algorithm is particularly well-suited to finding the largest conserved subpathway of the pathways under examination. PMID:24886436

  19. Metabolism pathways in chronic lymphocytic leukemia.

    PubMed

    Rozovski, Uri; Hazan-Halevy, Inbal; Barzilai, Merav; Keating, Michael J; Estrov, Zeev

    2016-01-01

    Alterations in chronic lymphocytic leukemia (CLL) cell metabolism have been studied by several investigators. Unlike normal B lymphocytes or other leukemia cells, CLL cells, like adipocytes, store lipids and utilize free fatty acids (FFA) to produce chemical energy. None of the recently identified mutations in CLL directly affects metabolic pathways, suggesting that genetic alterations do not directly contribute to CLL cells' metabolic reprogramming. Conversely, recent data suggest that activation of STAT3 or downregulation of microRNA-125 levels plays a crucial role in the utilization of FFA to meet the CLL cells' metabolic needs. STAT3, known to be constitutively activated in CLL, increases the levels of lipoprotein lipase (LPL) that mediates lipoprotein uptake and shifts the CLL cells' metabolism towards utilization of FFA. Herein, we review the evidence for altered lipid metabolism, increased mitochondrial activity and formation of reactive oxygen species (ROS) in CLL cells, and discuss the possible therapeutic strategies to inhibit lipid metabolism pathways in patient with CLL.

  20. Hormonal regulation of lipid metabolism in developing coho salmon, Oncorhynchus kisutch

    SciTech Connect

    Sheridan, M.A.

    1985-01-01

    Lipid metabolism in juvenile coho salmon is characterized, and adaptive changes in lipid mobilization are described in relation to development and hormonal influences. The rates of lipogenesis and lipolysis were determined in selected tissues of juvenile salmon during the period of seawater preadaptive development (smoltification). Neutral lipid (sterol) and fatty acid synthesis in the liver and mesenteric fat was measured by tritium incorporation. Fatty acid synthesis in the liver and mesenteric fat decreased by 88% and 81%, respectively, between late February (parr) and early June (smolt). To assess the role of hormones in smoltification-associated lipid depletion, growth hormone, prolactin, thyroxin and cortisol were administered in vivo early in development (parr) to determine if any of these factors could initiate the metabolic responses normally seen later in development (smolt). Growth hormone stimulated lipid mobilization from coho salmon parr. Prolactin strongly stimulated lipid mobilization in coho parr. Thyroxin and cortisol also stimulated lipid mobilization for coho salmon parr. The direct effect of hormones was studied by in vitro pH-stat incubation of liver slices. These data suggest that norepinephrine stimulates fatty acid release via ..beta..-adrenergic pathways. Somatostatin and its partial analogue from the fish caudal neurosecretory system, urotensin II, also affect lipid mobilization. These results establish the presence of hormone-sensitive lipase in salmon liver and suggest that the regulation of lipid metabolism in salmon involves both long-acting and short-acting hormonal agents.

  1. Metabolic pathways in the apicoplast of apicomplexa.

    PubMed

    Seeber, Frank; Soldati-Favre, Dominique

    2010-01-01

    Intracellular parasites of the phylum Apicomplexa harbor a plastid-like organelle called apicoplast that is the most reduced organelle of this type known. Due to the medical importance of some members of Apicomplexa, a number of fully sequenced genomes are available that have allowed to assemble metabolic pathways also from the apicoplast and have revealed initial clues to its essential nature for parasite survival in the host. We provide a compilation of Internet resources useful to access, reconstruct, verify, or annotate metabolic pathways. Then we show detailed and updated metabolic maps and discuss the three major biosynthetic pathways leading to the generation of isoprenoids, fatty acids, and heme, and compare these routes in the different species. Moreover, several auxiliary pathways, like iron-sulfur cluster assembly, are covered and put into context with the major metabolic routes. Finally, we highlight some aspects that emerged from recent publications and were not discussed previously with regard to Apicomplexa.

  2. New developments in engineering plant metabolic pathways.

    PubMed

    Tatsis, Evangelos C; O'Connor, Sarah E

    2016-12-01

    Plants contain countless metabolic pathways that are responsible for the biosynthesis of complex metabolites. Armed with new tools in sequencing and bioinformatics, the genes that encode these plant biosynthetic pathways have become easier to discover, putting us in an excellent position to fully harness the wealth of compounds and biocatalysts (enzymes) that plants provide. For overproduction and isolation of high-value plant-derived chemicals, plant pathways can be reconstituted in heterologous hosts. Alternatively, plant pathways can be modified in the native producer to confer new properties to the plant, such as better biofuel production or enhanced nutritional value. This perspective highlights a range of examples that demonstrate how the metabolic pathways of plants can be successfully harnessed with a variety of metabolic engineering approaches.

  3. Metabolic function of the CTRP family of hormones

    PubMed Central

    Seldin, Marcus M.; Tan, Stefanie Y.; Wong, G. William

    2013-01-01

    Maintaining proper energy balance in mammals entails intimate crosstalk between various tissues and organs. These inter-organ communications are mediated, to a great extent, by secreted hormones that circulate in blood. Regulation of the complex metabolic networks by secreted hormones (e.g., insulin, glucagon, leptin, adiponectin, FGF21) constitutes an important mechanism governing the integrated control of whole-body metabolism. Disruption of hormone-mediated metabolic circuits frequently results in dysregulated energy metabolism and pathology. As part of an effort to identify novel metabolic hormones, we recently characterized a highly conserved family of fifteen secreted proteins, the C1q/TNF-related proteins (CTRP1–15). While related to adiponectin in sequence and structural organization, each CTRP has its own unique tissue expression profile and non-redundant function in regulating sugar and/or fat metabolism. Here, we summarize the current understanding of the physiological functions of CTRPs, emphasizing their metabolic roles. Future studies using gain-of-function and loss-of-function mouse models will provide greater mechanistic insights into the critical role CTRPs play in regulating systemic energy homeostasis. PMID:23963681

  4. Evolutionary algorithm for metabolic pathways synthesis.

    PubMed

    Gerard, Matias F; Stegmayer, Georgina; Milone, Diego H

    2016-06-01

    Metabolic pathway building is an active field of research, necessary to understand and manipulate the metabolism of organisms. There are different approaches, mainly based on classical search methods, to find linear sequences of reactions linking two compounds. However, an important limitation of these methods is the exponential increase of search trees when a large number of compounds and reactions is considered. Besides, such models do not take into account all substrates for each reaction during the search, leading to solutions that lack biological feasibility in many cases. This work proposes a new evolutionary algorithm that allows searching not only linear, but also branched metabolic pathways, formed by feasible reactions that relate multiple compounds simultaneously. Tests performed using several sets of reactions show that this algorithm is able to find feasible linear and branched metabolic pathways.

  5. Metabolic control of signalling pathways and metabolic auto-regulation.

    PubMed

    Lorendeau, Doriane; Christen, Stefan; Rinaldi, Gianmarco; Fendt, Sarah-Maria

    2015-08-01

    Metabolic alterations have emerged as an important hallmark in the development of various diseases. Thus, understanding the complex interplay of metabolism with other cellular processes such as cell signalling is critical to rationally control and modulate cellular physiology. Here, we review in the context of mammalian target of rapamycin, AMP-activated protein kinase and p53, the orchestrated interplay between metabolism and cellular signalling as well as transcriptional regulation. Moreover, we discuss recent discoveries in auto-regulation of metabolism (i.e. how metabolic parameters such as metabolite levels activate or inhibit enzymes and thus metabolic pathways). Finally, we review functional consequences of post-translational modification on metabolic enzyme abundance and/or activities.

  6. Unique sugar metabolic pathways of bifidobacteria.

    PubMed

    Fushinobu, Shinya

    2010-01-01

    Bifidobacteria have many beneficial effects for human health. The gastrointestinal tract, where natural colonization of bifidobacteria occurs, is an environment poor in nutrition and oxygen. Therefore, bifidobacteria have many unique glycosidases, transporters, and metabolic enzymes for sugar fermentation to utilize diverse carbohydrates that are not absorbed by host humans and animals. They have a unique, effective central fermentative pathway called bifid shunt. Recently, a novel metabolic pathway that utilizes both human milk oligosaccharides and host glycoconjugates was found. The galacto-N-biose/lacto-N-biose I metabolic pathway plays a key role in colonization in the infant gastrointestinal tract. These pathways involve many unique enzymes and proteins. This review focuses on their molecular mechanisms, as revealed by biochemical and crystallographic studies.

  7. The Evolution of Fungal Metabolic Pathways

    PubMed Central

    Rokas, Antonis

    2014-01-01

    Fungi contain a remarkable range of metabolic pathways, sometimes encoded by gene clusters, enabling them to digest most organic matter and synthesize an array of potent small molecules. Although metabolism is fundamental to the fungal lifestyle, we still know little about how major evolutionary processes, such as gene duplication (GD) and horizontal gene transfer (HGT), have interacted with clustered and non-clustered fungal metabolic pathways to give rise to this metabolic versatility. We examined the synteny and evolutionary history of 247,202 fungal genes encoding enzymes that catalyze 875 distinct metabolic reactions from 130 pathways in 208 diverse genomes. We found that gene clustering varied greatly with respect to metabolic category and lineage; for example, clustered genes in Saccharomycotina yeasts were overrepresented in nucleotide metabolism, whereas clustered genes in Pezizomycotina were more common in lipid and amino acid metabolism. The effects of both GD and HGT were more pronounced in clustered genes than in their non-clustered counterparts and were differentially distributed across fungal lineages; specifically, GD, which was an order of magnitude more abundant than HGT, was most frequently observed in Agaricomycetes, whereas HGT was much more prevalent in Pezizomycotina. The effect of HGT in some Pezizomycotina was particularly strong; for example, we identified 111 HGT events associated with the 15 Aspergillus genomes, which sharply contrasts with the 60 HGT events detected for the 48 genomes from the entire Saccharomycotina subphylum. Finally, the impact of GD within a metabolic category was typically consistent across all fungal lineages, whereas the impact of HGT was variable. These results indicate that GD is the dominant process underlying fungal metabolic diversity, whereas HGT is episodic and acts in a category- or lineage-specific manner. Both processes have a greater impact on clustered genes, suggesting that metabolic gene clusters

  8. The evolution of fungal metabolic pathways.

    PubMed

    Wisecaver, Jennifer H; Slot, Jason C; Rokas, Antonis

    2014-12-01

    Fungi contain a remarkable range of metabolic pathways, sometimes encoded by gene clusters, enabling them to digest most organic matter and synthesize an array of potent small molecules. Although metabolism is fundamental to the fungal lifestyle, we still know little about how major evolutionary processes, such as gene duplication (GD) and horizontal gene transfer (HGT), have interacted with clustered and non-clustered fungal metabolic pathways to give rise to this metabolic versatility. We examined the synteny and evolutionary history of 247,202 fungal genes encoding enzymes that catalyze 875 distinct metabolic reactions from 130 pathways in 208 diverse genomes. We found that gene clustering varied greatly with respect to metabolic category and lineage; for example, clustered genes in Saccharomycotina yeasts were overrepresented in nucleotide metabolism, whereas clustered genes in Pezizomycotina were more common in lipid and amino acid metabolism. The effects of both GD and HGT were more pronounced in clustered genes than in their non-clustered counterparts and were differentially distributed across fungal lineages; specifically, GD, which was an order of magnitude more abundant than HGT, was most frequently observed in Agaricomycetes, whereas HGT was much more prevalent in Pezizomycotina. The effect of HGT in some Pezizomycotina was particularly strong; for example, we identified 111 HGT events associated with the 15 Aspergillus genomes, which sharply contrasts with the 60 HGT events detected for the 48 genomes from the entire Saccharomycotina subphylum. Finally, the impact of GD within a metabolic category was typically consistent across all fungal lineages, whereas the impact of HGT was variable. These results indicate that GD is the dominant process underlying fungal metabolic diversity, whereas HGT is episodic and acts in a category- or lineage-specific manner. Both processes have a greater impact on clustered genes, suggesting that metabolic gene clusters

  9. Light regulation of metabolic pathways in fungi.

    PubMed

    Tisch, Doris; Schmoll, Monika

    2010-02-01

    Light represents a major carrier of information in nature. The molecular machineries translating its electromagnetic energy (photons) into the chemical language of cells transmit vital signals for adjustment of virtually every living organism to its habitat. Fungi react to illumination in various ways, and we found that they initiate considerable adaptations in their metabolic pathways upon growth in light or after perception of a light pulse. Alterations in response to light have predominantly been observed in carotenoid metabolism, polysaccharide and carbohydrate metabolism, fatty acid metabolism, nucleotide and nucleoside metabolism, and in regulation of production of secondary metabolites. Transcription of genes is initiated within minutes, abundance and activity of metabolic enzymes are adjusted, and subsequently, levels of metabolites are altered to cope with the harmful effects of light or to prepare for reproduction, which is dependent on light in many cases. This review aims to give an overview on metabolic pathways impacted by light and to illustrate the physiological significance of light for fungi. We provide a basis for assessment whether a given metabolic pathway might be subject to regulation by light and how these properties can be exploited for improvement of biotechnological processes.

  10. PATHWAY OF INORGANIC ARSENIC METABOLISM

    EPA Science Inventory

    A remarkable aspect of the metabolism of inorganic arsenic in humans is its conversion to methylated metabolites. These metabolites account for most of the arsenic found in urine after exposure to inorganic arsenic. At least some of the adverse health effects attributed to inor...

  11. Hormonal alterations in PCOS and its influence on bone metabolism.

    PubMed

    Krishnan, Abhaya; Muthusami, Sridhar

    2017-02-01

    According to the World Health Organization (WHO) polycystic ovary syndrome (PCOS) occurs in 4-8% of women worldwide. The prevalence of PCOS in Indian adolescents is 12.2% according to the Indian Council of Medical Research (ICMR). The National Institute of Health has documented that it affects approximately 5 million women of reproductive age in the United States. Hormonal imbalance is the characteristic of many women with polycystic ovarian syndrome (PCOS). The influence of various endocrine changes in PCOS women and their relevance to bone remains to be documented. Hormones, which include gonadotrophin-releasing hormone (GnRH), insulin, the leutinizing/follicle-stimulating hormone (LH/FSH) ratio, androgens, estrogens, growth hormones (GH), cortisol, parathyroid hormone (PTH) and calcitonin are disturbed in PCOS women. These hormones influence bone metabolism in human subjects directly as well as indirectly. The imbalance in these hormones results in increased prevalence of osteoporosis in PCOS women. Limited evidence suggests that the drugs taken during the treatment of PCOS increase the risk of bone fracture in PCOS patients through endocrine disruption. This review is aimed at the identification of the relationship between bone mineral density and hormonal changes in PCOS subjects and identifies potential areas to study bone-related disorders in PCOS women.

  12. Origin and evolution of metabolic pathways

    NASA Astrophysics Data System (ADS)

    Fani, Renato; Fondi, Marco

    2009-03-01

    The emergence and evolution of metabolic pathways represented a crucial step in molecular and cellular evolution. In fact, the exhaustion of the prebiotic supply of amino acids and other compounds that were likely present in the ancestral environment, imposed an important selective pressure, favoring those primordial heterotrophic cells which became capable of synthesizing those molecules. Thus, the emergence of metabolic pathways allowed primitive organisms to become increasingly less-dependent on exogenous sources of organic compounds. Comparative analyses of genes and genomes from organisms belonging to Archaea, Bacteria and Eukarya revealed that, during evolution, different forces and molecular mechanisms might have driven the shaping of genomes and the arisal of new metabolic abilities. Among these gene elongations, gene and operon duplications undoubtedly played a major role since they can lead to the (immediate) appearance of new genetic material that, in turn, might undergo evolutionary divergence giving rise to new genes coding for new metabolic abilities. Gene duplication has been invoked in the different schemes proposed to explain why and how the extant metabolic pathways have arisen and shaped. Both the analysis of completely sequenced genomes and directed evolution experiments strongly support one of them, i.e. the patchwork hypothesis, according to which metabolic pathways have been assembled through the recruitment of primitive enzymes that could react with a wide range of chemically related substrates. However, the analysis of the structure and organization of genes belonging to ancient metabolic pathways, such as histidine biosynthesis and nitrogen fixation, suggested that other different hypothesis, i.e. the retrograde hypothesis or the semi-enzymatic theory, may account for the arisal of some metabolic routes.

  13. Hormone Metabolism During Potato Tuber Dormancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    At harvest and for an indeterminate period thereafter potato tubers will not sprout and are physiologically dormant. The length of tuber dormancy is dependent on cultivar and pre- and postharvest environmental conditions. Plant hormones have been shown to be involved in all phases of dormancy prog...

  14. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).

    PubMed

    Nykjaer, A; Fyfe, J C; Kozyraki, R; Leheste, J R; Jacobsen, C; Nielsen, M S; Verroust, P J; Aminoff, M; de la Chapelle, A; Moestrup, S K; Ray, R; Gliemann, J; Willnow, T E; Christensen, E I

    2001-11-20

    Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D(3) complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D(3) in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D(3). This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.

  15. Towards imaging metabolic pathways in tissues.

    PubMed

    Dekker, Tim J A; Jones, Emrys A; Corver, Willem E; van Zeijl, René J M; Deelder, André M; Tollenaar, Rob A E M; Mesker, Wilma E; Morreau, Hans; McDonnell, Liam A

    2015-03-01

    Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging using 9-aminoacridine as the matrix leads to the detection of low mass metabolites and lipids directly from cancer tissues. These included lactate and pyruvate for studying the Warburg effect, as well as succinate and fumarate, metabolites whose accumulation is associated with specific syndromes. By using the pathway information present in the human metabolome database, it was possible to identify regions within tumor tissue samples with distinct metabolic signatures that were consistent with known tumor biology. We present a data analysis workflow for assessing metabolic pathways in their histopathological context.

  16. Prenatal Exposures to Multiple Thyroid Hormone Disruptors: Effects on Glucose and Lipid Metabolism

    PubMed Central

    Molehin, Deborah

    2016-01-01

    Background. Thyroid hormones (THs) are essential for normal human fetal development and play a major role in the regulation of glucose and lipid metabolism. Delivery of TH to target tissues is dependent on processes including TH synthesis, transport, and metabolism. Thyroid hormone endocrine disruptors (TH-EDCs) are chemical substances that interfere with these processes, potentially leading to adverse pregnancy outcomes. Objectives. This review focuses on the effects of prenatal exposures to combinations of TH-EDCs on fetal and neonatal glucose and lipid metabolism and also discusses the various mechanisms by which TH-EDCs interfere with other hormonal pathways. Methods. We conducted a comprehensive narrative review on the effects of TH-EDCs with particular emphasis on exposure during pregnancy. Discussion. TH imbalance has been linked to many metabolic processes and the effects of TH imbalance are particularly pronounced in early fetal development due to fetal dependence on maternal TH for proper growth and development. The pervasive presence of EDCs in the environment results in ubiquitous exposure to either single or mixtures of EDCs with deleterious effects on metabolism. Conclusions. Further evaluation of combined effects of TH-EDCs on fetal metabolic endpoints could improve advice provided to expectant mothers. PMID:26989557

  17. Hormonal components of altered developmental pathways in the annual killifish, Austrofundulus limnaeus.

    PubMed

    Pri-Tal, Benjamin M; Blue, Steven; Pau, Francis K-Y; Podrabsky, Jason E

    2011-11-01

    The annual killifish, Austrofundulus limnaeus, typically enters embryonic diapause at two distinct points of development, termed diapause II and III. This study explores the role of maternal and embryonic steroid hormones, including 17-β-estradiol (E2), androstenedione (A4) and testosterone (T), in regulating the developmental decision to enter or escape diapause II. Steroid hormone levels were measured in tissues isolated from adult female killifish during the normal lifespan of this species and in individuals of the same age that were producing either high or low proportions of escape embryos. Levels of steroid hormones were also measured during early development and in fertilized eggs that were predicted to be on either an escape or diapausing developmental trajectory. Decreases in maternal E2 levels associated with age are correlated with decreasing escape embryo production. Maternal production of escape embryos is correlated with increased ratios of E2 to T in adult ovary tissue. Interestingly, neither hormone is significantly different in fish producing embryos on different developmental pathways when examined independently. Levels of steroid hormones in fertilized eggs are not correlated with entry or escape from diapause II, though levels of A4 tend to be higher in escape embryos. Escape embryos exhibit faster hormone metabolism and earlier hormone synthesis than embryos that will enter diapause II. Incubation of embryos in exogenous E2 is associated with a 7-fold increase in escape embryo production, and significantly elevated A4 levels. These data suggest that steroid hormones may be critical factors involved in determining developmental pathways in embryos of A. limnaeus.

  18. Establishing Adverse Outcome Pathways of Thyroid Hormone Disruption in an Amphibian Model

    EPA Science Inventory

    The Adverse Outcome Pathway (AOP) provides a framework for understanding the relevance of toxicology data in ecotoxicological hazard assessments. The AOP concept can be applied to many toxicological pathways including thyroid hormone disruption. Thyroid hormones play a critical r...

  19. Biotransformation of cobicistat: metabolic pathways and enzymes

    PubMed Central

    Wang, Pengcheng; Shehu, Amina I.; Liu, Ke; Lu, Jie; Ma, Xiaochao

    2017-01-01

    Background Cobicistat (COBI) is a pharmacoenhancer for antiretroviral therapy. Objective The current study was designed to profile the metabolic pathways of COBI and to determine the enzymes that contribute to COBI metabolism. Method We screened COBI metabolites in mice and human liver microsomes. We also used cDNA-expressed human cytochromes P450 (CYPs) to explore the role of human enzymes in COBI metabolism. Results Twenty new and three known metabolites of COBI were identified in mouse urine and feces. These new metabolic pathways of COBI include glycine conjugation, N-acetyl cysteine conjugation, morpholine ring-opening, and thiazole ring-opening. Twelve of COBI metabolites were further confirmed in mouse and human liver microsomes, including nine new metabolites. Consistent with the previous report, CYP3A4 and CYP2D6 were determined as the major enzymes that contribute to COBI metabolism. Conclusion This study provided a full map of COBI metabolism. These results can be used to manage CYP-mediated drug-drug interactions and adverse drug reactions that are associated with COBI-containing regimens in human. PMID:26935921

  20. Transcription Profiles Reveal Sugar and Hormone Signaling Pathways Mediating Flower Induction in Apple (Malus domestica Borkh.).

    PubMed

    Xing, Li-Bo; Zhang, Dong; Li, You-Mei; Shen, Ya-Wen; Zhao, Cai-Ping; Ma, Juan-Juan; An, Na; Han, Ming-Yu

    2015-10-01

    Flower induction in apple (Malus domestica Borkh.) is regulated by complex gene networks that involve multiple signal pathways to ensure flower bud formation in the next year, but the molecular determinants of apple flower induction are still unknown. In this research, transcriptomic profiles from differentiating buds allowed us to identify genes potentially involved in signaling pathways that mediate the regulatory mechanisms of flower induction. A hypothetical model for this regulatory mechanism was obtained by analysis of the available transcriptomic data, suggesting that sugar-, hormone- and flowering-related genes, as well as those involved in cell-cycle induction, participated in the apple flower induction process. Sugar levels and metabolism-related gene expression profiles revealed that sucrose is the initiation signal in flower induction. Complex hormone regulatory networks involved in cytokinin (CK), abscisic acid (ABA) and gibberellic acid pathways also induce apple flower formation. CK plays a key role in the regulation of cell formation and differentiation, and in affecting flowering-related gene expression levels during these processes. Meanwhile, ABA levels and ABA-related gene expression levels gradually increased, as did those of sugar metabolism-related genes, in developing buds, indicating that ABA signals regulate apple flower induction by participating in the sugar-mediated flowering pathway. Furthermore, changes in sugar and starch deposition levels in buds can be affected by ABA content and the expression of the genes involved in the ABA signaling pathway. Thus, multiple pathways, which are mainly mediated by crosstalk between sugar and hormone signals, regulate the molecular network involved in bud growth and flower induction in apple trees.

  1. On the origin of metabolic pathways

    NASA Technical Reports Server (NTRS)

    Lazcano, A.; Miller, S. L.; Bada, J. L. (Principal Investigator)

    1999-01-01

    The heterotrophic theory of the origin of life is the only proposal available with experimental support. This comes from the ease of prebiotic synthesis under strongly reducing conditions. The prebiotic synthesis of organic compounds by reduction of CO(2) to monomers used by the first organisms would also be considered an heterotrophic origin. Autotrophy means that the first organisms biosynthesized their cell constituents as well as assembling them. Prebiotic synthetic pathways are all different from the biosynthetic pathways of the last common ancestor (LCA). The steps leading to the origin of the metabolic pathways are closer to prebiotic chemistry than to those in the LCA. There may have been different biosynthetic routes between the prebiotic and the LCAs that played an early role in metabolism but have disappeared from extant organisms. The semienzymatic theory of the origin of metabolism proposed here is similar to the Horowitz hypothesis but includes the use of compounds leaking from preexisting pathways as well as prebiotic compounds from the environment.

  2. Hormones

    MedlinePlus

    ... affect many different processes, including Growth and development Metabolism - how your body gets energy from the foods you eat Sexual function Reproduction Mood Endocrine glands, which are special groups of cells, make hormones. The major endocrine glands are the ...

  3. Illness-induced changes in thyroid hormone metabolism: focus on the tissue level.

    PubMed

    Kwakkel, J; Fliers, E; Boelen, A

    2011-05-01

    During illness changes in thyroid hormone metabolism occur, collectively known as the non-thyroidal illness syndrome (NTIS). NTIS is characterised by low serum thyroid hormone levels without the expected rise in serum thyroid-stimulating hormone, indicating a major change in thyroid hormone feedback regulation. Recent studies have made clear that during NTIS differential changes in thyroid hormone metabolism occur in various tissues, the net effect of which may be either activation or inhibition of thyroid hormone action. In this review we discuss systemic and local changes in thyroid hormone metabolism during illness, highlighting their physiological implications in terms of disease course.

  4. Metabolic Impact Of Sex Hormones On Obesity

    PubMed Central

    Brown, Lynda M.; Gent, Lana; Davis, Kathryn; Clegg, Deborah J.

    2010-01-01

    Obesity and its associated health disorders and costs are increasing. Men and postmenopausal women have greater risk of developing complications of obesity than younger women. Within the brain, the hypothalamus is an important regulator of energy homeostasis. Two of its sub-areas, the ventrolateral portion of the ventral medial nucleus (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large lesions are made in the hypothalamus which includes both the VL VMN and the ARC, animals eat more, have reduced energy expenditure, and become obese. The ARC and the VL VMN, in addition to other regions in the hypothalamus, have been demonstrated to contain estrogen receptors. There are two estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). We and others have previously demonstrated that activation of ERα by estrogens reduces food intake and increases body weight. This review focuses on the relative contribution of activation of ERα by estrogens in the ARC and the VL VMN in the regulation of food intake and body weight. Additionally, estrogen receptors have been found in many peripheral tissues including adipose tissue. Estrogens are thought to have direct effects on adipose tissue and estrogens may provide anti-inflammatory properties both in the periphery and the in the central nervous system (CNS) which may protect women from diseases associated with inflammation. Understanding the mechanisms by which estrogens regulate body weight and inflammation will assist in determining potential therapeutic agents for menopausal women to decrease the propensity of diseases associated with obesity. PMID:20441773

  5. Secondary Metabolic Pathway-Targeted Metabolomics

    PubMed Central

    Vizcaino, Maria I.; Crawford, Jason M.

    2016-01-01

    This chapter provides step-by-step methods for building secondary metabolic pathway-targeted molecular networks to assess microbial natural product biosynthesis at a systems level and to aid in downstream natural product discovery efforts. Methods described include high-resolution mass spectrometry (HRMS)-based comparative metabolomics, pathway-targeted tandem MS (MS/MS) molecular networking, and isotopic labeling for the elucidation of natural products encoded by orphan biosynthetic pathways. The metabolomics network workflow covers the following six points: (1) method development, (2) bacterial culture growth and organic extraction, (3) HRMS data acquisition and analysis, (4) pathway-targeted MS/MS data acquisition, (5) mass spectral network building, and (6) network enhancement. This chapter opens with a discussion on the practical considerations of natural product extraction, chromatographic processing, and enhanced detection of the analytes of interest within complex organic mixtures using liquid chromatography (LC)-HRMS. Next, we discuss the utilization of a chemometric platform, focusing on Agilent Mass Profiler Professional software, to run MS-based differential analysis between sample groups and controls to acquire a unique set of molecular features that are dependent on the presence of a secondary metabolic pathway. Using this unique list of molecular features, the chapter then details targeted MS/MS acquisition for subsequent pathway-dependent network clustering through the online Global Natural Products Social Molecular Networking (GnPS) platform. Genetic information, ionization intensities, isotopic labeling, and additional experimental data can be mapped onto the pathway-dependent network, facilitating systems biosynthesis analyses. The finished product will provide a working molecular network to assess experimental perturbations and guide novel natural product discoveries. PMID:26831709

  6. An algorithm for efficient identification of branched metabolic pathways.

    PubMed

    Heath, Allison P; Bennett, George N; Kavraki, Lydia E

    2011-11-01

    This article presents a new graph-based algorithm for identifying branched metabolic pathways in multi-genome scale metabolic data. The term branched is used to refer to metabolic pathways between compounds that consist of multiple pathways that interact biochemically. A branched pathway may produce a target compound through a combination of linear pathways that split compounds into smaller ones, work in parallel with many compounds, and join compounds into larger ones. While branched metabolic pathways predominate in metabolic networks, most previous work has focused on identifying linear metabolic pathways. The ability to automatically identify branched pathways is important in applications that require a deeper understanding of metabolism, such as metabolic engineering and drug target identification. The algorithm presented in this article utilizes explicit atom tracking to identify linear metabolic pathways and then merges them together into branched metabolic pathways. We provide results on several well-characterized metabolic pathways that demonstrate that the new merging approach can efficiently find biologically relevant branched metabolic pathways.

  7. Signal transduction pathways mediating parathyroid hormone regulation of osteoblastic gene expression

    NASA Technical Reports Server (NTRS)

    Partridge, N. C.; Bloch, S. R.; Pearman, A. T.

    1994-01-01

    Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.

  8. Chemical Shifts to Metabolic Pathways: Identifying Metabolic Pathways Directly from a Single 2D NMR Spectrum.

    PubMed

    Dubey, Abhinav; Rangarajan, Annapoorni; Pal, Debnath; Atreya, Hanudatta S

    2015-12-15

    Identifying cellular processes in terms of metabolic pathways is one of the avowed goals of metabolomics studies. Currently, this is done after relevant metabolites are identified to allow their mapping onto specific pathways. This task is daunting due to the complex nature of cellular processes and the difficulty in establishing the identity of individual metabolites. We propose here a new method: ChemSMP (Chemical Shifts to Metabolic Pathways), which facilitates rapid analysis by identifying the active metabolic pathways directly from chemical shifts obtained from a single two-dimensional (2D) [(13)C-(1)H] correlation NMR spectrum without the need for identification and assignment of individual metabolites. ChemSMP uses a novel indexing and scoring system comprised of a "uniqueness score" and a "coverage score". Our method is demonstrated on metabolic pathways data from the Small Molecule Pathway Database (SMPDB) and chemical shifts from the Human Metabolome Database (HMDB). Benchmarks show that ChemSMP has a positive prediction rate of >90% in the presence of decluttered data and can sustain the same at 60-70% even in the presence of noise, such as deletions of peaks and chemical shift deviations. The method tested on NMR data acquired for a mixture of 20 amino acids shows a success rate of 93% in correct recovery of pathways. When used on data obtained from the cell lysate of an unexplored oncogenic cell line, it revealed active metabolic pathways responsible for regulating energy homeostasis of cancer cells. Our unique tool is thus expected to significantly enhance analysis of NMR-based metabolomics data by reducing existing impediments.

  9. [Lead compound optimization strategy (1)--changing metabolic pathways and optimizing metabolism stability].

    PubMed

    Wang, Jiang; Liu, Hong

    2013-10-01

    Lead compound optimization plays an important role in new drug discovery and development. The strategies for changing metabolic pathways can modulate pharmacokinetic properties, prolong the half life, improve metabolism stability and bioavailability of lead compounds. The strategies for changing metabolic pathways and improving metabolism stability are reviewed. These methods include blocking metabolic site, reduing lipophilicity, changing ring size, bioisosterism, and prodrug.

  10. kpath: integration of metabolic pathway linked data

    PubMed Central

    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. Database URL: The public Linked Data repository can be queried at http://sparql.kpath.khaos.uma.es using the graph URI “www.khaos.uma.es/metabolic-pathways-app”. The GUI providing navigational access to kpath database is available at http://browser.kpath.khaos.uma.es. PMID:26055101

  11. Customized optimization of metabolic pathways by combinatorial transcriptional engineering.

    PubMed

    Yuan, Yongbo; Du, Jing; Zhao, Huimin

    2013-01-01

    Introduction of a heterologous metabolic pathway into a platform microorganism for applications in metabolic engineering and synthetic biology is often technically straightforward. However, the major challenge is to balance the flux in the pathway to obtain high yield and productivity in a target microorganism. To address this limitation, we recently developed a simple, efficient, and programmable approach named "customized optimization of metabolic pathways by combinatorial transcriptional engineering" (COMPACTER) for balancing the flux in a pathway under distinct metabolic backgrounds. Here we use two examples including a cellobiose-utilizing pathway and a xylose-utilizing pathway to illustrate the key steps in the COMPACTER method.

  12. Thyroid hormones changes in infants and children with metabolic acidosis.

    PubMed

    Tahirović, H F

    1991-10-01

    The influence of the acidotic state on the thyroxine (T4) peripheral metabolism was studied in two different forms of metabolic acidosis, ie infantile diarrhea and diabetic ketoacidosis. The serum concentrations of T4, free T4 (FT4), triiodothyronine (T3), reverse T3 (rT3), thyrotropin (TSH) and thyroxine-binding globulin (TBG) were measured and compared to healthy control groups. Lower T4 and T3 and higher rT3 serum concentrations were found in both tested groups of patients in relation to the control groups. In infants with severe metabolic acidosis FT4 values were lower than those observed in the control group. In addition, serum TBG levels were lower in diabetic patients as compared to control subjects. Despite the reduced serum T3 and T4 concentrations in both groups of patients, TSH concentrations, were within the normal range. Therefore, we concluded that acidosis caused either by diarrhea (not so far described) or by diabetes mellitus (well documented up to now) affects the thyroid hormones metabolism in a similar way, at least as far as the thyroid hormones blood levels are concerned.

  13. Synthesis of inositol phosphate ligands of plant hormone-receptor complexes: pathways of inositol hexakisphosphate turnover.

    PubMed

    Hanke, David E; Parmar, Paroo N; Caddick, Samuel E K; Green, Porntip; Brearley, Charles A

    2012-06-15

    Reduction of phytate is a major goal of plant breeding programs to improve the nutritional quality of crops. Remarkably, except for the storage organs of crops such as barley, maize and soybean, we know little of the stereoisomeric composition of inositol phosphates in plant tissues. To investigate the metabolic origins of higher inositol phosphates in photosynthetic tissues, we have radiolabelled leaf tissue of Solanum tuberosum with myo-[2-3H]inositol, undertaken a detailed analysis of inositol phosphate stereoisomerism and permeabilized mesophyll protoplasts in media containing inositol phosphates. We describe the inositol phosphate composition of leaf tissue and identify pathways of inositol phosphate metabolism that we reveal to be common to other kingdoms. Our results identify the metabolic origins of a number of higher inositol phosphates including ones that are precursors of cofactors, or cofactors of plant hormone-receptor complexes. The present study affords alternative explanations of the effects of disruption of inositol phosphate metabolism reported in other species, and identifies different inositol phosphates from that described in photosynthetic tissue of the monocot Spirodela polyrhiza. We define the pathways of inositol hexakisphosphate turnover and shed light on the occurrence of a number of inositol phosphates identified in animals, for which metabolic origins have not been defined.

  14. Kynurenine pathway metabolism and neuroinflammatory disease

    PubMed Central

    Braidy, Nady; Grant, Ross

    2017-01-01

    Immune-mediated activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP) is a consistent finding in all inflammatory disorders. Several studies by our group and others have examined the neurotoxic potential of neuroreactive TRYP metabolites, including quinolinic acid (QUIN) in neuroinflammatory neurological disorders, including Alzheimer's disease (AD), multiple sclerosis, amylotropic lateral sclerosis (ALS), and AIDS related dementia complex (ADC). Our current work aims to determine whether there is any benefit to the affected individuals in enhancing the catabolism of TRYP via the KP during an immune response. Under physiological conditions, QUIN is metabolized to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+), which represents an important metabolic cofactor and electron transporter. NAD+ also serves as a substrate for the DNA ‘nick sensor’ and putative nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP). Free radical initiated DNA damage, PARP activation and NAD+ depletion may contribute to brain dysfunction and cell death in neuroinflammatory disease. PMID:28250737

  15. kpath: integration of metabolic pathway linked data.

    PubMed

    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.

  16. Metabolic and hormonal changes during aerobic exercise in distance runners.

    PubMed

    Fernández-Pastor, V J; Ruiz, M; Diego-Acosta, A M; Avila, C; García, J C; Pérez, F; Guirado, F; Noguer, N

    1999-03-01

    A group of long-distance runners is studied in order to clarify aspects concerning neuroendocrine mechanisms regulating organic adaptation to maximum effort, with special interest in the function of the growth hormone in fat metabolism and the possible use of ketone bodies as an alternative source of energy. A test is designed on a treadmill with a gradient of 3% and progressive increases in speed of 2 Km/h every 10 min, starting at 6 Km/h, and continuing until exhaustion. Masks are worn to enable the breath by breath measurement of expired gases and the subjects are monitored electrocardiographically using V5. For blood sample collection an antecubital vein is catheterized with a system enabling the replacement of the blood volume extracted by means of perfusion with physiological saline solution, and the increasing concentration of hormones in the blood is evaluated. The results obtained, indicate that epinephrine as well as GH hormones increase significatively from 20 min of exercise in runners promoting changes from carbohydrates to lipids as fuels to carry out exercise. The concomitant variations in energy substrates support the former hypothesis of work. Moreover, the muscle could employ acetylCoA originating from acetoacetate as an alternative metabolic source of fuel during maximum effort.

  17. Novel biological and clinical aspects of thyroid hormone metabolism.

    PubMed

    Dumitrescu, Alexandra M; Refetoff, Samuel

    2007-01-01

    Intracellular metabolism of thyroid hormone (TH) and availability of the active hormone T3 is regulated by three selenoprotein iodothyronine deiodinases (Ds). D1 and D2 convert the precursor T4 into the active hormone, T3. D3 is the principal inactivator of T4 and T3 to their respective metabolites, rT3 and T2. While acquired changes in D activities are common, inherited defects in humans were not known. Recently, two families with abnormal thyroid function tests, high serum T4, high rT3, low T3 and slightly increased TSH, were identified. Linkage analysis and sequencing excluded abnormalities in all 3 DIO genes, yet clinical studies showed reduced responsiveness to T4 but not to T3. Extensive search for putative defects in genes involved in D2 metabolism led to the identification of mutations in the Sec insertion sequence binding protein (SBP)2 gene, involved in the synthesis of selenoproteins, including Ds. Affected children were either homozygous or compound heterozygous for these mutations. Other selenoproteins, including glutathione peroxidase, were also reduced in affected subjects, confirming a generalized effect of the SBP2 defect. Opposite thyroid test abnormalities are found in mutations of the TH transporter MCT8, and appear to be caused by the resulting increases in D2 and D1 activities.

  18. Cancer cachexia: mediators, signaling, and metabolic pathways.

    PubMed

    Fearon, Kenneth C H; Glass, David J; Guttridge, Denis C

    2012-08-08

    Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies.

  19. Hormonal regulation of medullary bone metabolism in the laying hen

    SciTech Connect

    Harrison, J.R.

    1987-01-01

    A new organ culture system for the study of bone formation has been developed using medullary bone, a non-structural, metabolically active form of bone which is found in the marrow cavities of egg-laying birds. In the presence of fetal calf serum, bone explants were viable in culture by morphological criteria, and retained large numbers of osteoblasts and osteoclasts. Incorporation of /sup 3/H-proline into collagenase-digestible protein (CDP) and non-collagen protein (NCP) was determined using purified bacterial collagenase. Collagen accounted for over 10% of the total protein labeled. The calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), caused a dose-dependent inhibition of /sup 3/H-proline incorporation into CDP. The effective dose range of 1,25(OH)2D3 was 0.1 nM to 100 nM, while that of PTH was 1.0 nM to 100 nM. The effect of both hormones was specific for collagen, since /sup 3/H-proline incorporation into NCP was unaffected. Hydroxyproline analysis of bone explants and culture medium revealed that both hormones decreased the total hydroxyroline content of the cultures, suggesting that the inhibition of /sup 3/H-proline incorporation into DCP is due to inhibition of collagen synthesis.

  20. Chronic exposure to pentachlorophenol alters thyroid hormones and thyroid hormone pathway mRNAs in zebrafish.

    PubMed

    Yu, Li-Qin; Zhao, Gao-Feng; Feng, Min; Wen, Wu; Li, Kun; Zhang, Pan-Wei; Peng, Xi; Huo, Wei-Jie; Zhou, Huai-Dong

    2014-01-01

    Pentachlorophenol (PCP) is frequently detected in the aquatic environment and has been implicated as an endocrine disruptor in fish. In the present study, 4-month-old zebrafish (Danio rerio) were exposed to 1 of 4 concentrations of PCP (0.1, 1, 9, and 27 µg/L) for 70 d. The effects of PCP exposure on plasma thyroid hormone levels, and the expression levels of selected genes, were measured in the brain and liver. The PCP exposure at 27 µg/L resulted in elevated plasma thyroxine concentrations in male and female zebrafish and depressed 3, 5, 3'-triiodothyronine concentrations in males only. In both sexes, PCP exposure resulted in decreased messenger RNA (mRNA) expression levels of thyroid-stimulating hormone β-subunit (tshβ) and thyroid hormone receptor β (trβ) in the brain, as well as increased liver levels of uridine diphosphoglucuronosyl transferase (ugt1ab) and decreased deiodinase 1 (dio1). The authors also identified several sex-specific effects of PCP exposure, including changes in mRNA levels for deiodinase 2 (dio2), cytosolic sulfotransferase (sult1 st5), and transthyretin (ttr) genes in the liver. Environmental PCP exposure also caused an increased malformation rate in offspring that received maternal exposure to PCP. The present study demonstrates that chronic exposure to environmental levels of PCP alters plasma thyroid hormone levels, as well as the expression of genes associated with thyroid hormone signaling and metabolism in the hypothalamic-pituitary-thyroid (HPT) axis and liver, resulting in abnormal zebrafish development.

  1. Hormonal and metabolic changes in the perinatal period.

    PubMed

    Mayor, F; Cuezva, J M

    1985-01-01

    A review of some hormonal and metabolic changes occurring during the four stages of the perinatal period is presented. Glucocorticoids and insulin are the hormones that mediate liver glycogen accumulation during late fetal stage. In the presuckling period, muscle glycogenolysis supplies the lactate moieties that are oxidized by the neonatal tissues, representing the alternative substrate until glucose and ketone bodies become available. The postnatal increase in plasma catecholamine concentrations and the decrease in the insulin/glucagon ratio triggers liver glycogenolysis and gluconeogenesis, and hence postnatal hypoglycemia is reversed. In the suckling period, the oxidation of fatty acids, ketone bodies utilization and active gluconeogenesis supply the bulk of the energy and carbon components required to support the rapid growth rate of this period. The increase in the insulin/glucagon ratio that occurs with the change to a carbohydrate-rich diet starts the induction of lipogenesis at weaning.

  2. Metabolic pathways in immune cell activation and quiescence.

    PubMed

    Pearce, Erika L; Pearce, Edward J

    2013-04-18

    Studies of immune system metabolism ("immunometabolism") segregate along two paths. The first investigates the effects of immune cells on organs that regulate whole-body metabolism, such as adipose tissue and liver. The second explores the role of metabolic pathways within immune cells and how this regulates immune response outcome. Distinct metabolic pathways diverge and converge at many levels, and, therefore, cells face choices as to how to achieve their metabolic goals. There is interest in fully understanding how and why immune cells commit to particular metabolic fates and in elucidating the immunologic consequences of reaching a metabolic endpoint by one pathway versus another. This is particularly intriguing, given that metabolic commitment is influenced not only by substrate availability but also by signaling pathways elicited by metabolites. Thus, metabolic choices in cells enforce fate and function, and this area will be the subject of this review.

  3. Vitamin D metabolism, sex hormones, and male reproductive function.

    PubMed

    Blomberg Jensen, Martin

    2012-08-01

    The spectrum of vitamin D (VD)-mediated effects has expanded in recent years, and VD is now recognized as a versatile signaling molecule rather than being solely a regulator of bone health and calcium homeostasis. One of the recently identified target areas of VD is male reproductive function. The VD receptor (VDR) and the VD metabolizing enzyme expression studies documented the presence of this system in the testes, mature spermatozoa, and ejaculatory tract, suggesting that both systemic and local VD metabolism may influence male reproductive function. However, it is still debated which cell is the main VD target in the testis and to what extent VD is important for sex hormone production and function of spermatozoa. This review summarizes descriptive studies on testicular VD metabolism and spatial distribution of VDR and the VD metabolizing enzymes in the mammalian testes and discusses mechanistic and association studies conducted in animals and humans. The reviewed evidence suggests some effects of VD on estrogen and testosterone biosynthesis and implicates involvement of both systemic and local VD metabolism in the regulation of male fertility potential.

  4. Plant responses to insect herbivory: interactions between photosynthesis, reactive oxygen species and hormonal signalling pathways.

    PubMed

    Kerchev, Pavel I; Fenton, Brian; Foyer, Christine H; Hancock, Robert D

    2012-02-01

    Under herbivore attack plants mount a defence response characterized by the accumulation of secondary metabolites and inhibitory proteins. Significant changes are observed in the transcriptional profiles of genes encoding enzymes of primary metabolism. Such changes have often been interpreted in terms of a requirement for an increased investment of resources to 'fuel' the synthesis of secondary metabolites. While enhanced secondary metabolism undoubtedly exerts an influence on primary metabolism, accumulating evidence suggests that rather than stimulating photosynthesis insect herbivory reduces photosynthetic carbon fixation and this response occurs by a re-programming of gene expression. Within this context, reactive oxygen species (ROS) and reductant/oxidant (redox) signalling play a central role. Accumulating evidence suggests that ROS signalling pathways are closely interwoven with hormone-signalling pathways in plant-insect interactions. Here we consider how insect infestation impacts on the stress signalling network through effects on ROS and cellular redox metabolism with particular emphasis on the roles of ROS in the plant responses to phloem-feeding insects.

  5. Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways.

    PubMed

    Jenwitheesuk, Anorut; Nopparat, Chutikorn; Mukda, Sujira; Wongchitrat, Prapimpun; Govitrapong, Piyarat

    2014-09-22

    Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

  6. Regulatory Cross-Talks and Cascades in Rice Hormone Biosynthesis Pathways Contribute to Stress Signaling

    PubMed Central

    Deb, Arindam; Grewal, Rumdeep K.; Kundu, Sudip

    2016-01-01

    Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus, independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each others production directly. Thus, multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones. PMID:27617021

  7. High-throughput evaluation of synthetic metabolic pathways

    PubMed Central

    Klesmith, Justin R.; Whitehead, Timothy A.

    2016-01-01

    A central challenge in the field of metabolic engineering is the efficient identification of a metabolic pathway genotype that maximizes specific productivity over a robust range of process conditions. Here we review current methods for optimizing specific productivity of metabolic pathways in living cells. New tools for library generation, computational analysis of pathway sequence-flux space, and high-throughput screening and selection techniques are discussed. PMID:27453919

  8. [Analyze and compare metabolic pathways of Bacillus cereus group].

    PubMed

    Yu, Chan; Wang, Yan; Xu, Cheng-Chen; He, Jin; Zhang, Qing-Ye; Yu, Zi-Niu

    2011-10-01

    A large number of data and information was obtained from genome sequencing and high-throughput genomic studies, use of the information to study metabolic networks become a new hotspot in biological research. This article compared different methods to reconstruct metabolic networks and analyzed the advantages and disadvantages of each methods, and then introduced some researches about carbohydrate metabolism pathways, amino acid metabolic pathways, and energy metabolism pathways of 9 strains of Bacillus cereus, 6 strains of B. anthracis,,6 strain of B. thuringiensis, and finds out their similarities and characteristics. These three strains have some necessary metabolic pathways, such as glycolysis, tri-carboxylic acid cycle, alanine metabolism, histidine metabolism, and energy metabolism, but they may have some specific pathways. B cereus has higher efficiency in utilizing monosaccharide, B. anthracis is rich in degradation and transport pathways of amino acids. A glutamate metabolic bypass way exists in B. thuringiensis. Analysis of metabolic pathways provides a new way to study and use food toxin, anthrax toxin, and insecticidal toxin of these strains in future.

  9. Alternative Cell Death Pathways and Cell Metabolism

    PubMed Central

    Fulda, Simone

    2013-01-01

    While necroptosis has for long been viewed as an accidental mode of cell death triggered by physical or chemical damage, it has become clear over the last years that necroptosis can also represent a programmed form of cell death in mammalian cells. Key discoveries in the field of cell death research, including the identification of critical components of the necroptotic machinery, led to a revised concept of cell death signaling programs. Several regulatory check and balances are in place in order to ensure that necroptosis is tightly controlled according to environmental cues and cellular needs. This network of regulatory mechanisms includes metabolic pathways, especially those linked to mitochondrial signaling events. A better understanding of these signal transduction mechanisms will likely contribute to open new avenues to exploit our knowledge on the regulation of necroptosis signaling for therapeutic application in the treatment of human diseases. PMID:23401689

  10. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR-gamma.

    PubMed

    Herzig, Stephan; Hedrick, Susan; Morantte, Ianessa; Koo, Seung-Hoi; Galimi, Francesco; Montminy, Marc

    2003-11-13

    Fasting triggers a series of hormonal cues that promote energy balance by inducing glucose output and lipid breakdown in the liver. In response to pancreatic glucagon and adrenal cortisol, the cAMP-responsive transcription factor CREB activates gluconeogenic and fatty acid oxidation programmes by stimulating expression of the nuclear hormone receptor coactivator PGC-1 (refs 2-5). In parallel, fasting also suppresses lipid storage and synthesis (lipogenic) pathways, but the underlying mechanism is unknown. Here we show that mice deficient in CREB activity have a fatty liver phenotype and display elevated expression of the nuclear hormone receptor PPAR-gamma, a key regulator of lipogenic genes. CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo. The coordinate induction of PGC-1 and repression of PPAR-gamma by CREB during fasting provides a molecular rationale for the antagonism between insulin and counter-regulatory hormones, and indicates a potential role for CREB antagonists as therapeutic agents in enhancing insulin sensitivity in the liver.

  11. Updating and curating metabolic pathways of TB.

    PubMed

    Slayden, Richard A; Jackson, Mary; Zucker, Jeremy; Ramirez, Melissa V; Dawson, Clinton C; Crew, Rebecca; Sampson, Nicole S; Thomas, Suzanne T; Jamshidi, Neema; Sisk, Peter; Caspi, Ron; Crick, Dean C; McNeil, Michael R; Pavelka, Martin S; Niederweis, Michael; Siroy, Axel; Dona, Valentina; McFadden, Johnjoe; Boshoff, Helena; Lew, Jocelyne M

    2013-01-01

    The sequencing of complete genomes has accelerated biomedical research by providing information about the overall coding capacity of bacterial chromosomes. The original TB annotation resulted in putative functional assignment of ∼60% of the genes to specific metabolic functions, however, the other 40% of the encoded ORFs where annotated as conserved hypothetical proteins, hypothetical proteins or encoding proteins of unknown function. The TB research community is now at the beginning of the next phases of post-genomics; namely reannotation and functional characterization by targeted experimentation. Arguably, this is the most significant time for basic microbiology in recent history. To foster basic TB research, the Tuberculosis Community Annotation Project (TBCAP) jamboree exercise began the reannotation effort by providing additional information for previous annotations, and refining and substantiating the functional assignment of ORFs and genes within metabolic pathways. The overall goal of the TBCAP 2012 exercise was to gather and compile various data types and use this information with oversight from the scientific community to provide additional information to support the functional annotations of encoding genes. Another objective of this effort was to standardize the publicly accessible Mycobacterium tuberculosis reference sequence and its annotation. The greatest benefit of functional annotation information of genome sequence is that it fuels TB research for drug discovery, diagnostics, vaccine development and epidemiology.

  12. Variations in metabolic pathways create challenges for automated metabolic reconstructions: Examples from the tetrahydrofolate synthesis pathway

    PubMed Central

    de Crécy-Lagard, Valérie

    2014-01-01

    The availability of thousands of sequenced genomes has revealed the diversity of biochemical solutions to similar chemical problems. Even for molecules at the heart of metabolism, such as cofactors, the pathway enzymes first discovered in model organisms like Escherichia coli or Saccharomyces cerevisiae are often not universally conserved. Tetrahydrofolate (THF) (or its close relative tetrahydromethanopterin) is a universal and essential C1-carrier that most microbes and plants synthesize de novo. The THF biosynthesis pathway and enzymes are, however, not universal and alternate solutions are found for most steps, making this pathway a challenge to annotate automatically in many genomes. Comparing THF pathway reconstructions and functional annotations of a chosen set of folate synthesis genes in specific prokaryotes revealed the strengths and weaknesses of different microbial annotation platforms. This analysis revealed that most current platforms fail in metabolic reconstruction of variant pathways. However, all the pieces are in place to quickly correct these deficiencies if the different databases were built on each other's strengths. PMID:25210598

  13. The Role of Gastrointestinal Hormones in Hepatic Lipid Metabolism

    PubMed Central

    Mells, Jamie Eugene; Anania, Frank A.

    2014-01-01

    Hepatocellular accumulation of free fatty acids (FFAs) in the form of triglycerides constitutes the metabolic basis for the development of nonalcoholic fatty liver disease (NAFLD). Recent data demonstrate that excess FFA hepatocyte storage is likely to lead to lipotoxicity and hepatocyte apoptosis. Hence, FFA-mediated hepatocyte injury is a key contributor to the pathogenesis of nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis, obesity, type 2 diabetes, essential hypertension, and other common medical problems together comprise metabolic syndrome. Evidence suggests that peptide hormones from the L cells of the distal small intestine, which comprise the core of the enteroendocrine system (EES), play two key roles, serving either as incretins, or as mediators of appetite and satiety in the central nervous system. Recent data related to glucagon-like peptide-1 (GLP-1) and other known L-cell hormones have accumulated due to the increasing frequency of bariatric surgery, which increase delivery of bile salts to the hindgut. Bile acids are a key stimulus for the TGR5 receptor of the L cells. Enhanced bile-salt flow and subsequent EES stimulation may be central to elimination of hepatic steatosis following bariatric surgery. Although GLP-1 is a clinically relevant pharmacological analogue that drives pancreatic β-cell insulin output, GLP-1 analogues also have independent benefits via their effects on hepatocellular FFA metabolism. The authors also discuss recent data regarding the role of the major peptides released by the EES, which promote satiety and modulate energy homeostasis and utilization, as well as those that control fat absorption and intestinal permeability. Taken together, elucidating novel functions for EES-related peptides and pharmacologic development of peptide analogues offer potential far-ranging treatment for obesity-related human disease. PMID:24222092

  14. Nuclear hormone receptor coregulator: role in hormone action, metabolism, growth, and development.

    PubMed

    Mahajan, Muktar A; Samuels, Herbert H

    2005-06-01

    Nuclear hormone receptor coregulator (NRC) (also referred to as activating signal cointegrator-2, thyroid hormone receptor-binding protein, peroxisome proliferator activating receptor-interacting protein, and 250-kDa receptor associated protein) belongs to a growing class of nuclear cofactors widely known as coregulators or coactivators that are necessary for transcriptional activation of target genes. The NRC gene is also amplified and overexpressed in breast, colon, and lung cancers. NRC is a 2063-amino acid protein that harbors a potent N-terminal activation domain (AD1) and a second more centrally located activation domain (AD2) that is rich in Glu and Pro. Near AD2 is a receptor-interacting domain containing an LxxLL motif (LxxLL-1), which interacts with a wide variety of ligand-bound nuclear hormone receptors with high affinity. A second LxxLL motif (LxxLL-2) located in the C-terminal region of NRC is more restricted in its nuclear hormone receptor specificity. The intrinsic activation potential of NRC is regulated by a C-terminal serine, threonine, leucine-regulatory domain. The potential role of NRC as a cointegrator is suggested by its ability to enhance transcriptional activation of a wide variety of transcription factors and from its in vivo association with a number of known transcriptional regulators including CBP/p300. Recent studies in mice indicate that deletion of both NRC alleles leads to embryonic lethality resulting from general growth retardation coupled with developmental defects in the heart, liver, brain, and placenta. NRC(-/-) mouse embryo fibroblasts spontaneously undergo apoptosis, indicating the importance of NRC as a prosurvival and antiapoptotic gene. Studies with 129S6 NRC(+/-) mice indicate that NRC is a pleiotropic regulator that is involved in growth, development, reproduction, metabolism, and wound healing.

  15. Glucose metabolic gene expression in growth hormone transgenic coho salmon.

    PubMed

    Panserat, Stéphane; Kamalam, Biju Sam; Fournier, Jeanne; Plagnes-Juan, Elisabeth; Woodward, Krista; Devlin, Robert H

    2014-04-01

    Salmonids are generally known to be glucose intolerant. However, previous studies have shown that growth hormone (GH) transgenic coho salmon display modified nutritional regulation of glycolysis and lipogenesis compared to non-transgenic fish, suggesting the potential for better use of glucose in GH transgenic fish. To examine this in detail, GH transgenic and non-transgenic coho salmon were subjected to glucose tolerance test and subsequent metabolic assessments. After intra-peritoneal injection of 250mg/kg glucose, we analysed post-injection kinetics of glycaemia and expression of several key target genes highly involved in glucose homeostasis in muscle and liver tissues. Our data show no significant differences in plasma glucose levels during peak hyperglycaemia (3-6h after injection), demonstrating a similar glucose tolerance between transgenic and non transgenic. However, and unrelated to the hyperglycaemic episode, GH transgenic fish return to a slightly lower basal glycaemia values 24h after injection. Correspondingly, GH transgenic fish exhibited higher mRNA levels of glucokinase (GK) and glucose-6-phosphate dehydrogenase (G6PDH) in liver, and glucose transporter (GLUT4) in muscle. These data suggest that these metabolic actors may be involved in different glucose use in GH transgenic fish, which would be expected to influence the glucose challenge response. Overall, our data demonstrate that GH transgenic coho salmon may be a pertinent animal model for further study of glucose metabolism in carnivorous fish.

  16. [Genes in the cAMP pathway causing skeletal dysplasia with or without hormonal resistance].

    PubMed

    Silve, Caroline

    2016-01-01

    Acrodysostosis refers to a heterogeneous group of rare skeletal dysplasia that share characteristic features including severe brachydactyly, facial dysostosis and nasal hypoplasia. The literature describing acrodysostosis cases has been confusing because some reported patients may have had other phenotypically related diseases presenting Albright Hereditary Osteodystrophy (AHO) such as pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP). A question has been whether patients display or not abnormal mineral metabolism associated with resistance to PTH and/or resistance to other hormones that bind G-protein coupled receptors (GPCR) linked to Gsa, as observed in PHP1a. Defects in two genes, PRKAR1A and PDE4D, both important players in the GPCR-Gsa-cAMP-PKA signaling, were recently identified in patients affected with acrodysostosis. This has helped clarify some issues regarding the heterogeneity of acrodysostosis, in particular the presence of hormonal resistance. Two different genetic and phenotypic syndromes are now identified, both with a similar bone dysplasia: acrodysostosis type 1 due to PRKAR1A defects, and acrodysostosis type 2, due to PDE4D defects. The existence of hormone resistance is typical of the acrodysostosis type 1 syndrome. We discuss here the PRKAR1A and PDE4D gene defects and phenotypes identified in acrodysostosis syndromes, in particular in regard to phenotypically related diseases caused by Gsa gene defects in the same signaling pathway.

  17. Production of bulk chemicals via novel metabolic pathways in microorganisms.

    PubMed

    Shin, Jae Ho; Kim, Hyun Uk; Kim, Dong In; Lee, Sang Yup

    2013-11-01

    Metabolic engineering has been playing important roles in developing high performance microorganisms capable of producing various chemicals and materials from renewable biomass in a sustainable manner. Synthetic and systems biology are also contributing significantly to the creation of novel pathways and the whole cell-wide optimization of metabolic performance, respectively. In order to expand the spectrum of chemicals that can be produced biotechnologically, it is necessary to broaden the metabolic capacities of microorganisms. Expanding the metabolic pathways for biosynthesizing the target chemicals requires not only the enumeration of a series of known enzymes, but also the identification of biochemical gaps whose corresponding enzymes might not actually exist in nature; this issue is the focus of this paper. First, pathway prediction tools, effectively combining reactions that lead to the production of a target chemical, are analyzed in terms of logics representing chemical information, and designing and ranking the proposed metabolic pathways. Then, several approaches for potentially filling in the gaps of the novel metabolic pathway are suggested along with relevant examples, including the use of promiscuous enzymes that flexibly utilize different substrates, design of novel enzymes for non-natural reactions, and exploration of hypothetical proteins. Finally, strain optimization by systems metabolic engineering in the context of novel metabolic pathways constructed is briefly described. It is hoped that this review paper will provide logical ways of efficiently utilizing 'big' biological data to design and develop novel metabolic pathways for the production of various bulk chemicals that are currently produced from fossil resources.

  18. Metabolic Pathways Visualization Skills Development by Undergraduate Students

    ERIC Educational Resources Information Center

    dos Santos, Vanessa J. S. V.; Galembeck, Eduardo

    2015-01-01

    We have developed a metabolic pathways visualization skill test (MPVST) to gain greater insight into our students' abilities to comprehend the visual information presented in metabolic pathways diagrams. The test is able to discriminate students' visualization ability with respect to six specific visualization skills that we identified as key to…

  19. Gustatory perception and fat body energy metabolism are jointly affected by vitellogenin and juvenile hormone in honey bees.

    PubMed

    Wang, Ying; Brent, Colin S; Fennern, Erin; Amdam, Gro V

    2012-06-01

    Honey bees (Apis mellifera) provide a system for studying social and food-related behavior. A caste of workers performs age-related tasks: young bees (nurses) usually feed the brood and other adult bees inside the nest, while older bees (foragers) forage outside for pollen, a protein/lipid source, or nectar, a carbohydrate source. The workers' transition from nursing to foraging and their foraging preferences correlate with differences in gustatory perception, metabolic gene expression, and endocrine physiology including the endocrine factors vitellogenin (Vg) and juvenile hormone (JH). However, the understanding of connections among social behavior, energy metabolism, and endocrine factors is incomplete. We used RNA interference (RNAi) to perturb the gene network of Vg and JH to learn more about these connections through effects on gustation, gene transcripts, and physiology. The RNAi perturbation was achieved by single and double knockdown of the genes ultraspiracle (usp) and vg, which encode a putative JH receptor and Vg, respectively. The double knockdown enhanced gustatory perception and elevated hemolymph glucose, trehalose, and JH. We also observed transcriptional responses in insulin like peptide 1 (ilp1), the adipokinetic hormone receptor (AKHR), and cGMP-dependent protein kinase (PKG, or "foraging gene" Amfor). Our study demonstrates that the Vg-JH regulatory module controls changes in carbohydrate metabolism, but not lipid metabolism, when worker bees shift from nursing to foraging. The module is also placed upstream of ilp1, AKHR, and PKG for the first time. As insulin, adipokinetic hormone (AKH), and PKG pathways influence metabolism and gustation in many animals, we propose that honey bees have conserved pathways in carbohydrate metabolism and conserved connections between energy metabolism and gustatory perception. Thus, perhaps the bee can make general contributions to the understanding of food-related behavior and metabolic disorders.

  20. Oxygen and the evolution of metabolic pathways

    NASA Technical Reports Server (NTRS)

    Jahnke, L. L.

    1986-01-01

    While a considerable amount of evidence has been accumulated about the history of oxygen on this planet, little is known about the relative amounts to which primitive cells might have been exposed. One clue may be found in the metabolic pathways of extant microorganisms. While eucaryotes are principally aerobic organisms, a number are capable of anaerobic growth by fermentation. One such eucaryotic microorganism, Saccharomyces cerevisiae, will grow in the complete absence of oxygen when supplemented with unsaturated fatty acid and sterol. Oxygen-requiring enzymes are involved in the synthesis of both of these compounds. Studies have demonstrated that the oxidative desaturation of palmitic acid and the conversion of squalene to sterols occur in the range of 10-(3) to 10(-2) PAL. Thus, if the oxygen requirements of these enzymatic processes are an indication, eucaryotes might be more primitive than anticipated from the microfossil record. Results of studies on the oxygen requirements for sterol and unsaturated fatty acid synthesis in a more primitive procaryotic system are also discussed.

  1. Curation and Computational Design of Bioenergy-Related Metabolic Pathways

    SciTech Connect

    Karp, Peter D.

    2014-09-12

    Pathway Tools is a systems-biology software package written by SRI International (SRI) that produces Pathway/Genome Databases (PGDBs) for organisms with a sequenced genome. Pathway Tools also provides a wide range of capabilities for analyzing predicted metabolic networks and user-generated omics data. More than 5,000 academic, industrial, and government groups have licensed Pathway Tools. This user community includes researchers at all three DOE bioenergy centers, as well as academic and industrial metabolic engineering (ME) groups. An integral part of the Pathway Tools software is MetaCyc, a large, multiorganism database of metabolic pathways and enzymes that SRI and its academic collaborators manually curate. This project included two main goals: I. Enhance the MetaCyc content of bioenergy-related enzymes and pathways. II. Develop computational tools for engineering metabolic pathways that satisfy specified design goals, in particular for bioenergy-related pathways. In part I, SRI proposed to significantly expand the coverage of bioenergy-related metabolic information in MetaCyc, followed by the generation of organism-specific PGDBs for all energy-relevant organisms sequenced at the DOE Joint Genome Institute (JGI). Part I objectives included: 1: Expand the content of MetaCyc to include bioenergy-related enzymes and pathways. 2: Enhance the Pathway Tools software to enable display of complex polymer degradation processes. 3: Create new PGDBs for the energy-related organisms sequenced by JGI, update existing PGDBs with new MetaCyc content, and make these data available to JBEI via the BioCyc website. In part II, SRI proposed to develop an efficient computational tool for the engineering of metabolic pathways. Part II objectives included: 4: Develop computational tools for generating metabolic pathways that satisfy specified design goals, enabling users to specify parameters such as starting and ending compounds, and preferred or disallowed intermediate compounds

  2. JNK pathway decreases thyroid hormones via TRH receptor: a novel mechanism for disturbance of thyroid hormone homeostasis by PCB153.

    PubMed

    Liu, Changjiang; Ha, Mei; Cui, Yushan; Wang, Chengmin; Yan, Maosheng; Fu, Wenjuan; Quan, Chao; Zhou, Jun; Yang, Kedi

    2012-12-08

    PCBs, widespread and well-characterized endocrine disruptors, cause the disruption of thyroid hormone (TH) homeostasis in humans and animals. In order to verify the hypotheses that MAPK pathways would play roles in disturbance of TH levels caused by PCBs, and that TH-associated receptors could function in certain MAPK pathway, Sprague-Dawley rats were dosed with PCB153 intraperitoneally (i.p.) at 0, 4, 16 and 32mg/kg for 5 consecutive days, and Nthy-ori 3-1 cells were treated with PCB153 (0, 1, 5, 10μM) for 30min. Results showed that after the treatment with PCB153, serum total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3) and thyrotropin releasing hormone (TRH) were decreased, whereas free triiodothyronine (FT3) and serum thyroid stimulating hormone (TSH) were not altered. In vivo and in vitro studies indicated that JNK pathway was activated after PCB153 exposure. Moreover, TRH receptor (TRHr) level was suppressed after the activation of JNK pathway and was elevated after the inhibition of JNK pathway, but TSH receptor (TSHr) level was not affected by the status of JNK pathway though it was reduced after PCB153 treatment. The activated signs of ERK and P38 pathways were not observed in this study. Taken together, observed effects suggested that JNK pathway could decrease TH levels via TRHr, and that would be one novel mechanism of PCB153-mediated disruption of THs.

  3. Metabolic and Hormonal Derangements in Pulmonary Hypertension: From Mouse to Man

    PubMed Central

    Pugh, Meredith E.; Hemnes, Anna R.

    2010-01-01

    Summary Pulmonary arterial hypertension (PAH) is a complex disease with significant morbidity and mortality. Recent animal and human studies have highlighted abnormalities in regulation and metabolism of insulin, sex hormones, adipokines, and lipids that may play a role in disease development. Mouse studies suggest features of the metabolic syndrome including insulin resistance, deficiencies in PPARγ and apolipoprotein E, and low adiponectin are linked to development of PAH. In humans, insulin resistance, the metabolic syndrome, and low levels of high-density lipoprotein have been associated with PAH. In addition, abnormal metabolism of estrogens has been demonstrated in human and animal models of PAH, suggesting an important relationship of sex hormones and pulmonary vascular disease. Improved understanding of how metabolic and hormonal derangements relate to development and progression of pulmonary hypertension may lead to better disease therapies and understanding of potential risk factors. This review will focus on the animal and human data regarding metabolic and sex hormone derangements in PAH. PMID:20939841

  4. Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.

    PubMed

    Lehmann, J M; Kliewer, S A; Moore, L B; Smith-Oliver, T A; Oliver, B B; Su, J L; Sundseth, S S; Winegar, D A; Blanchard, D E; Spencer, T A; Willson, T M

    1997-02-07

    Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7alpha-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXRalpha and LXRbeta, two orphan members of the nuclear receptor superfamily, are activated by 24(S), 25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7alpha-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.

  5. Customized optimization of metabolic pathways by combinatorial transcriptional engineering

    PubMed Central

    Du, Jing; Yuan, Yongbo; Si, Tong; Lian, Jiazhang; Zhao, Huimin

    2012-01-01

    A major challenge in metabolic engineering and synthetic biology is to balance the flux of an engineered heterologous metabolic pathway to achieve high yield and productivity in a target organism. Here, we report a simple, efficient and programmable approach named ‘customized optimization of metabolic pathways by combinatorial transcriptional engineering (COMPACTER)’ for rapid tuning of gene expression in a heterologous pathway under distinct metabolic backgrounds. Specifically, a library of mutant pathways is created by de novo assembly of promoter mutants of varying strengths for each pathway gene in a target organism followed by high-throughput screening/selection. To demonstrate this approach, a single round of COMPACTER was used to generate both a xylose utilizing pathway with near-highest efficiency and a cellobiose utilizing pathway with highest efficiency that were ever reported in literature for both laboratory and industrial yeast strains. Interestingly, these engineered xylose and cellobiose utilizing pathways were all host-specific. Therefore, COMPACTER represents a powerful approach to tailor-make metabolic pathways for different strain backgrounds, which is difficult if not impossible to achieve by existing pathway engineering methods. PMID:22718979

  6. Customized optimization of metabolic pathways by combinatorial transcriptional engineering.

    PubMed

    Du, Jing; Yuan, Yongbo; Si, Tong; Lian, Jiazhang; Zhao, Huimin

    2012-10-01

    A major challenge in metabolic engineering and synthetic biology is to balance the flux of an engineered heterologous metabolic pathway to achieve high yield and productivity in a target organism. Here, we report a simple, efficient and programmable approach named 'customized optimization of metabolic pathways by combinatorial transcriptional engineering (COMPACTER)' for rapid tuning of gene expression in a heterologous pathway under distinct metabolic backgrounds. Specifically, a library of mutant pathways is created by de novo assembly of promoter mutants of varying strengths for each pathway gene in a target organism followed by high-throughput screening/selection. To demonstrate this approach, a single round of COMPACTER was used to generate both a xylose utilizing pathway with near-highest efficiency and a cellobiose utilizing pathway with highest efficiency that were ever reported in literature for both laboratory and industrial yeast strains. Interestingly, these engineered xylose and cellobiose utilizing pathways were all host-specific. Therefore, COMPACTER represents a powerful approach to tailor-make metabolic pathways for different strain backgrounds, which is difficult if not impossible to achieve by existing pathway engineering methods.

  7. Targeting Metabolic Survival Pathways in Lung Cancer via Combination Therapy

    DTIC Science & Technology

    2014-06-01

    critical metabolic pathways necessary for survival of liver kinase B1 (LKB1)- deficient non-small cell lung cancer (NSCLC) cell lines. We have conducted...13C metabolic flux analysis studies in LKB1 proficient or deficient NSCLC cells under nutrient complete or metabolic stress conditions (e.g. hypoxia...derived pyruvate in mitochondria. LKB1- deficient cells also exhibit increased reliance on glutamine metabolism. Treatment with biguanides such as

  8. Metabolic pathways promoting cancer cell survival and growth.

    PubMed

    Boroughs, Lindsey K; DeBerardinis, Ralph J

    2015-04-01

    Activation of oncogenes and loss of tumour suppressors promote metabolic reprogramming in cancer, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathways. However, nutrient limitations within solid tumours may require that malignant cells exhibit metabolic flexibility to sustain growth and survival. Here, we highlight these adaptive mechanisms and also discuss emerging approaches to probe tumour metabolism in vivo and their potential to expand the metabolic repertoire of malignant cells even further.

  9. Metabolic pathway resources at MaizeGDB

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two maize metabolic networks are available at MaizeGDB: MaizeCyc (http://maizecyc.maizegdb.org, also at Gramene) and CornCyc (http://corncyc.maizegdb.org, also at the Plant Metabolic Network). MaizeCyc was developed by Gramene, and CornCyc by the Plant Metabolic Network, both in collaboration with M...

  10. EXPath: a database of comparative expression analysis inferring metabolic pathways for plants

    PubMed Central

    2015-01-01

    Background In general, the expression of gene alters conditionally to catalyze a specific metabolic pathway. Microarray-based datasets have been massively produced to monitor gene expression levels in parallel with numerous experimental treatments. Although several studies facilitated the linkage of gene expression data and metabolic pathways, none of them are amassed for plants. Moreover, advanced analysis such as pathways enrichment or how genes express under different conditions is not rendered. Description Therefore, EXPath was developed to not only comprehensively congregate the public microarray expression data from over 1000 samples in biotic stress, abiotic stress, and hormone secretion but also allow the usage of this abundant resource for coexpression analysis and differentially expression genes (DEGs) identification, finally inferring the enriched KEGG pathways and gene ontology (GO) terms of three model plants: Arabidopsis thaliana, Oryza sativa, and Zea mays. Users can access the gene expression patterns of interest under various conditions via five main functions (Gene Search, Pathway Search, DEGs Search, Pathways/GO Enrichment, and Coexpression analysis) in EXPath, which are presented by a user-friendly interface and valuable for further research. Conclusions In conclusion, EXPath, freely available at http://expath.itps.ncku.edu.tw, is a database resource that collects and utilizes gene expression profiles derived from microarray platforms under various conditions to infer metabolic pathways for plants. PMID:25708775

  11. Regulation of Appetite, Body Composition, and Metabolic Hormones by Vasoactive Intestinal Polypeptide (VIP).

    PubMed

    Vu, John P; Larauche, Muriel; Flores, Martin; Luong, Leon; Norris, Joshua; Oh, Suwan; Liang, Li-Jung; Waschek, James; Pisegna, Joseph R; Germano, Patrizia M

    2015-06-01

    Vasoactive intestinal peptide (VIP) is a 28-amino acid neuropeptide that belongs to the secretin-glucagon superfamily of peptides and has 68 % homology with PACAP. VIP is abundantly expressed in the central and peripheral nervous system and in the gastrointestinal tract, where it exercises several physiological functions. Previously, it has been reported that VIP regulates feeding behavior centrally in different species of vertebrates such as goldfishes, chicken and rodents. Additional studies are necessary to analyze the role of endogenous VIP on the regulation of appetite/satiety, feeding behavior, metabolic hormones, body mass composition and energy balance. The aim of the study was to elucidate the physiological pathways by which VIP regulates appetite/satiety, feeding behavior, metabolic hormones, and body mass composition. VIP deficient (VIP -/-) and age-matched wild-type (WT) littermates were weekly monitored from 5 to 22 weeks of age using a whole body composition EchoMRI analyzer. Food intake and feeding behavior were analyzed using the BioDAQ automated monitoring system. Plasma levels of metabolic hormones including active-ghrelin, GLP-1, leptin, PYY, pancreatic polypeptide (PP), adiponectin, and insulin were measured in fasting as well as in postprandial conditions. The genetic lack of VIP led to a significant reduction of body weight and fat mass and to an increase of lean mass as the mice aged. Additionally, VIP-/- mice had a disrupted pattern of circadian feeding behavior resulting in an abolished regular nocturnal/diurnal feeding. These changes were associated with an altered secretion of adiponectin, GLP-1, leptin, PYY and insulin in VIP-/- mice. Our data demonstrates that endogenous VIP is involved in the control of appetite/satiety, feeding behavior, body mass composition and in the secretion of six different key regulatory metabolic hormones. VIP plays a key role in the regulation of body phenotype by significantly enhancing body weight and fat

  12. The Impact of Sleep and Circadian Disturbance on Hormones and Metabolism

    PubMed Central

    Kim, Tae Won; Jeong, Jong-Hyun; Hong, Seung-Chul

    2015-01-01

    The levels of several hormones fluctuate according to the light and dark cycle and are also affected by sleep, feeding, and general behavior. The regulation and metabolism of several hormones are influenced by interactions between the effects of sleep and the intrinsic circadian system; growth hormone, melatonin, cortisol, leptin, and ghrelin levels are highly correlated with sleep and circadian rhythmicity. There are also endogenous circadian mechanisms that serve to regulate glucose metabolism and similar rhythms pertaining to lipid metabolism, regulated through the actions of various clock genes. Sleep disturbance, which negatively impacts hormonal rhythms and metabolism, is also associated with obesity, insulin insensitivity, diabetes, hormonal imbalance, and appetite dysregulation. Circadian disruption, typically induced by shift work, may negatively impact health due to impaired glucose and lipid homeostasis, reversed melatonin and cortisol rhythms, and loss of clock gene rhythmicity. PMID:25861266

  13. Mapping human metabolic pathways in the small molecule chemical space.

    PubMed

    Macchiarulo, Antonio; Thornton, Janet M; Nobeli, Irene

    2009-10-01

    The work presented here is a study of human metabolic pathways, as projected in the chemical space of the small molecules they comprise, and it is composed of three parts: a) a study of the extent of clustering and overlap of these pathways in chemical space, b) the development and assessment of a statistical model for estimating the proximity to a given pathway of any small molecule, and c) the use of the above model in estimating the proximity of marketed drugs to human metabolic pathways. The distribution, overlap, and relationships of human metabolic pathways in this space are revealed using both visual and quantitative approaches. A set of selected physicochemical and topological descriptors is used to build a classifier, whose aim is to predict metabolic class and pathway membership of any small molecule. The classifier performs well for tightly clustered, isolated pathways but is, naturally, much less accurate for strongly overlapping pathways. Finally, the extent of overlap of a set of known drugs with the human metabolome is examined, and the classifier is used to predict likely cross-interactions between drugs and the major metabolic pathways in humans.

  14. Sex steroid hormone metabolism takes place in human ocular cells.

    PubMed

    Coca-Prados, Miguel; Ghosh, Sikha; Wang, Yugang; Escribano, Julio; Herrala, Annakaisa; Vihko, Pirkko

    2003-08-01

    Steroids are potentially important mediators in the pathophysiology of ocular diseases. In this study, we report on the gene expression in the human eye of a group of enzymes, the 17beta-hydroxysteroid dehydrogenases (17HSDs), involved in the biosynthesis and inactivation of sex steroid hormones. In the eye, the ciliary epithelium, a neuroendocrine secretory epithelium, co-expresses the highest levels of 17HSD2 and 5 mRNAs, and in lesser level 17HSD7 mRNA. The regulation of gene expression of these enzymes was investigated in vitro in cell lines, ODM-C4 and chronic open glaucoma (GCE), used as cell models of the human ciliary epithelium. The estrogen, 17beta-estradiol (10(-7) M) and androgen agonist, R1881 (10(-8) M) elicited in ODM-C4 and GCE cells over a 24 h time course a robust up-regulation of 17HSD7 mRNA expression. 17HSD2 was up-regulated by estradiol in ODM-C4 cells, but not in GCE cells. Under steady-state conditions, ODM-C4 cells exhibited a predominant 17HSD2 oxidative enzymatic activity. In contrast, 17HSD2 activity was low or absent in GCE cells. Our collective data suggest that cultured human ciliary epithelial cells are able to metabolize estrogen, androgen and progesterone, and that 17HSD2 and 7 in these cells are sex steroid hormone-responsive genes and 17HSD7 is responsible to keep on intra/paracrine estrogenic milieu.

  15. Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients.

    PubMed

    Sonne, David P; Hare, Kristine J; Martens, Pernille; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2013-02-15

    Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

  16. Synthetic metabolism: engineering biology at the protein and pathway scales.

    PubMed

    Martin, Collin H; Nielsen, David R; Solomon, Kevin V; Prather, Kristala L Jones

    2009-03-27

    Biocatalysis has become a powerful tool for the synthesis of high-value compounds, particularly so in the case of highly functionalized and/or stereoactive products. Nature has supplied thousands of enzymes and assembled them into numerous metabolic pathways. Although these native pathways can be use to produce natural bioproducts, there are many valuable and useful compounds that have no known natural biochemical route. Consequently, there is a need for both unnatural metabolic pathways and novel enzymatic activities upon which these pathways can be built. Here, we review the theoretical and experimental strategies for engineering synthetic metabolic pathways at the protein and pathway scales, and highlight the challenges that this subfield of synthetic biology currently faces.

  17. Changes in the ghrelin hormone pathway maybe part of an unusual gastric system in monotremes.

    PubMed

    He, Chuan; Tsend-Ayush, Enkhjargal; Myers, Mark A; Forbes, Briony E; Grützner, Frank

    2013-09-15

    Ghrelin is a growth hormone (GH)-releasing and appetite-regulating peptide predominately released from the stomach. Ghrelin is evolutionarily highly conserved and known to have a wide range of functions including the regulation of metabolism by maintaining an insulin-glucose balance. The peptide is produced as a single proprotein, which is later proteolytically cleaved. Ghrelin exerts its biological function after O-n-octanoylation at residue serine 3, which is catalyzed by ghrelin O-acyl transferase (GOAT) and allows binding to the growth hormone secretagogue receptor (GHS-R 1a). Genes involved in the ghrelin pathway have been identified in a broad range of vertebrate species, however, little is known about this pathway in the basal mammalian lineage of monotremes (platypus and echidna). Monotremes are particularly interesting in this context, as they have undergone massive changes in stomach anatomy and physiology, accompanied by a striking loss of genes involved in gastric function. In this study, we investigated genes in the ghrelin pathway in monotremes. Using degenerate PCR, database searches and synteny analysis we found that genes encoding ghrelin and GOAT are missing in the platypus genome, whilst, as has been reported in other species, the GHSR is present and expressed in brain, pancreas, kidney, intestine, heart and stomach. This is the first report suggesting the loss of ghrelin in a mammal. The loss of this gene may be related to changes to the platypus digestive system and raises questions about the control of blood glucose levels and insulin response in monotreme mammals. In addition, the conservation of the ghrelin receptor gene in platypus indicates that another ligand(s) maybe acting via this receptor in monotremes.

  18. Role of thyroid hormone in postnatal circulatory and metabolic adjustments.

    PubMed Central

    Breall, J A; Rudolph, A M; Heymann, M A

    1984-01-01

    To assess the role of the early postnatal surge in plasma thyroid hormone concentrations on cardiovascular and metabolic adaptations, we measured cardiac output, total oxygen consumption, and plasma triiodothyronine (T3) concentrations in three groups of lambs in the first 6 h after delivery. 15 fetal lambs were prepared at gestational ages of 128-129 d by placing catheters in the brachiocephalic artery, descending aorta, distal inferior vena cava, left atrium, and pulmonary artery so that measurements could be made soon after delivery. They were divided into three groups: Group I comprised five control animals; Group II consisted of five fetuses in which thyroidectomy was performed at surgery at 129 d gestation; and Group III consisted of five animals in which thyroidectomy was performed at term gestation during delivery by caesarian section, prior to severing the umbilical cord. The lambs in Group I exhibited a rapid postnatal rise in T3 concentrations, similar to that described previously, reaching a peak value of about 5 ng/ml. Although the postnatal surge in T3 concentration was arrested in Group II and III animals, Group II had no detectable plasma T3, while the Group III animals had T3 concentrations of about 0.8 ng/ml, which were within the range previously reported for term lamb fetuses. The lambs in group II showed 40-50% lower left ventricular outputs (190 vs. 297 ml/kg per min), systemic blood flows (155 vs. 286 ml/kg per min), and oxygen consumptions (9.8 vs. 20.2 ml/kg per min) as compared with Group I animals over the entire 6-h period. The lambs in Group II also had significantly lower heart rates (131 vs. 192 beats/min) and mean systemic arterial pressures (56 vs. 72 torr). However, there were no significant differences for any of these measurements between the Group III and Group I lambs. The reduction in cardiac output in the Group II animals were reflected in a significantly lower blood flow to the peripheral circulation, but there were no

  19. What is the role of metabolic hormones in taste buds of the tongue.

    PubMed

    Cai, Huan; Maudsley, Stuart; Martin, Bronwen

    2014-01-01

    Gustation is one of the important chemical senses that guides the organism to identify nutrition while avoiding toxic chemicals. An increasing number of metabolic hormones and/or hormone receptors have been identified in the taste buds of the tongue and are involved in modulating taste perception. The gustatory system constitutes an additional endocrine regulatory locus that affects food intake, and in turn whole-body energy homeostasis. Here we provide an overview of the main metabolic hormones known to be present in the taste buds of the tongue; discuss their potential functional roles in taste perception and energy homeostasis and how their functional integrity is altered in the metabolic imbalance status (obesity and diabetes) and aging process. Better understanding of the functional roles of metabolic hormones in flavor perception as well as the link between taste perception and peripheral metabolism may be vital for developing strategies to promote healthier eating and prevent obesity or lifestyle-related disorders.

  20. The metabolic sensor Sirt1 and the hypothalamus: Interplay between peptide hormones and pro-hormone convertases.

    PubMed

    Nillni, Eduardo A

    2016-12-15

    The last decade had witnessed a tremendous progress in our understanding of the causes of metabolic diseases including obesity. Among the contributing factors regulating energy balance are nutrient sensors such as sirtuins. Sirtuin1 (Sirt1), a NAD + - dependent deacetylase is affected by diet, environmental stress, and also plays a critical role in metabolic health by deacetylating proteins in many tissues, including liver, muscle, adipose tissue, heart, endothelium, and in the complexity of the hypothalamus. Because of its dependence on NAD+, Sirt1 also functions as a nutrient/redox sensor, and new novel data show a function of this enzyme in the maturation of hypothalamic peptide hormones controlling energy balance either through regulation of specific nuclear transcription factors or by regulating specific pro-hormone convertases (PCs) involved in the post-translational processing of pro-hormones. The post-translational processing mechanism of pro-hormones is critical in the pathogenesis of obesity as recently shown that metabolic and physiological triggers affect the biosynthesis and processing of many peptides hormones. Specific regulation of pro-hormone processing is likely another key step where final amounts of bioactive peptides can be tightly regulated. Different factors stimulate or inhibit pro-hormones biosynthesis in concert with an increase in the PCs involved in the maturation of bioactive hormones. Adding more complexity to the system, the new studies describe here suggest that Sirt1 could also regulate the fate of peptide hormone biosynthesis. The present review summarizes the recent progress in hypothalamic SIRT1 research with a particular emphasis on the tissue-specific control of neuropeptide hormone maturation. The series of studies done in mouse and rat models strongly advocate for the first time that a deacetylating enzyme could be a regulator in the maturation of peptide hormones and their processing enzymes. These discoveries are the

  1. Digital gene expression analysis of male and female bud transition in Metasequoia reveals high activity of MADS-box transcription factors and hormone-mediated sugar pathways.

    PubMed

    Zhao, Ying; Liang, Haiying; Li, Lan; Tang, Sha; Han, Xiao; Wang, Congpeng; Xia, Xinli; Yin, Weilun

    2015-01-01

    Metasequoia glyptostroboides is a famous redwood tree of ecological and economic importance, and requires more than 20 years of juvenile-to-adult transition before producing female and male cones. Previously, we induced reproductive buds using a hormone solution in juvenile Metasequoia trees as young as 5-to-7 years old. In the current study, hormone-treated shoots found in female and male buds were used to identify candidate genes involved in reproductive bud transition in Metasequoia. Samples from hormone-treated cone reproductive shoots and naturally occurring non-cone setting shoots were analyzed using 24 digital gene expression (DGE) tag profiles using Illumina, generating a total of 69,520 putative transcripts. Next, 32 differentially and specifically expressed transcripts were determined using quantitative real-time polymerase chain reaction, including the upregulation of MADS-box transcription factors involved in male bud transition and flowering time control proteins involved in female bud transition. These differentially expressed transcripts were associated with 243 KEGG pathways. Among the significantly changed pathways, sugar pathways were mediated by hormone signals during the vegetative-to-reproductive phase transition, including glycolysis/gluconeogenesis and sucrose and starch metabolism pathways. Key enzymes were identified in these pathways, including alcohol dehydrogenase (NAD) and glutathione dehydrogenase for the glycolysis/gluconeogenesis pathway, and glucanphosphorylase for sucrose and starch metabolism pathways. Our results increase our understanding of the reproductive bud transition in gymnosperms. In addition, these studies on hormone-mediated sugar pathways increase our understanding of the relationship between sugar and hormone signaling during female and male bud initiation in Metasequoia.

  2. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development.

    PubMed

    Mueller, Kristina M; Themanns, Madeleine; Friedbichler, Katrin; Kornfeld, Jan-Wilhelm; Esterbauer, Harald; Tuckermann, Jan P; Moriggl, Richard

    2012-09-25

    Growth hormone (GH) and glucocorticoids (GCs) are involved in the control of processes that are essential for the maintenance of vital body functions including energy supply and growth control. GH and GCs have been well characterized to regulate systemic energy homeostasis, particular during certain conditions of physical stress. However, dysfunctional signaling in both pathways is linked to various metabolic disorders associated with aberrant carbohydrate and lipid metabolism. In liver, GH-dependent activation of the transcription factor signal transducer and activator of transcription (STAT) 5 controls a variety of physiologic functions within hepatocytes. Similarly, GCs, through activation of the glucocorticoid receptor (GR), influence many important liver functions such as gluconeogenesis. Studies in hepatic Stat5 or GR knockout mice have revealed that they similarly control liver function on their target gene level and indeed, the GR functions often as a cofactor of STAT5 for GH-induced genes. Gene sets, which require physical STAT5-GR interaction, include those controlling body growth and maturation. More recently, it has become evident that impairment of GH-STAT5 signaling in different experimental models correlates with metabolic liver disease, ranging from hepatic steatosis to hepatocellular carcinoma (HCC). While GH-activated STAT5 has a protective role in chronic liver disease, experimental disruption of GC-GR signaling rather seems to ameliorate metabolic disorders under metabolic challenge. In this review, we focus on the current knowledge about hepatic GH-STAT5 and GC-GR signaling in body growth, metabolism, and protection from fatty liver disease and HCC development.

  3. Abnormal serum thyroid hormones concentration with healthy functional gland: a review on the metabolic role of thyroid hormones transporter proteins.

    PubMed

    Azad, Reza Mansourian

    2011-03-01

    Laboratory findings can definitely help the patients not to enter into status, where the damage might be happen due to a miss-diagnosis based on clinical assessment alone. The secondary disease accompanied with thyroid patients should also carefully check out due to the interference which some diseases can cause in the amount of serum thyroid hormone, particularly the free thyroxin. The dilemma over thyroid clinical diagnosis occur due to variation on serum thyroid hormone which initiated by other non-thyroidal disorders which can play an important roles in metabolic disorders of thyroid hormone due to the alteration which occur on the serum level of thyroid hormone transporter proteins. The majority of serum thyroid hormones of up to 95-99% are bound to the carrier proteins mainly to Thyroxin-Binding Globulins (TBG), some transthyretin already known as pre-albumin and albumin which are all synthesis in the liver and any modification which alter their production may alter the status of thyroid hormones. It seems TBG, transthyretin and albumin carries 75, 20, 5% of thyroid hormones within blood circulation, respectively. The dilemma facing the thyroid hormones following disruption of thyroid hormone transporter protein synthesis originate from this fact that any alteration of these protein contribute to the alteration of total thyroid and free serum thyroid hormones which are in fact the biologically active form of thyroid hormones. The subsequent of latter implication result in miss-understanding and miss-diagnosis of thyroid function tests, with possible wrongly thyroid clinical care, followed by undesired therapy of otherwise healthy thyroid.

  4. A Method for Finding Metabolic Pathways Using Atomic Group Tracking

    PubMed Central

    Zhong, Cheng; Lin, Hai Xiang; Wang, Jianyi

    2017-01-01

    A fundamental computational problem in metabolic engineering is to find pathways between compounds. Pathfinding methods using atom tracking have been widely used to find biochemically relevant pathways. However, these methods require the user to define the atoms to be tracked. This may lead to failing to predict the pathways that do not conserve the user-defined atoms. In this work, we propose a pathfinding method called AGPathFinder to find biochemically relevant metabolic pathways between two given compounds. In AGPathFinder, we find alternative pathways by tracking the movement of atomic groups through metabolic networks and use combined information of reaction thermodynamics and compound similarity to guide the search towards more feasible pathways and better performance. The experimental results show that atomic group tracking enables our method to find pathways without the need of defining the atoms to be tracked, avoid hub metabolites, and obtain biochemically meaningful pathways. Our results also demonstrate that atomic group tracking, when incorporated with combined information of reaction thermodynamics and compound similarity, improves the quality of the found pathways. In most cases, the average compound inclusion accuracy and reaction inclusion accuracy for the top resulting pathways of our method are around 0.90 and 0.70, respectively, which are better than those of the existing methods. Additionally, AGPathFinder provides the information of thermodynamic feasibility and compound similarity for the resulting pathways. PMID:28068354

  5. Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

    SciTech Connect

    Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

    2010-07-01

    Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

  6. Tracking the pathway of arsenic metabolism

    EPA Science Inventory

    Although the toxic and carcinogenic properties of arsenic have been recognized for centuries, only in the past few decades has research focused on understanding the metabolic fate of arsenic in humans and relating metabolism to adverse health effects. In humans, conversion of in...

  7. A graph-theoretic approach to modeling metabolic pathways

    NASA Astrophysics Data System (ADS)

    Gifford, Eric; Johnson, Mark; Tsai, Chun-che

    1991-08-01

    The metabolic pathways of medazepam, oxazepam, and diazepam were modeled using graph-theoretic transforms which are incorporable into computer-assisted metabolic analysis programs. The information, represented in the form of a graph-theoretic transform kit, which was obtained from these pathways was then used to predict the metabolites of other benzodiazepine compounds. The transform kits gave statistically significant predictions with respect to a statistical method for evaluating the performance of the transform kits.

  8. Direct and indirect effects of growth hormone receptor ablation on liver expression of xenobiotic metabolizing genes.

    PubMed

    Li, Xinna; Bartke, Andrzej; Berryman, Darlene E; Funk, Kevin; Kopchick, John J; List, Edward O; Sun, Liou; Miller, Richard A

    2013-10-15

    Detoxification of ingested xenobiotic chemicals, and of potentially toxic endogenous metabolites, is carried out largely through a series of enzymes synthesized in the liver, sometimes called "xenobiotic metabolizing enzymes" (XME). Expression of these XME is sexually dimorphic in rodents and humans, with many of the XME expressed at higher levels in females. This expression pattern is thought to be regulated, in part, by the sex differences in circadian growth hormone (GH) pulsatility. We have evaluated mRNA, in the liver, for 52 XME genes in male and female mice of four mutant stocks, with diminished levels of GH receptor (GHR) either globally (GKO), or in liver (LKO), fat (FKO), or muscle (MKO) tissue specifically. The data show complex, sex-specific changes. For some XME, the expression pattern is consistent with direct control of hepatic mRNA by GHR in the liver. In contrast, other XME show evidence for indirect pathways in which hepatic XME expression is altered by GH signals in fat or skeletal muscle. The effects of GHR-null mutations on glucose control, responses to dietary interventions, steroid metabolism, detoxification pathways, and lifespan may depend on a mixture of direct hepatic effects and cross talk between different GH-responsive tissues.

  9. Stress hormones: physiological stress and regulation of metabolism.

    PubMed

    Kyrou, Ioannis; Tsigos, Constantine

    2009-12-01

    Stress, defined as a state of threatened homeostasis, mobilizes a complex spectrum of adaptive physiologic and behavioral responses that aim to re-establish the challenged body homeostasis. The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) constitute the main effector pathways of the stress system, mediating its adaptive functions. In western societies, indices of stress correlate with increasing rates of both obesity and metabolic syndrome which have reached epidemic proportions. Recent data indicate that chronic stress, associated with mild hypercortisolemia and prolonged SNS activation, favors accumulation of visceral fat and contributes to the clinical presentation of visceral obesity, type 2 diabetes, and related cardiometabolic complications. Reciprocally, obesity promotes a systemic low-grade inflammation state, mediated by increased adipokine secretion, which can chronically stimulate the stress system.

  10. Enumerating Minimal Active Metabolic Pathways by Model Generation

    NASA Astrophysics Data System (ADS)

    Soh, Takehide; Inoue, Katsumi

    In systems biology, identifying vital functions like glycolysis from a given metabolic pathway is important to understand living organisms. In this paper, we particularly focus on the problem of enumerating minimal active pathways producing target metabolites from source metabolites. We represent the problem in propositional formulas and solve it through minimal model generation. An advantage of our method is that each solution satisfies qualitative laws of biochemical reactions. Moreover, we can calculate such solutions for a cellular scale metabolic pathway within a few seconds. In experiments, we have applied our method to a whole Escherichia coli metabolic pathway. As a result, we found a minimal set of reactions corresponding to the conventional glycolysis pathway described in a biological database EcoCyc.

  11. Metabolic pathways of tetraidothyronine and triidothyronine production by thyroid gland: a review of articles.

    PubMed

    Mansourian, A R

    2011-01-01

    Tetraidothyronine (T4) and Triiodothyronine (T3) are the two vital hormones in human metabolism produced by thyroid gland. The major pathways in thyroid hormone biosynthesis begin with iodine metabolism which occurs in three sequential steps: active iodide transport into thyroid followed by iodide oxidation and subsequent iodination of tyrosyl residues of thyroglobulin (Tg) to produce idotyrosines monoidotyrosine (MIT) and diiodothyrosine (DIT) on Tg. Oxidized iodine and tyrosyle residues which are an aromatic amino acids are integral part of T4 and T3. The thyroid iodine deficiency of either dietary, thyroid malfunction, or disorder of hypothalamus and pituitary to produce enough Thyroid Stimulating Hormone (TSH), eventually lead to hypothyroidism with sever side effects. Iodine oxidation is the initial step for thyroid hormone synthesis within thyroid, is mediated by thyroperoxidase enzyme (TPO), which itself is activated by TSH required for production of MIT and DIT. T4 and T3 are subsequently are synthesized on Tg following MIT and DIT coupling reaction. Thyroid hormones eventually produced and released into circulation through Tg pinocytosis from follicular space and subsequent lysozomal function, a process again stimulated by TSH. The production of T4 and T3 are highly regulated externally by a negative feed-back interrelation between serum T4, T3 and TSH and internally by the elevated iodine within thyroid gland. It is believed the extra iodine concentration within thyroid gland control thyroid hormones synthesis by inhibition of the TPO and hydrogen peroxide (H2O2) formation which is also an essential factor of iodine oxidation, via a complex mechanism. In healthy subjects the entire procedures of T4 and T3 synthesis re-start again following a drop in serum T4 and T3 concentration. On conditions of thyroid disorders, which caused by the distruption of either of above mechanisms, thyroid hormone deficiency and related clinical manifestations eventually begin

  12. Integrated Interactive Chart as a Tool for Teaching Metabolic Pathways

    ERIC Educational Resources Information Center

    Kalogiannis, Stavros; Pagkalos, Ioannis; Koufoudakis, Panagiotis; Dashi, Ino; Pontikeri, Kyriaki; Christodoulou, Constantina

    2014-01-01

    An interactive chart of energy metabolism with didactic function, complementary to the already existing metabolic maps, located at the URL www.metpath.teithe.gr is being presented. The chart illustrates the major catabolic and biosynthetic pathways of glucose, fatty acids, and aminoacids, individually as well as in an integrated view. For every…

  13. The challenge of constructing, classifying, and representing metabolic pathways.

    PubMed

    Caspi, Ron; Dreher, Kate; Karp, Peter D

    2013-08-01

    Scientists, educators, and students benefit from having free and centralized access to the wealth of metabolic information that has been gathered over the decades. Curators of the MetaCyc database work to present this information in an easily understandable pathway-based framework. MetaCyc is used not only as an encyclopedic resource for metabolic information but also as a template for the pathway prediction software that generates pathway/genome databases for thousands of organisms with sequenced genomes (available at www.biocyc.org). Curators need to define pathway boundaries and classify pathways within a broader pathway ontology to maximize the utility of the pathways to both users and the pathway prediction software. These seemingly simple tasks pose several challenges. This review describes these challenges as well as the criteria that need to be considered, and the rules that have been developed by MetaCyc curators as they make decisions regarding the representation and classification of metabolic pathway information in MetaCyc. The functional consequences of these decisions in regard to pathway prediction in new species are also discussed.

  14. Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer

    DTIC Science & Technology

    2012-10-01

    Intervention for Breast Cancer PRINCIPAL INVESTIGATOR: Yan Cheng, Ph.D. CONTRACTING ORGANIZATION: Pennsylvania State University...Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer 5b. GRANT NUMBER W81XWH-11-1-0649 5c. PROGRAM ELEMENT NUMBER...causes of cancer mortality in women. Current therapies for breast cancer mainly target molecular signaling pathways that promote tumor cell

  15. New insights into the regulation of plant immunity by amino acid metabolic pathways.

    PubMed

    Zeier, Jürgen

    2013-12-01

    Besides defence pathways regulated by classical stress hormones, distinct amino acid metabolic pathways constitute integral parts of the plant immune system. Mutations in several genes involved in Asp-derived amino acid biosynthetic pathways can have profound impact on plant resistance to specific pathogen types. For instance, amino acid imbalances associated with homoserine or threonine accumulation elevate plant immunity to oomycete pathogens but not to pathogenic fungi or bacteria. The catabolism of Lys produces the immune signal pipecolic acid (Pip), a cyclic, non-protein amino acid. Pip amplifies plant defence responses and acts as a critical regulator of plant systemic acquired resistance, defence priming and local resistance to bacterial pathogens. Asp-derived pyridine nucleotides influence both pre- and post-invasion immunity, and the catabolism of branched chain amino acids appears to affect plant resistance to distinct pathogen classes by modulating crosstalk of salicylic acid- and jasmonic acid-regulated defence pathways. It also emerges that, besides polyamine oxidation and NADPH oxidase, Pro metabolism is involved in the oxidative burst and the hypersensitive response associated with avirulent pathogen recognition. Moreover, the acylation of amino acids can control plant resistance to pathogens and pests by the formation of protective plant metabolites or by the modulation of plant hormone activity.

  16. Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment.

    PubMed

    Perl, Andras

    2010-02-01

    Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T and B cells in SLE. In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes, enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells. MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common T and B cell biomarkers and targets for treatment in SLE.

  17. Interdisciplinary Pathways for Urban Metabolism Research

    NASA Astrophysics Data System (ADS)

    Newell, J. P.

    2011-12-01

    With its rapid rise as a metaphor to express coupled natural-human systems in cities, the concept of urban metabolism is evolving into a series of relatively distinct research frameworks amongst various disciplines, with varying definitions, theories, models, and emphases. In industrial ecology, housed primarily within the disciplinary domain of engineering, urban metabolism research has focused on quantifying material and energy flows into, within, and out of cities, using methodologies such as material flow analysis and life cycle assessment. In the field of urban ecology, which is strongly influenced by ecology and urban planning, research focus has been placed on understanding and modeling the complex patterns and processes of human-ecological systems within urban areas. Finally, in political ecology, closely aligned with human geography and anthropology, scholars theorize about the interwoven knots of social and natural processes, material flows, and spatial structures that form the urban metabolism. This paper offers three potential interdisciplinary urban metabolism research tracks that might integrate elements of these three "ecologies," thereby bridging engineering and the social and physical sciences. First, it presents the idea of infrastructure ecology, which explores the complex, emergent interdependencies between gray (water and wastewater, transportation, etc) and green (e.g. parks, greenways) infrastructure systems, as nested within a broader socio-economic context. For cities to be sustainable and resilient over time-space, the theory follows, these is a need to understand and redesign these infrastructure linkages. Second, there is the concept of an urban-scale carbon metabolism model which integrates consumption-based material flow analysis (including goods, water, and materials), with the carbon sink and source dynamics of the built environment (e.g. buildings, etc) and urban ecosystems. Finally, there is the political ecology of the material

  18. Cellular Metabolic and Autophagic Pathways: Traffic Control by Redox Signaling

    PubMed Central

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-01-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality, and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function. PMID:23702245

  19. Cellular metabolic and autophagic pathways: traffic control by redox signaling.

    PubMed

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-10-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

  20. Dissecting thyroid hormone transport and metabolism in dendritic cells.

    PubMed

    Gigena, Nicolás; Alamino, Vanina A; Montesinos, María Del Mar; Nazar, Magalí; Louzada, Ruy A; Wajner, Simone M; Maia, Ana L; Masini-Repiso, Ana M; Carvalho, Denise P; Cremaschi, Graciela A; Pellizas, Claudia G

    2017-02-01

    We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T4) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T4 did not reproduce those registered T3-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T3 with a favored involvement of MCT10 as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T3 increased MCT10 and LAT2 expression and T3 efflux from DCs but not T3 uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.

  1. Metabolic methanol: molecular pathways and physiological roles.

    PubMed

    Dorokhov, Yuri L; Shindyapina, Anastasia V; Sheshukova, Ekaterina V; Komarova, Tatiana V

    2015-04-01

    Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde.

  2. A Revolution in Plant Metabolism: Genome-Enabled Pathway Discovery

    PubMed Central

    Kim, Jeongwoon; Buell, C. Robin

    2015-01-01

    Genome-enabled discoveries are the hallmark of 21st century biology, including major discoveries in the biosynthesis and regulation of plant metabolic pathways. Access to next generation sequencing technologies has enabled research on the biosynthesis of diverse plant metabolites, especially secondary metabolites, resulting in a broader understanding of not only the structural and regulatory genes involved in metabolite biosynthesis but also in the evolution of chemical diversity in the plant kingdom. Several paradigms that govern secondary metabolism have emerged, including that (1) gene family expansion and diversification contribute to the chemical diversity found in the plant kingdom, (2) genes encoding biochemical pathway components are frequently transcriptionally coregulated, and (3) physical clustering of nonhomologous genes that encode components of secondary metabolic pathways can occur. With an increasing knowledge base that is coupled with user-friendly and inexpensive technologies, biochemists are poised to accelerate the annotation of biochemical pathways relevant to human health, agriculture, and the environment. PMID:26224805

  3. Metabolism of steroid hormones by Taenia solium and Taenia crassiceps cysticerci.

    PubMed

    Jiménez, P; Valdez, R A; Romano, M C

    2006-06-01

    Previous in vitro experiments showed that both, Taenia crassiceps and Taenia solium cysticerci have the ability to metabolize exogenous androstenedione to testosterone. Here we evaluate on the capacity of both cysticerci to synthesize several sex steroid hormones, using different hormonal precursors. Experiments using thin layer chromatography (TLC) showed that both cysticerci were able to produce (3)H-hydroxyprogesterone, (3)H-androstenedione and (3)H-testosterone when (3)H-progesterone was used as the precursor. They also synthesized (3)H-androstenediol and (3)H-testosterone when (3)H-dehydroepiandrosterone was the precursor. In addition, both cysticerci interconverted (3)H-estradiol and (3)H-estrone. These results, strongly suggest the presence and activity of the Delta4 and Delta5 steroid pathway enzymes, 3beta-hydroxysteroid dehydrogenase/Delta(5-4) isomerase-like enzyme (3beta-HSD), that converts androstenediol into testosterone; and the 17beta-hydroxysteroid dehydrogenase that interconverts estradiol and estrone, in both types of cysticerci.

  4. Melatonin Regulates Aging and Neurodegeneration through Energy Metabolism, Epigenetics, Autophagy and Circadian Rhythm Pathways

    PubMed Central

    Jenwitheesuk, Anorut; Nopparat, Chutikorn; Mukda, Sujira; Wongchitrat, Prapimpun; Govitrapong, Piyarat

    2014-01-01

    Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions. PMID:25247581

  5. Thyroid hormones correlate with resting metabolic rate, not daily energy expenditure, in two charadriiform seabirds.

    PubMed

    Elliott, Kyle H; Welcker, Jorg; Gaston, Anthony J; Hatch, Scott A; Palace, Vince; Hare, James F; Speakman, John R; Anderson, W Gary

    2013-06-15

    Thyroid hormones affect in vitro metabolic intensity, increase basal metabolic rate (BMR) in the lab, and are sometimes correlated with basal and/or resting metabolic rate (RMR) in a field environment. Given the difficulty of measuring metabolic rate in the field-and the likelihood that capture and long-term restraint necessary to measure metabolic rate in the field jeopardizes other measurements-we examined the possibility that circulating thyroid hormone levels were correlated with RMR in two free-ranging bird species with high levels of energy expenditure (the black-legged kittiwake, Rissa tridactyla, and thick-billed murre, Uria lomvia). Because BMR and daily energy expenditure (DEE) are purported to be linked, we also tested for a correlation between thyroid hormones and DEE. We examined the relationships between free and bound levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) with DEE and with 4-hour long measurements of post-absorptive and thermoneutral resting metabolism (resting metabolic rate; RMR). RMR but not DEE increased with T3 in both species; both metabolic rates were independent of T4. T3 and T4 were not correlated with one another. DEE correlated with body mass in kittiwakes but not in murres, presumably owing to the larger coefficient of variation in body mass during chick rearing for the more sexually dimorphic kittiwakes. We suggest T3 provides a good proxy for resting metabolism but not DEE in these seabird species.

  6. Computational identification of altered metabolism using gene expression and metabolic pathways.

    PubMed

    Nam, Hojung; Lee, Jinwon; Lee, Doheon

    2009-07-01

    Understanding altered metabolism is an important issue because altered metabolism is often revealed as a cause or an effect in pathogenesis. It has also been shown to be an important factor in the manipulation of an organism's metabolism in metabolic engineering. Unfortunately, it is not yet possible to measure the concentration levels of all metabolites in the genome-wide scale of a metabolic network; consequently, a method that infers the alteration of metabolism is beneficial. The present study proposes a computational method that identifies genome-wide altered metabolism by analyzing functional units of KEGG pathways. As control of a metabolic pathway is accomplished by altering the activity of at least one rate-determining step enzyme, not all gene expressions of enzymes in the pathway demonstrate significant changes even if the pathway is altered. Therefore, we measure the alteration levels of a metabolic pathway by selectively observing expression levels of significantly changed genes in a pathway. The proposed method was applied to two strains of Saccharomyces cerevisiae gene expression profiles measured in very high-gravity (VHG) fermentation. The method identified altered metabolic pathways whose properties are related to ethanol and osmotic stress responses which had been known to be observed in VHG fermentation because of the high sugar concentration in growth media and high ethanol concentration in fermentation products. With the identified altered pathways, the proposed method achieved best accuracy and sensitivity rates for the Red Star (RS) strain compared to other three related studies (gene-set enrichment analysis (GSEA), significance analysis of microarray to gene set (SAM-GS), reporter metabolite), and for the CEN.PK 113-7D (CEN) strain, the proposed method and the GSEA method showed comparably similar performances.

  7. Metabolic and hormonal signatures in pre-manifest and manifest Huntington's disease patients.

    PubMed

    Wang, Rui; Ross, Christopher A; Cai, Huan; Cong, Wei-Na; Daimon, Caitlin M; Carlson, Olga D; Egan, Josephine M; Siddiqui, Sana; Maudsley, Stuart; Martin, Bronwen

    2014-01-01

    Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be "pre-manifest." Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development.

  8. Natural Polyphenol Disposition via Coupled Metabolic Pathways

    PubMed Central

    Liu, Zhongqiu; Hu, Ming

    2009-01-01

    A major challenge associated with the development of chemopreventive polyphenols is the lack of bioavailability in vivo, which are primarily the result of coupled metabolic activities of conjugating enzymes and efflux transporters. These coupling processes are present in most of tissues and organs in mammals and are efficient for the purposes of drug metabolism, elimination and detoxification. Therefore, it was expected that these coupling processes represent a significant barrier to the oral bioavailabilities of polyphenols. In various studies of this coupling process, it was identified that various conjugating enzymes such as UGT and SULT are capable of producing very hydrophilic metabolites of polyphenols, which cannot diffuse out of the cells and needs the action of efflux transporters to pump them out of the cells. Additional studies have shown that efflux transporters such as MRP2, BCRP and OAT appear to serve as the gate keeper when there is an excess capacity to metabolize the compounds. These efflux transporters may also act as the facilitator of metabolism when there is a product/metabolite inhibition. For polyphenols, these coupled processes enable a duo recycling scheme of enteric and enterohepatic recycling, which allows the polyphenols to be reabsorbed and results in longer than expected apparent plasma half-lives for these compounds and their conjugates. Since the vast majority of polyphenols in plasma are hydrophilic conjugates, more research is needed to determine if the metabolites are active or reactive, which will help explain their mechanism of actions. PMID:17539746

  9. Predicting novel pathways in genome-scale metabolic networks.

    PubMed

    Schuster, Stefan; de Figueiredo, Luís F; Kaleta, Christoph

    2010-10-01

    Elementary-modes analysis has become a well-established theoretical tool in metabolic pathway analysis. It allows one to decompose complex metabolic networks into the smallest functional entities, which can be interpreted as biochemical pathways. This analysis has, in medium-size metabolic networks, led to the successful theoretical prediction of hitherto unknown pathways. For illustration, we discuss the example of the phosphoenolpyruvate-glyoxylate cycle in Escherichia coli. Elementary-modes analysis meets with the problem of combinatorial explosion in the number of pathways with increasing system size, which has hampered scaling it up to genome-wide models. We present a novel approach to overcoming this obstacle. That approach is based on elementary flux patterns, which are defined as sets of reactions representing the basic routes through a particular subsystem that are compatible with admissible fluxes in a (possibly) much larger metabolic network. The subsystem can be made up by reactions in which we are interested in, for example, reactions producing a certain metabolite. This allows one to predict novel metabolic pathways in genome-scale networks.

  10. Aligning Metabolic Pathways Exploiting Binary Relation of Reactions

    PubMed Central

    Zhong, Cheng; Lin, Hai Xiang; Huang, Jing

    2016-01-01

    Metabolic pathway alignment has been widely used to find one-to-one and/or one-to-many reaction mappings to identify the alternative pathways that have similar functions through different sets of reactions, which has important applications in reconstructing phylogeny and understanding metabolic functions. The existing alignment methods exhaustively search reaction sets, which may become infeasible for large pathways. To address this problem, we present an effective alignment method for accurately extracting reaction mappings between two metabolic pathways. We show that connected relation between reactions can be formalized as binary relation of reactions in metabolic pathways, and the multiplications of zero-one matrices for binary relations of reactions can be accomplished in finite steps. By utilizing the multiplications of zero-one matrices for binary relation of reactions, we efficiently obtain reaction sets in a small number of steps without exhaustive search, and accurately uncover biologically relevant reaction mappings. Furthermore, we introduce a measure of topological similarity of nodes (reactions) by comparing the structural similarity of the k-neighborhood subgraphs of the nodes in aligning metabolic pathways. We employ this similarity metric to improve the accuracy of the alignments. The experimental results on the KEGG database show that when compared with other state-of-the-art methods, in most cases, our method obtains better performance in the node correctness and edge correctness, and the number of the edges of the largest common connected subgraph for one-to-one reaction mappings, and the number of correct one-to-many reaction mappings. Our method is scalable in finding more reaction mappings with better biological relevance in large metabolic pathways. PMID:27936108

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

    PubMed

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

    2015-01-01

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

  12. Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

    PubMed

    Stark, Romana; Reichenbach, Alex; Andrews, Zane B

    2015-12-15

    The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

  13. Parallelization of Nullspace Algorithm for the computation of metabolic pathways.

    PubMed

    Jevremović, Dimitrije; Trinh, Cong T; Srienc, Friedrich; Sosa, Carlos P; Boley, Daniel

    2011-06-01

    Elementary mode analysis is a useful metabolic pathway analysis tool in understanding and analyzing cellular metabolism, since elementary modes can represent metabolic pathways with unique and minimal sets of enzyme-catalyzed reactions of a metabolic network under steady state conditions. However, computation of the elementary modes of a genome- scale metabolic network with 100-1000 reactions is very expensive and sometimes not feasible with the commonly used serial Nullspace Algorithm. In this work, we develop a distributed memory parallelization of the Nullspace Algorithm to handle efficiently the computation of the elementary modes of a large metabolic network. We give an implementation in C++ language with the support of MPI library functions for the parallel communication. Our proposed algorithm is accompanied with an analysis of the complexity and identification of major bottlenecks during computation of all possible pathways of a large metabolic network. The algorithm includes methods to achieve load balancing among the compute-nodes and specific communication patterns to reduce the communication overhead and improve efficiency.

  14. Kynurenine pathway metabolism and the microbiota-gut-brain axis.

    PubMed

    Kennedy, P J; Cryan, J F; Dinan, T G; Clarke, G

    2017-01-01

    It has become increasingly clear that the gut microbiota influences not only gastrointestinal physiology but also central nervous system (CNS) function by modulating signalling pathways of the microbiota-gut-brain axis. Understanding the neurobiological mechanisms underpinning the influence exerted by the gut microbiota on brain function and behaviour has become a key research priority. Microbial regulation of tryptophan metabolism has become a focal point in this regard, with dual emphasis on the regulation of serotonin synthesis and the control of kynurenine pathway metabolism. Here, we focus in detail on the latter pathway and begin by outlining the structural and functional dynamics of the gut microbiota and the signalling pathways of the brain-gut axis. We summarise preclinical and clinical investigations demonstrating that the gut microbiota influences CNS physiology, anxiety, depression, social behaviour, cognition and visceral pain. Pertinent studies are drawn from neurogastroenterology demonstrating the importance of tryptophan and its metabolites in CNS and gastrointestinal function. We outline how kynurenine pathway metabolism may be regulated by microbial control of neuroendocrine function and components of the immune system. Finally, preclinical evidence demonstrating direct and indirect mechanisms by which the gut microbiota can regulate tryptophan availability for kynurenine pathway metabolism, with downstream effects on CNS function, is reviewed. Targeting the gut microbiota represents a tractable target to modulate kynurenine pathway metabolism. Efforts to develop this approach will markedly increase our understanding of how the gut microbiota shapes brain and behaviour and provide new insights towards successful translation of microbiota-gut-brain axis research from bench to bedside. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.

  15. Inhibition of the Thyroid Hormone Pathway in Xenopus by Mercaptobenzothiazole

    EPA Science Inventory

    Amphibian metamorphosis is a thyroid hormone-dependent process that provides a potential model system to assess chemicals for their ability to disrupt the hypothalamic-pituitary-thyroid (HPT) axis. Several studies have demonstrated the sensitivity of this system to a variety of ...

  16. Evidence That Humans Metabolize Benzene via Two Pathways

    PubMed Central

    Rappaport, Stephen M.; Kim, Sungkyoon; Lan, Qing; Vermeulen, Roel; Waidyanatha, Suramya; Zhang, Luoping; Li, Guilan; Yin, Songnian; Hayes, Richard B.; Rothman, Nathaniel; Smith, Martyn T.

    2009-01-01

    Background Recent evidence has shown that humans metabolize benzene more efficiently at environmental air concentrations than at concentrations > 1 ppm. This led us to speculate that an unidentified metabolic pathway was mainly responsible for benzene metabolism at ambient levels. Objective We statistically tested whether human metabolism of benzene is better fitted by a kinetic model having two pathways rather than one. Methods We fit Michaelis-Menten-like models to levels of urinary benzene metabolites and the corresponding air concentrations for 263 nonsmoking Chinese females. Estimated benzene concentrations ranged from less than 0.001 ppm to 299 ppm, with 10th and 90th percentile values of 0.002 ppm and 8.97 ppm, respectively. Results Using values of Akaike’s information criterion obtained under the two models, we found strong statistical evidence favoring two metabolic pathways, with respective affinities (benzene air concentrations analogous to Km values) of 301 ppm for the low-affinity pathway (probably dominated by cytochrome P450 enzyme 2E1) and 0.594 ppm for the high-affinity pathway (unknown). The exposure-specific metabolite level predicted by our two-pathway model at nonsaturating concentrations was 184 μM/ppm of benzene, a value close to an independent estimate of 194 μM/ppm for a typical nonsmoking Chinese female. Our results indicate that a nonsmoking woman would metabolize about three times more benzene from the ambient environment under the two-pathway model (184 μM/ppm) than under the one-pathway model (68.6 μM/ppm). In fact, 73% of the ambient benzene dose would be metabolized via the unidentified high-affinity pathway. Conclusion Because regulatory risk assessments have assumed nonsaturating metabolism of benzene in persons exposed to air concentrations well above 10 ppm, our findings suggest that the true leukemia risks could be substantially greater than currently thought at ambient levels of exposure—about 3-fold higher among

  17. Co-evolution of Hormone Metabolism and Signaling Networks Expands Plant Adaptive Plasticity.

    PubMed

    Weng, Jing-Ke; Ye, Mingli; Li, Bin; Noel, Joseph P

    2016-08-11

    Classically, hormones elicit specific cellular responses by activating dedicated receptors. Nevertheless, the biosynthesis and turnover of many of these hormone molecules also produce chemically related metabolites. These molecules may also possess hormonal activities; therefore, one or more may contribute to the adaptive plasticity of signaling outcomes in host organisms. Here, we show that a catabolite of the plant hormone abscisic acid (ABA), namely phaseic acid (PA), likely emerged in seed plants as a signaling molecule that fine-tunes plant physiology, environmental adaptation, and development. This trait was facilitated by both the emergence-selection of a PA reductase that modulates PA concentrations and by the functional diversification of the ABA receptor family to perceive and respond to PA. Our results suggest that PA serves as a hormone in seed plants through activation of a subset of ABA receptors. This study demonstrates that the co-evolution of hormone metabolism and signaling networks can expand organismal resilience.

  18. Analysis of the aspartic acid metabolic pathway using mutant genes.

    PubMed

    Azevedo, R A

    2002-01-01

    Amino acid metabolism is a fundamental process for plant growth and development. Although a considerable amount of information is available, little is known about the genetic control of enzymatic steps or regulation of several pathways. Much of the information about biochemical pathways has arisen from the use of mutants lacking key enzymes. Although mutants were largely used already in the 60's, by bacterial and fungal geneticists, it took plant research a long time to catch up. The advance in this area was rapid in the 80's, which was followed in the 90's by the development of techniques of plant transformation. In this review we present an overview of the aspartic acid metabolic pathway, the key regulatory enzymes and the mutants and transgenic plants produced for lysine and threonine metabolism. We also discuss and propose a new study of high-lysine mutants.

  19. Cinnamon polyphenols regulate multiple metabolic pathways involved in intestinal lipid metabolism of primary small intestinal enterocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increasing evidence suggests that dietary factors may affect the expression of multiple genes and signaling pathways including those that regulate intestinal lipoprotein metabolism. The small intestine is actively involved in the regulation of dietary lipid absorption, intracellular transport and me...

  20. Transcription Analysis of Arabidopsis Membrane Transporters and Hormone Pathways during Developmental and Induced Leaf Senescence1[W

    PubMed Central

    van der Graaff, Eric; Schwacke, Rainer; Schneider, Anja; Desimone, Marcelo; Flügge, Ulf-Ingo; Kunze, Reinhard

    2006-01-01

    A comparative transcriptome analysis for successive stages of Arabidopsis (Arabidopsis thaliana) developmental leaf senescence (NS), darkening-induced senescence of individual leaves attached to the plant (DIS), and senescence in dark-incubated detached leaves (DET) revealed many novel senescence-associated genes with distinct expression profiles. The three senescence processes share a high number of regulated genes, although the overall number of regulated genes during DIS and DET is about 2 times lower than during NS. Consequently, the number of NS-specific genes is much higher than the number of DIS- or DET-specific genes. The expression profiles of transporters (TPs), receptor-like kinases, autophagy genes, and hormone pathways were analyzed in detail. The Arabidopsis TPs and other integral membrane proteins were systematically reclassified based on the Transporter Classification system. Coordinate activation or inactivation of several genes is observed in some TP families in all three or only in individual senescence types, indicating differences in the genetic programs for remobilization of catabolites. Characteristic senescence type-specific differences were also apparent in the expression profiles of (putative) signaling kinases. For eight hormones, the expression of biosynthesis, metabolism, signaling, and (partially) response genes was investigated. In most pathways, novel senescence-associated genes were identified. The expression profiles of hormone homeostasis and signaling genes reveal additional players in the senescence regulatory network. PMID:16603661

  1. Metabolic tinker: an online tool for guiding the design of synthetic metabolic pathways.

    PubMed

    McClymont, Kent; Soyer, Orkun S

    2013-06-01

    One of the primary aims of synthetic biology is to (re)design metabolic pathways towards the production of desired chemicals. The fast pace of developments in molecular biology increasingly makes it possible to experimentally redesign existing pathways and implement de novo ones in microbes or using in vitro platforms. For such experimental studies, the bottleneck is shifting from implementation of pathways towards their initial design. Here, we present an online tool called 'Metabolic Tinker', which aims to guide the design of synthetic metabolic pathways between any two desired compounds. Given two user-defined 'target' and 'source' compounds, Metabolic Tinker searches for thermodynamically feasible paths in the entire known metabolic universe using a tailored heuristic search strategy. Compared with similar graph-based search tools, Metabolic Tinker returns a larger number of possible paths owing to its broad search base and fast heuristic, and provides for the first time thermodynamic feasibility information for the discovered paths. Metabolic Tinker is available as a web service at http://osslab.ex.ac.uk/tinker.aspx. The same website also provides the source code for Metabolic Tinker, allowing it to be developed further or run on personal machines for specific applications.

  2. Metabolic Pathways in Anopheles stephensi mitochondria

    PubMed Central

    Giulivi, Cecilia; Ross-Inta, Catherine; Horton, Ashley A.; Luckhart, Shirley

    2017-01-01

    No studies have been performed on mitochondria of malaria vector mosquitoes. This information would be valuable in understanding mosquito aging and detoxification of insecticides, two parameters that significantly impact malaria parasite transmission in endemic regions. Here, we report the analyses of respiration and oxidative phosphorylation in mitochondria of cultured cells (ASE line) from Anopheles stephensi, a major vector of malaria in India, Southeast Asia and parts of the Middle East. ASE cell mitochondria shared many features in common with mammalian muscle mitochondria, despite the fact that these cells have a larval origin. However, two major differences with mammalian mitochondria were apparent. One, the glycerol-phosphate shuttle plays a major role in NADH oxidation in ASE cell mitochondria as it does in insect muscle mitochondria. In contrast, mammalian white muscle mitochondria depend primarily on lactate dehydrogenase, whereas red muscle mitochondria depend on the malate-oxaloacetate shuttle. Two, ASE mitochondria were able to oxidize Pro at a rate comparable with that of α-glycerophosphate. However, the Pro pathway appeared to differ from the currently accepted pathway, in that ketoglutarate could be catabolyzed completely by the Krebs cycle or via transamination depending on the ATP need. PMID:18588503

  3. Characterization of the juvenile hormone pathway in the viviparous cockroach, Diploptera punctata.

    PubMed

    Huang, Juan; Marchal, Elisabeth; Hult, Ekaterina F; Tobe, Stephen S

    2015-01-01

    Juvenile hormones (JHs) are key regulators of insect development and reproduction. The JH biosynthetic pathway is known to involve 13 discrete enzymatic steps. In the present study, we have characterized the JH biosynthetic pathway in the cockroach Diploptera punctata. The effect of exogenous JH precursors on JH biosynthesis was also determined. Based on sequence similarity, orthologs for the genes directly involved in the pathway were cloned, and their spatial and temporal transcript profiles were determined. The effect of shutting down the JH pathway in adult female cockroaches was studied by knocking down genes encoding HMG-CoA reductase (HMGR) and Juvenile hormone acid methyltransferase (JHAMT). As a result, oocyte development slowed as a consequence of reduction in JH biosynthesis. Oocyte length, fat body transcription of Vg and ovarian vitellin content significantly decreased. In addition, silencing HMGR and JHAMT resulted in a decrease in the transcript levels of other genes in the pathway.

  4. Drug target identification in sphingolipid metabolism by computational systems biology tools: metabolic control analysis and metabolic pathway analysis.

    PubMed

    Ozbayraktar, F Betül Kavun; Ulgen, Kutlu O

    2010-08-01

    Sphingolipids regulate cellular processes that are critically important in cell's fate and function in cancer development and progression. This fact underlies the basics of the novel cancer therapy approach. The pharmacological manipulation of the sphingolipid metabolism in cancer therapeutics necessitates the detailed understanding of the pathway. Two computational systems biology tools are used to identify potential drug target enzymes among sphingolipid pathway that can be further utilized in drug design studies for cancer therapy. The enzymes in sphingolipid pathway were ranked according to their roles in controlling the metabolic network by metabolic control analysis. The physiologically connected reactions, i.e. biologically significant and functional modules of network, were identified by metabolic pathway analysis. The final set of candidate drug target enzymes are selected such that their manipulation leads to ceramide accumulation and long chain base phosphates depletion. The mathematical tools' efficiency for drug target identification performed in this study is validated by clinically available drugs.

  5. The PI3K pathway in B cell metabolism.

    PubMed

    Jellusova, Julia; Rickert, Robert C

    2016-09-01

    B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprograming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor-mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

  6. Obesity-Driven Gut Microbiota Inflammatory Pathways to Metabolic Syndrome

    PubMed Central

    Cavalcante-Silva, Luiz H. A.; Galvão, José G. F. M.; da Silva, Juliane Santos de França; de Sales-Neto, José M.; Rodrigues-Mascarenhas, Sandra

    2015-01-01

    The intimate interplay between immune system, metabolism, and gut microbiota plays an important role in controlling metabolic homeostasis and possible obesity development. Obesity involves impairment of immune response affecting both innate and adaptive immunity. The main factors involved in the relationship of obesity with inflammation have not been completely elucidated. On the other hand, gut microbiota, via innate immune receptors, has emerged as one of the key factors regulating events triggering acute inflammation associated with obesity and metabolic syndrome. Inflammatory disorders lead to several signaling transduction pathways activation, inflammatory cytokine, chemokine production and cell migration, which in turn cause metabolic dysfunction. Inflamed adipose tissue, with increased macrophages infiltration, is associated with impaired preadipocyte development and differentiation to mature adipose cells, leading to ectopic lipid accumulation and insulin resistance. This review focuses on the relationship between obesity and inflammation, which is essential to understand the pathological mechanisms governing metabolic syndrome. PMID:26635627

  7. Diabetes, growth hormone-insulin-like growth factor pathways and association to benign prostatic hyperplasia.

    PubMed

    Wang, Zongwei; Olumi, Aria F

    2011-01-01

    Diabetes significantly increases the risk of benign prostatic hyperplasia (BPH) and low urinary tract symptoms (LUTS). The major endocrine aberration in connection with the metabolic syndrome is hyperinsulinemia. Insulin is an independent risk factor and a promoter of BPH. Insulin resistance may change the risk of BPH through several biological pathways. Hyperinsulinemia stimulates the liver to produce more insulin-like growth factor (IGF), another mitogen and an anti-apoptotic agent which binds insulin receptor/IGF receptor and stimulates prostate growth. The levels of IGFs and IGF binding proteins (IGFBPs) in prostate tissue and in blood are associated with BPH risk, with the regulation of circulating androgen and growth hormone. Stromal-epithelial interactions play a critical role in the development and growth of the prostate gland and BPH. Previously, we have shown that the expression of c-Jun in the fibroblastic stroma can promote secretion of IGF-I, which stimulates prostate epithelial cell proliferation through activating specific target genes. Here, we will review the epidemiologic, clinical, and molecular findings which have evaluated the relation between diabetes and development of BPH.

  8. Central Pathways Integrating Metabolism and Reproduction in Teleosts

    PubMed Central

    Shahjahan, Md.; Kitahashi, Takashi; Parhar, Ishwar S.

    2014-01-01

    Energy balance plays an important role in the control of reproduction. However, the cellular and molecular mechanisms connecting the two systems are not well understood especially in teleosts. The hypothalamus plays a crucial role in the regulation of both energy balance and reproduction, and contains a number of neuropeptides, including gonadotropin-releasing hormone (GnRH), orexin, neuropeptide-Y, ghrelin, pituitary adenylate cyclase-activating polypeptide, α-melanocyte stimulating hormone, melanin-concentrating hormone, cholecystokinin, 26RFamide, nesfatin, kisspeptin, and gonadotropin-inhibitory hormone. These neuropeptides are involved in the control of energy balance and reproduction either directly or indirectly. On the other hand, synthesis and release of these hypothalamic neuropeptides are regulated by metabolic signals from the gut and the adipose tissue. Furthermore, neurons producing these neuropeptides interact with each other, providing neuronal basis of the link between energy balance and reproduction. This review summarizes the advances made in our understanding of the physiological roles of the hypothalamic neuropeptides in energy balance and reproduction in teleosts, and discusses how they interact with GnRH, kisspeptin, and pituitary gonadotropins to control reproduction in teleosts. PMID:24723910

  9. Targeting Energy Metabolic Pathways as Therapeutic Intervention for Breast Cancer

    DTIC Science & Technology

    2014-12-01

    observed that the cells with knockdown of eEF-2K expression exhibited a decreased glucose consumption (Fig. 1B), as measured by flow cytometric analysis of......3. DATES COVERED 30 Sep 2011 - 20 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Energy Metabolic Pathways as Therapeutic

  10. A Guided Discovery Approach for Learning Metabolic Pathways

    ERIC Educational Resources Information Center

    Schultz, Emeric

    2005-01-01

    Learning the wealth of information in metabolic pathways is both challenging and overwhelming for students. A step-by-step guided discovery approach to the learning of the chemical steps in gluconeogenesis and the citric acid cycle is described. This approach starts from concepts the student already knows, develops these further in a logical…

  11. Malaria Parasite Metabolic Pathways (MPMP) Upgraded with Targeted Chemical Compounds.

    PubMed

    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.

  12. Metabolic pathways in the post-genome era.

    PubMed

    Papin, Jason A; Price, Nathan D; Wiback, Sharon J; Fell, David A; Palsson, Bernhard O

    2003-05-01

    Metabolic pathways are a central paradigm in biology. Historically, they have been defined on the basis of their step-by-step discovery. However, the genome-scale metabolic networks now being reconstructed from annotation of genome sequences demand new network-based definitions of pathways to facilitate analysis of their capabilities and functions, such as metabolic versatility and robustness, and optimal growth rates. This demand has led to the development of a new mathematically based analysis of complex, metabolic networks that enumerates all their unique pathways that take into account all requirements for cofactors and byproducts. Applications include the design of engineered biological systems, the generation of testable hypotheses regarding network structure and function, and the elucidation of properties that can not be described by simple descriptions of individual components (such as product yield, network robustness, correlated reactions and predictions of minimal media). Recently, these properties have also been studied in genome-scale networks. Thus, network-based pathways are emerging as an important paradigm for analysis of biological systems.

  13. Connecting proline metabolism and signaling pathways in plant senescence

    PubMed Central

    Zhang, Lu; Becker, Donald F.

    2015-01-01

    The amino acid proline has a unique biological role in stress adaptation. Proline metabolism is manipulated under stress by multiple and complex regulatory pathways and can profoundly influence cell death and survival in microorganisms, plants, and animals. Though the effects of proline are mediated by diverse signaling pathways, a common theme appears to be the generation of reactive oxygen species (ROS) due to proline oxidation being coupled to the respiratory electron transport chain. Considerable research has been devoted to understand how plants exploit proline metabolism in response to abiotic and biotic stress. Here, we review potential mechanisms by which proline metabolism influences plant senescence, namely in the petal and leaf. Recent studies of petal senescence suggest proline content is manipulated to meet energy demands of senescing cells. In the flower and leaf, proline metabolism may influence ROS signaling pathways that delay senescence progression. Future studies focusing on the mechanisms by which proline metabolic shifts occur during senescence may lead to novel methods to rescue crops under stress and to preserve post-harvest agricultural products. PMID:26347750

  14. Circadian acetylome reveals regulation of mitochondrial metabolic pathways.

    PubMed

    Masri, Selma; Patel, Vishal R; Eckel-Mahan, Kristin L; Peleg, Shahaf; Forne, Ignasi; Ladurner, Andreas G; Baldi, Pierre; Imhof, Axel; Sassone-Corsi, Paolo

    2013-02-26

    The circadian clock is constituted by a complex molecular network that integrates a number of regulatory cues needed to maintain organismal homeostasis. To this effect, posttranslational modifications of clock proteins modulate circadian rhythms and are thought to convert physiological signals into changes in protein regulatory function. To explore reversible lysine acetylation that is dependent on the clock, we have characterized the circadian acetylome in WT and Clock-deficient (Clock(-/-)) mouse liver by quantitative mass spectrometry. Our analysis revealed that a number of mitochondrial proteins involved in metabolic pathways are heavily influenced by clock-driven acetylation. Pathways such as glycolysis/gluconeogenesis, citric acid cycle, amino acid metabolism, and fatty acid metabolism were found to be highly enriched hits. The significant number of metabolic pathways whose protein acetylation profile is altered in Clock(-/-) mice prompted us to link the acetylome to the circadian metabolome previously characterized in our laboratory. Changes in enzyme acetylation over the circadian cycle and the link to metabolite levels are discussed, revealing biological implications connecting the circadian clock to cellular metabolic state.

  15. Metabolic pathway reconstruction strategies for central metabolism and natural product biosynthesis.

    PubMed

    Kotera, Masaaki; Goto, Susumu

    2016-01-01

    Metabolic pathway reconstruction presents a challenge for understanding metabolic pathways in organisms of interest. Different strategies, i.e., reference-based vs. de novo, must be used for pathway reconstruction depending on the availability of well-characterized enzymatic reactions. If at least one enzyme is already known to catalyze a reaction, its amino acid sequence can be used as a reference for identifying homologous enzymes in the genome of an organism of interest. Where there is no known enzyme able to catalyze a corresponding reaction, however, the reaction and the corresponding enzyme must be predicted de novo from chemical transformations of the putative substrate-product pair. This review summarizes studies involving reference-based and de novo metabolic pathway reconstruction and discusses the importance of the classification and structure-function relationships of enzymes.

  16. Metabolic pathway reconstruction strategies for central metabolism and natural product biosynthesis

    PubMed Central

    Kotera, Masaaki; Goto, Susumu

    2016-01-01

    Metabolic pathway reconstruction presents a challenge for understanding metabolic pathways in organisms of interest. Different strategies, i.e., reference-based vs. de novo, must be used for pathway reconstruction depending on the availability of well-characterized enzymatic reactions. If at least one enzyme is already known to catalyze a reaction, its amino acid sequence can be used as a reference for identifying homologous enzymes in the genome of an organism of interest. Where there is no known enzyme able to catalyze a corresponding reaction, however, the reaction and the corresponding enzyme must be predicted de novo from chemical transformations of the putative substrate-product pair. This review summarizes studies involving reference-based and de novo metabolic pathway reconstruction and discusses the importance of the classification and structure-function relationships of enzymes. PMID:27924274

  17. Bioinformatic Approaches to Metabolic Pathways Analysis

    PubMed Central

    Maudsley, Stuart; Chadwick, Wayne; Wang, Liyun; Zhou, Yu; Martin, Bronwen; Park, Sung-Soo

    2015-01-01

    The growth and development in the last decade of accurate and reliable mass data collection techniques has greatly enhanced our comprehension of cell signaling networks and pathways. At the same time however, these technological advances have also increased the difficulty of satisfactorily analyzing and interpreting these ever-expanding datasets. At the present time, multiple diverse scientific communities including molecular biological, genetic, proteomic, bioinformatic, and cell biological, are converging upon a common endpoint, that is, the measurement, interpretation, and potential prediction of signal transduction cascade activity from mass datasets. Our ever increasing appreciation of the complexity of cellular or receptor signaling output and the structural coordination of intracellular signaling cascades has to some extent necessitated the generation of a new branch of informatics that more closely associates functional signaling effects to biological actions and even whole-animal phenotypes. The ability to untangle and hopefully generate theoretical models of signal transduction information flow from transmembrane receptor systems to physiological and pharmacological actions may be one of the greatest advances in cell signaling science. In this overview, we shall attempt to assist the navigation into this new field of cell signaling and highlight several methodologies and technologies to appreciate this exciting new age of signal transduction. PMID:21870222

  18. Bioinformatic approaches to metabolic pathways analysis.

    PubMed

    Maudsley, Stuart; Chadwick, Wayne; Wang, Liyun; Zhou, Yu; Martin, Bronwen; Park, Sung-Soo

    2011-01-01

    The growth and development in the last decade of accurate and reliable mass data collection techniques has greatly enhanced our comprehension of cell signaling networks and pathways. At the same time however, these technological advances have also increased the difficulty of satisfactorily analyzing and interpreting these ever-expanding datasets. At the present time, multiple diverse scientific communities including molecular biological, genetic, proteomic, bioinformatic, and cell biological, are converging upon a common endpoint, that is, the measurement, interpretation, and potential prediction of signal transduction cascade activity from mass datasets. Our ever increasing appreciation of the complexity of cellular or receptor signaling output and the structural coordination of intracellular signaling cascades has to some extent necessitated the generation of a new branch of informatics that more closely associates functional signaling effects to biological actions and even whole-animal phenotypes. The ability to untangle and hopefully generate theoretical models of signal transduction information flow from transmembrane receptor systems to physiological and pharmacological actions may be one of the greatest advances in cell signaling science. In this overview, we shall attempt to assist the navigation into this new field of cell signaling and highlight several methodologies and technologies to appreciate this exciting new age of signal transduction.

  19. Association of thyroid hormones with obesity and metabolic syndrome in Japanese children.

    PubMed

    Minami, Yukako; Takaya, Ryuzo; Takitani, Kimitaka; Ishiro, Manabu; Okasora, Keisuke; Niegawa, Tomomi; Tamai, Hiroshi

    2015-09-01

    Obesity is associated with health consequences, and thyroid dysfunction may be an adaption to the increased energy expenditure in obesity. With the rising prevalence of obesity in childhood, the prevalence of metabolic syndrome may also increase. In the current study, we have shown gender differences in the association of thyroid hormones with obesity, and attempted to elucidate the relationship between thyroid hormones and anthropometric parameters and biochemical data in obese Japanese children. We analyzed anthropometric measurements, blood pressure, body composition, thyroid hormones, and lipid profiles in 283 obese children. The association between thyroid hormones and several parameters differed by gender. The free T3 to free T4 ratio (fT3/fT4) in boys was negatively associated with the quantitative insulin sensitivity check index, whereas in girls, thyroid-stimulating hormone levels were positively correlated with levels of glucose, diastolic blood pressure, and non-high density lipoprotein-cholesterol, and fT3/fT4 was positively correlated with uric acid levels. FT3/fT4 in boys with metabolic syndrome was relatively higher than in those without metabolic syndrome. The cause of gender differences is unknown. Therefore, further studies with larger sample sizes and a long-term follow-up period are needed to address the influence of thyroid hormones on various parameters.

  20. Association of thyroid hormones with obesity and metabolic syndrome in Japanese children

    PubMed Central

    Minami, Yukako; Takaya, Ryuzo; Takitani, Kimitaka; Ishiro, Manabu; Okasora, Keisuke; Niegawa, Tomomi; Tamai, Hiroshi

    2015-01-01

    Obesity is associated with health consequences, and thyroid dysfunction may be an adaption to the increased energy expenditure in obesity. With the rising prevalence of obesity in childhood, the prevalence of metabolic syndrome may also increase. In the current study, we have shown gender differences in the association of thyroid hormones with obesity, and attempted to elucidate the relationship between thyroid hormones and anthropometric parameters and biochemical data in obese Japanese children. We analyzed anthropometric measurements, blood pressure, body composition, thyroid hormones, and lipid profiles in 283 obese children. The association between thyroid hormones and several parameters differed by gender. The free T3 to free T4 ratio (fT3/fT4) in boys was negatively associated with the quantitative insulin sensitivity check index, whereas in girls, thyroid-stimulating hormone levels were positively correlated with levels of glucose, diastolic blood pressure, and non-high density lipoprotein-cholesterol, and fT3/fT4 was positively correlated with uric acid levels. FT3/fT4 in boys with metabolic syndrome was relatively higher than in those without metabolic syndrome. The cause of gender differences is unknown. Therefore, further studies with larger sample sizes and a long-term follow-up period are needed to address the influence of thyroid hormones on various parameters. PMID:26388669

  1. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection.

    PubMed

    Boelen, Anita; Kwakkel, Joan; Fliers, Eric

    2011-10-01

    Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

  2. Revealing parasite influence in metabolic pathways in Apicomplexa infected patients

    PubMed Central

    2010-01-01

    Background As an obligate intracellular parasite, Apicomplexa interacts with the host in the special living environment, competing for energy and nutrients from the host cells by manipulating the host metabolism. Previous studies of host-parasite interaction mainly focused on using cellular and biochemical methods to investigate molecular functions in metabolic pathways of parasite infected hosts. Computational approaches taking advantage of high-throughput biological data and topology of metabolic pathways have a great potential in revealing the details and mechanism of parasites-to-host interactions. A new analytical method was designed in this work to study host-parasite interactions in human cells infected with Plasmodium falciparum and Cryptosporidium parvum. Results We introduced a new method that analyzes the host metabolic pathways in divided parts: host specific subpathways and host-parasite common subpathways. Upon analysis on gene expression data from cells infected by Plasmodium falciparum or Cryptosporidium parvum, we found: (i) six host-parasite common subpathways and four host specific subpathways were significantly altered in plasmodium infected human cells; (ii) plasmodium utilized fatty acid biosynthesis and elongation, and Pantothenate and CoA biosynthesis to obtain nutrients from host environment; (iii) in Cryptosporidium parvum infected cells, most of the host-parasite common enzymes were down-regulated, whereas the host specific enzymes up-regulated; (iv) the down-regulation of common subpathways in host cells might be caused by competition for the substrates and up-regulation of host specific subpathways may be stimulated by parasite infection. Conclusion Results demonstrated a significantly coordinated expression pattern between the two groups of subpathways. The method helped expose the impact of parasite infection on host cell metabolism, which was previously concealed in the pathway enrichment analysis. Our approach revealed detailed

  3. Cellular metabolism in colorectal carcinogenesis: Influence of lifestyle, gut microbiome and metabolic pathways.

    PubMed

    Hagland, Hanne R; Søreide, Kjetil

    2015-01-28

    The interconnectivity between diet, gut microbiota and cell molecular responses is well known; however, only recently has technology allowed the identification of strains of microorganisms harbored in the gastrointestinal tract that may increase susceptibility to cancer. The colonic environment appears to play a role in the development of colon cancer, which is influenced by the human metabolic lifestyle and changes in the gut microbiome. Studying metabolic changes at the cellular level in cancer be useful for developing novel improved preventative measures, such as screening through metabolic breath-tests or treatment options that directly affect the metabolic pathways responsible for the carcinogenicity.

  4. Effect of menopausal hormone therapy on components of the metabolic syndrome.

    PubMed

    Lovre, Dragana; Lindsey, Sarah H; Mauvais-Jarvis, Franck

    2016-05-27

    The world population is aging, and women will spend an increasing share of their lives in a postmenopausal state that predisposes to metabolic dysfunction. Thus, the prevalence of metabolic syndrome (MetS) in women is likely to increase dramatically. This article summarizes the effects of menopause in predisposing to components of MetS including visceral obesity, dyslipidemia, type 2 diabetes (T2D) and hypertension (HTN). We also summarize the effects of menopausal hormone therapy (MHT) in reversing these metabolic alterations and discuss therapeutic advances of novel menopausal treatment on metabolic function.

  5. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.

    PubMed

    Woodfield, George W; Horan, Annamarie D; Chen, Yizhen; Weigel, Ronald J

    2007-09-15

    Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21(CIP1) and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

  6. How Did Arthropod Sesquiterpenoids and Ecdysteroids Arise? Comparison of Hormonal Pathway Genes in Noninsect Arthropod Genomes

    PubMed Central

    Qu, Zhe; Kenny, Nathan James; Lam, Hon Ming; Chan, Ting Fung; Chu, Ka Hou; Bendena, William G.; Tobe, Stephen S.; Hui, Jerome Ho Lam

    2015-01-01

    The phylum Arthropoda contains the largest number of described living animal species, with insects and crustaceans dominating the terrestrial and aquatic environments, respectively. Their successful radiations have long been linked to their rigid exoskeleton in conjunction with their specialized endocrine systems. In order to understand how hormones can contribute to the evolution of these animals, here, we have categorized the sesquiterpenoid and ecdysteroid pathway genes in the noninsect arthropod genomes, which are known to play important roles in the regulation of molting and metamorphosis in insects. In our analyses, the majority of gene homologs involved in the biosynthetic, degradative, and signaling pathways of sesquiterpenoids and ecdysteroids can be identified, implying these two hormonal systems were present in the last common ancestor of arthropods. Moreover, we found that the “Broad-Complex” was specifically gained in the Pancrustacea, and the innovation of juvenile hormone (JH) in the insect linage correlates with the gain of the JH epoxidase (CYP15A1/C1) and the key residue changes in the binding domain of JH receptor (“Methoprene-tolerant”). Furthermore, the gain of “Phantom” differentiates chelicerates from the other arthropods in using ponasterone A rather than 20-hydroxyecdysone as molting hormone. This study establishes a comprehensive framework for interpreting the evolution of these vital hormonal pathways in these most successful animals, the arthropods, for the first time. PMID:26112967

  7. Alterations in metabolic pathways and networks in Alzheimer's disease.

    PubMed

    Kaddurah-Daouk, R; Zhu, H; Sharma, S; Bogdanov, M; Rozen, S G; Matson, W; Oki, N O; Motsinger-Reif, A A; Churchill, E; Lei, Z; Appleby, D; Kling, M A; Trojanowski, J Q; Doraiswamy, P M; Arnold, S E

    2013-04-09

    The pathogenic mechanisms of Alzheimer's disease (AD) remain largely unknown and clinical trials have not demonstrated significant benefit. Biochemical characterization of AD and its prodromal phase may provide new diagnostic and therapeutic insights. We used targeted metabolomics platform to profile cerebrospinal fluid (CSF) from AD (n=40), mild cognitive impairment (MCI, n=36) and control (n=38) subjects; univariate and multivariate analyses to define between-group differences; and partial least square-discriminant analysis models to classify diagnostic groups using CSF metabolomic profiles. A partial correlation network was built to link metabolic markers, protein markers and disease severity. AD subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine and glutathione versus controls. MCI subjects had elevated 5-HIAA, MET, hypoxanthine and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET. These findings indicate that MCI and AD are associated with an overlapping pattern of perturbations in tryptophan, tyrosine, MET and purine pathways, and suggest that profound biochemical alterations are linked to abnormal Ab42 and tau metabolism. Metabolomics provides powerful tools to map interlinked biochemical pathway perturbations and study AD as a disease of network failure.

  8. Metabolic engineering of biosynthetic pathway for production of renewable biofuels.

    PubMed

    Singh, Vijai; Mani, Indra; Chaudhary, Dharmendra Kumar; Dhar, Pawan Kumar

    2014-02-01

    Metabolic engineering is an important area of research that involves editing genetic networks to overproduce a certain substance by the cells. Using a combination of genetic, metabolic, and modeling methods, useful substances have been synthesized in the past at industrial scale and in a cost-effective manner. Currently, metabolic engineering is being used to produce sufficient, economical, and eco-friendly biofuels. In the recent past, a number of efforts have been made towards engineering biosynthetic pathways for large scale and efficient production of biofuels from biomass. Given the adoption of metabolic engineering approaches by the biofuel industry, this paper reviews various approaches towards the production and enhancement of renewable biofuels such as ethanol, butanol, isopropanol, hydrogen, and biodiesel. We have also identified specific areas where more work needs to be done in the future.

  9. [Effects of growth hormone replacement therapy on bone metabolism].

    PubMed

    Yamamoto, Masahiro; Sugimoto, Toshitsugu

    2014-06-01

    Growth hormone (GH) as well as insulin like growth factor-1 (IGF-1) are essential hormones to maintain homeostasis of bone turnover by activating osteoblastogenesis and osteoclastogenesis. Results from GH replacement therapy for primary osteoporosis and adult-onset GH deficiency (AGHD) suggest that one year or more treatment period by this agent is required to gain bone mineral density (BMD) over the basal level after compensating BMD loss caused by dominant increase in bone resorption which was observed at early phase of GH treatment. A recent meta-analysis demonstrates the efficacy of GH replacement therapy on increases in BMD in male patients with AGHD. Additional analyses are needed to draw firm conclusions in female patients with AGHD, because insufficient amounts of GH might be administrated to them without considerations of influence of estrogen replacement therapy on IGF-1 production. Further observational studies are needed to clarify whether GH replacement therapy prevent fracture risk in these patients.

  10. Human stanniocalcin: a possible hormonal regulator of mineral metabolism.

    PubMed Central

    Olsen, H S; Cepeda, M A; Zhang, Q Q; Rosen, C A; Vozzolo, B L

    1996-01-01

    We have isolated a human cDNA clone encoding the mammalian homolog of stanniocalcin (STC), a calcium- and phosphate-regulating hormone that was first described in fishes where it functions in preventing hypercalcemia. STC has a unique amino acid sequence and, until now, has remained one of the few polypeptide hormones never described in higher vertebrates. Human STC (hSTC) was found to be 247 amino acids long and to share 73% amino acid sequence similarity with fish STC. Polyclonal antibodies to recombinant hSTC localized to a distinct cell type in the nephron tubule, suggesting kidney as a possible site of synthesis. Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat. The evidence suggests that mammalian STC, like its piscine counterpart, is a regulator of mineral homeostasis. Images Fig. 5 Fig. 6 PMID:8700837

  11. Debottlenecking the 1,3-propanediol pathway by metabolic engineering.

    PubMed

    Celińska, E

    2010-01-01

    The history of 1,3-propanediol (1,3-PD) conversion from being a specialty chemical to being a bulk chemical illustrates that the concerted effort of different metabolic engineering approaches brings the most successful results. In order to metabolically tailor the 1,3-PD production pathway multiple strategies have been pursued. Knocking-out genes responsible for by-products formation, intergeneric transfer and overexpression of the genes directly involved in the pathway, manipulation with internal redox balance, introduction of a synthetic flux control point, and modification of the substrate mechanism of transport are some of the strategies applied. The metabolic engineering of the microbial 1,3-PD production exploits both native producers and microorganisms with acquired ability to produce the diol via genetic manipulations. Combination of the appropriate genes from homologous and heterologous hosts is expected to bring a desired objective of production of 1,3-PD cheaply, efficiently and independently from non-renewable resources. The state-of-the-art of the 1,3-PD pathway metabolic engineering is reviewed in this paper.

  12. Potential therapeutic targets in energy metabolism pathways of breast cancer.

    PubMed

    Islam, Rowshan Ara; Hossain, Sazzad; Chowdhury, Ezharul Hoque

    2017-03-30

    Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions. This paper summarizes the roles of energy metabolism and their cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer. As breast cancer is a highly heterogeneous disease, a clear understanding of the variations of energy metabolism in different molecular subtypes would help in treating each type with a very customized, safer and efficient treatment regimen, by targeting specific glucose metabolism and related pathways with gene silencing nucleic acid sequences or small molecule drugs, or the combination of both.

  13. Engineering metabolic pathways in plants by multigene transformation.

    PubMed

    Zorrilla-López, Uxue; Masip, Gemma; Arjó, Gemma; Bai, Chao; Banakar, Raviraj; Bassie, Ludovic; Berman, Judit; Farré, Gemma; Miralpeix, Bruna; Pérez-Massot, Eduard; Sabalza, Maite; Sanahuja, Georgina; Vamvaka, Evangelia; Twyman, Richard M; Christou, Paul; Zhu, Changfu; Capell, Teresa

    2013-01-01

    Metabolic engineering in plants can be used to increase the abundance of specific valuable metabolites, but single-point interventions generally do not improve the yields of target metabolites unless that product is immediately downstream of the intervention point and there is a plentiful supply of precursors. In many cases, an intervention is necessary at an early bottleneck, sometimes the first committed step in the pathway, but is often only successful in shifting the bottleneck downstream, sometimes also causing the accumulation of an undesirable metabolic intermediate. Occasionally it has been possible to induce multiple genes in a pathway by controlling the expression of a key regulator, such as a transcription factor, but this strategy is only possible if such master regulators exist and can be identified. A more robust approach is the simultaneous expression of multiple genes in the pathway, preferably representing every critical enzymatic step, therefore removing all bottlenecks and ensuring completely unrestricted metabolic flux. This approach requires the transfer of multiple enzyme-encoding genes to the recipient plant, which is achieved most efficiently if all genes are transferred at the same time. Here we review the state of the art in multigene transformation as applied to metabolic engineering in plants, highlighting some of the most significant recent advances in the field.

  14. Pathway thermodynamics highlights kinetic obstacles in central metabolism.

    PubMed

    Noor, Elad; Bar-Even, Arren; Flamholz, Avi; Reznik, Ed; Liebermeister, Wolfram; Milo, Ron

    2014-02-01

    In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG'). Accordingly, if an enzyme catalyzes a reaction with a ΔrG' of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG' approaches equilibrium (ΔrG' = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the

  15. Regulation of hormone metabolism in Arabidopsis seeds: phytochrome regulation of abscisic acid metabolism and abscisic acid regulation of gibberellin metabolism.

    PubMed

    Seo, Mitsunori; Hanada, Atsushi; Kuwahara, Ayuko; Endo, Akira; Okamoto, Masanori; Yamauchi, Yukika; North, Helen; Marion-Poll, Annie; Sun, Tai-Ping; Koshiba, Tomokazu; Kamiya, Yuji; Yamaguchi, Shinjiro; Nambara, Eiji

    2006-11-01

    In a wide range of plant species, seed germination is regulated antagonistically by two plant hormones, abscisic acid (ABA) and gibberellin (GA). In the present study, we have revealed that ABA metabolism (both biosynthesis and inactivation) was phytochrome-regulated in an opposite fashion to GA metabolism during photoreversible seed germination in Arabidopsis. Endogenous ABA levels were decreased by irradiation with a red (R) light pulse in dark-imbibed seeds pre-treated with a far-red (FR) light pulse, and the reduction in ABA levels in response to R light was inhibited in a phytochrome B (PHYB)-deficient mutant. Expression of an ABA biosynthesis gene, AtNCED6, and the inactivation gene, CYP707A2, was regulated in a photoreversible manner, suggesting a key role for the genes in PHYB-mediated regulation of ABA metabolism. Abscisic acid-deficient mutants such as nced6-1, aba2-2 and aao3-4 exhibited an enhanced ability to germinate relative to wild type when imbibed in the dark after irradiation with an FR light pulse. In addition, the ability to synthesize GA was improved in the aba2-2 mutant compared with wild type during dark-imbibition after an FR light pulse. Activation of GA biosynthesis in the aba2-2 mutant was also observed during seed development. These data indicate that ABA is involved in the suppression of GA biosynthesis in both imbibed and developing seeds. Spatial expression patterns of the AtABA2 and AAO3 genes, responsible for last two steps of ABA biosynthesis, were distinct from that of the GA biosynthesis gene, AtGA3ox2, in both imbibed and developing seeds, suggesting that biosynthesis of ABA and GA in seeds occurs in different cell types.

  16. Metabolic Control Analysis: A Tool for Designing Strategies to Manipulate Metabolic Pathways

    PubMed Central

    Moreno-Sánchez, Rafael; Saavedra, Emma; Rodríguez-Enríquez, Sara; Olín-Sandoval, Viridiana

    2008-01-01

    The traditional experimental approaches used for changing the flux or the concentration of a particular metabolite of a metabolic pathway have been mostly based on the inhibition or over-expression of the presumed rate-limiting step. However, the attempts to manipulate a metabolic pathway by following such approach have proved to be unsuccessful. Metabolic Control Analysis (MCA) establishes how to determine, quantitatively, the degree of control that a given enzyme exerts on flux and on the concentration of metabolites, thus substituting the intuitive, qualitative concept of rate limiting step. Moreover, MCA helps to understand (i) the underlying mechanisms by which a given enzyme exerts high or low control and (ii) why the control of the pathway is shared by several pathway enzymes and transporters. By applying MCA it is possible to identify the steps that should be modified to achieve a successful alteration of flux or metabolite concentration in pathways of biotechnological (e.g., large scale metabolite production) or clinical relevance (e.g., drug therapy). The different MCA experimental approaches developed for the determination of the flux-control distribution in several pathways are described. Full understanding of the pathway properties when is working under a variety of conditions can help to attain a successful manipulation of flux and metabolite concentration. PMID:18629230

  17. Design of pathway-preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues

    PubMed Central

    Madak-Erdogan, Zeynep; Kim, Sung-Hoon; Gong, Ping; Zhao, Yiru C.; Zhang, Hui; Chambliss, Ken L.; Carlson, Kathryn E.; Mayne, Christopher G.; Shaul, Philip W.; Korach, Kenneth S.; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.

    2016-01-01

    There is great medical need for estrogens with favorable pharmacological profiles, that support desirable activities for menopausal women such as metabolic and vascular protection but that lack stimulatory activities on the breast and uterus. Here, we report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained “Pathway Preferential Estrogens” (PaPEs) which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear pathway-preferential estrogens, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily. PMID:27221711

  18. Pathway analysis of kidney cancer using proteomics and metabolic profiling

    PubMed Central

    Perroud, Bertrand; Lee, Jinoo; Valkova, Nelly; Dhirapong, Amy; Lin, Pei-Yin; Fiehn, Oliver; Kültz, Dietmar; Weiss, Robert H

    2006-01-01

    Background Renal cell carcinoma (RCC) is the sixth leading cause of cancer death and is responsible for 11,000 deaths per year in the US. Approximately one-third of patients present with disease which is already metastatic and for which there is currently no adequate treatment, and no biofluid screening tests exist for RCC. In this study, we have undertaken a comprehensive proteomic analysis and subsequently a pathway and network approach to identify biological processes involved in clear cell RCC (ccRCC). We have used these data to investigate urinary markers of RCC which could be applied to high-risk patients, or to those being followed for recurrence, for early diagnosis and treatment, thereby substantially reducing mortality of this disease. Results Using 2-dimensional electrophoresis and mass spectrometric analysis, we identified 31 proteins which were differentially expressed with a high degree of significance in ccRCC as compared to adjacent non-malignant tissue, and we confirmed some of these by immunoblotting, immunohistochemistry, and comparison to published transcriptomic data. When evaluated by several pathway and biological process analysis programs, these proteins are demonstrated to be involved with a high degree of confidence (p values < 2.0 E-05) in glycolysis, propanoate metabolism, pyruvate metabolism, urea cycle and arginine/proline metabolism, as well as in the non-metabolic p53 and FAS pathways. In a pilot study using random urine samples from both ccRCC and control patients, we performed metabolic profiling and found that only sorbitol, a component of an alternative glycolysis pathway, is significantly elevated at 5.4-fold in RCC patients as compared to controls. Conclusion Extensive pathway and network analysis allowed for the discovery of highly significant pathways from a set of clear cell RCC samples. Knowledge of activation of these processes will lead to novel assays identifying their proteomic and/or metabolomic signatures in biofluids

  19. Cardioselective Dominant-negative Thyroid Hormone Receptor (Δ337T) Modulates Myocardial Metabolism and Contractile Dfficiency

    SciTech Connect

    Hyyti, Outi M.; Olson, Aaron; Ge, Ming; Ning, Xue-Han; Buroker, Norman E.; Chung, Youngran; Jue, Thomas; Portman, Michael A.

    2008-06-03

    Dominant- negative thyroid hormone receptors (TRs) show elevated expression relative to ligand-binding TRs during cardiac hypertrophy. We tested the hypothesis that overexpression of a dominant-negative TR alters cardiac metabolism and contractile efficiency (CE). We used mice expressing the cardioselective dominant-negative TRβ1 mutation Δ337T. Isolated working Δ337T hearts and nontransgenic control (Con) hearts were perfused with 13C-labeled free fatty acids (FFA), acetoacetate (ACAC), lactate, and glucose at physiological concentrations for 30 min. 13C NMR spectroscopy and isotopomer analyses were used to determine substrate flux and fractional contributions (Fc) of acetyl-CoA to the citric acid cycle (CAC). Δ337T hearts exhibited rate depression but higher developed pressure and CE, defined as work per oxygen consumption (MV˙ O2). Unlabeled substrate Fc from endogenous sources was higher in Δ337T, but ACAC Fc was lower. Fluxes through CAC, lactate, ACAC, and FFA were reduced in Δ337T. CE and Fc differences were reversed by pacing Δ337T to Con rates, accompanied by an increase in FFA Fc. Δ337T hearts lacked the ability to increase MV˙ O2. Decreases in protein expression for glucose transporter-4 and hexokinase-2 and increases in pyruvate dehydrogenase kinase-2 and -4 suggest that these hearts are unable to increase carbohydrate oxidation in response to stress. These data show that Δ337T alters the metabolic phenotype in murine heart by reducing substrate flux for multiple pathways. Some of these changes are heart rate dependent, indicating that the substrate shift may represent an accommodation to altered contractile protein kinetics, which can be disrupted by pacing stress.

  20. Discovery of a metabolic alternative to the classical mevalonate pathway

    PubMed Central

    Dellas, Nikki; Thomas, Suzanne T; Manning, Gerard; Noel, Joseph P

    2013-01-01

    Eukarya, Archaea, and some Bacteria encode all or part of the essential mevalonate (MVA) metabolic pathway clinically modulated using statins. Curiously, two components of the MVA pathway are often absent from archaeal genomes. The search for these missing elements led to the discovery of isopentenyl phosphate kinase (IPK), one of two activities necessary to furnish the universal five-carbon isoprenoid building block, isopentenyl diphosphate (IPP). Unexpectedly, we now report functional IPKs also exist in Bacteria and Eukarya. Furthermore, amongst a subset of species within the bacterial phylum Chloroflexi, we identified a new enzyme catalyzing the missing decarboxylative step of the putative alternative MVA pathway. These results demonstrate, for the first time, a functioning alternative MVA pathway. Key to this pathway is the catalytic actions of a newly uncovered enzyme, mevalonate phosphate decarboxylase (MPD) and IPK. Together, these two discoveries suggest that unforeseen variation in isoprenoid metabolism may be widespread in nature. DOI: http://dx.doi.org/10.7554/eLife.00672.001 PMID:24327557

  1. Effect of alcohol consumption on hormones involved in carbohydrate and lipid metabolism in premenopausal women

    SciTech Connect

    Law, J.S.; Bhathena, S.J.; Kim, Y.C.; Berlin, E.; Judd, J.T.; Reichman, M.E.; Taylor, P.R.; Schatzkin, A. NCI, Bethesda, MD )

    1991-03-15

    Alcohol consumption alters carbohydrate and lipid metabolism which are in part regulated by pancreatic and adrenal hormones. The menstrual cycle per se produces changes in several peptide and steroid hormones besides the sex hormones. The authors investigated the effect of moderate alcohol consumption on plasma hormone levels in 40 premenopausal women. The subjects were fed controlled diets containing 35% of calories from fat. In a random crossover design women were given either alcohol or a soft-drink of equal caloric value for 3 menstrual cycles. Fasting blood samples were collected in the third cycle during follicular, ovulatory and luteal phases. Plasma dehydroepiandrosterone-sulphate (DHEA-S), insulin, glucagon and cortisol levels were measured by radioimmunoassay. Moderate alcohol consumption had no effect on plasma insulin and DHEA-S levels but significantly increased glucagon and cortisol levels. Menstrual cycle per se affected plasma glucagon level in that the levels were higher during follicular phase than luteal phase. Thus, changes in carbohydrate and lipid metabolism following alcohol consumption are mediated in part by alterations in hormones involved in their metabolism.

  2. Hormone signaling pathways as treatment targets in renal cell cancer (Review).

    PubMed

    Czarnecka, Anna M; Niedzwiedzka, Magdalena; Porta, Camillo; Szczylik, Cezary

    2016-06-01

    Epidemiological, clinical, biochemical and genetic research has revealed that renal cell cancer (RCC) etiology is hormone-related. It was shown that hormone receptors are abnormally expressed in RCC cells. Abnormal endocrine stimulation also plays a significant role in RCC pathophysiology. Cellular proliferation, migration, angiogenesis, and drug resistance in RCC is modulated by para- and autocrine hormonal stimulation. In particular, RCC overexpression of gonadotropin-releasing hormone and its receptor was reported. On the contrary, corticotropin releasing hormone was reported to inhibit RCC cell proliferation and regulate angiogenesis. Overexpression of luteinizing hormone also promotes RCC tumor angiogenesis. Estrogen receptor α overexpression increases the transcriptional factor activity of hypoxia inducible factor HIF-1α, but estrogen receptor β has a cancer suppressive role. Glucocorticoid receptors and androgen receptor are markers of indolent RCC and assigned tumor suppressive activity. Proopiomelanocortin is upregulated in VHL-mutated renal cell carcinoma via Nur77 transcription factor signaling. In RCC, follicle-stimulating hormone receptor promotes angiogenesis and metastatic formation via VEGF release. Mineralocorticoid receptor overexpression promotes cell survival and increases RCC cell proliferation. Vitamin D receptor expression is downregulated or absent in RCC and differentiate subtypes of renal cell tumors. RAR-β promotes tumorigenesis but retinoic acid receptor γ expression correlates negatively with the TNM stage at diagnosis. Finally, progesterone receptor expression is negatively correlated with the cancer stage. Molecular data analysis revealed the possibility of renal cancer cell proliferation induction via hormone activated pathways. Inhibition of hormonal signaling may thus play a putative role in supportive therapies against this cancer type.

  3. The quality of metabolic pathway resources depends on initial enzymatic function assignments: a case for maize

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As metabolic pathway resources become more commonly available, researchers have unprecedented access to information about their organism of interest. Despite efforts to ensure consistency between various resources, information content and quality can vary widely. Two maize metabolic pathway resource...

  4. Endogenous sex hormones, metabolic syndrome, and diabetes in men and women.

    PubMed

    Kim, Catherine; Halter, Jeffrey B

    2014-04-01

    Endogenous sex hormones predict impairments of glucose regulation. Cross-sectional studies suggest that lower levels of testosterone in men and higher levels in women increase risk of metabolic syndrome and diabetes, whereas lower levels of sex hormone binding globulin in both men and women increase risk of metabolic syndrome and diabetes. In a systematic review, we summarize existing longitudinal studies, which suggest similar patterns. However, these studies are often limited to a single sex steroid measure. Whether these associations are primarily a marker of adiposity, and whether these associations differ between younger eugonadal vs older hypogonadal adults is also uncertain. The impact of exogenous sex steroid therapy may not reflect relationships between sex hormones and impaired glucose regulation that occur without supplementation. Therefore, examination of endogenous sex steroid trajectories and obesity trajectories within individuals might aid our understanding of how sex steroids contribute to glucose regulation.

  5. Creation of a genome-wide metabolic pathway database for Populus trichocarpa using a new approach for reconstruction and curation of metabolic pathways for plants.

    PubMed

    Zhang, Peifen; Dreher, Kate; Karthikeyan, A; Chi, Anjo; Pujar, Anuradha; Caspi, Ron; Karp, Peter; Kirkup, Vanessa; Latendresse, Mario; Lee, Cynthia; Mueller, Lukas A; Muller, Robert; Rhee, Seung Yon

    2010-08-01

    Metabolic networks reconstructed from sequenced genomes or transcriptomes can help visualize and analyze large-scale experimental data, predict metabolic phenotypes, discover enzymes, engineer metabolic pathways, and study metabolic pathway evolution. We developed a general approach for reconstructing metabolic pathway complements of plant genomes. Two new reference databases were created and added to the core of the infrastructure: a comprehensive, all-plant reference pathway database, PlantCyc, and a reference enzyme sequence database, RESD, for annotating metabolic functions of protein sequences. PlantCyc (version 3.0) includes 714 metabolic pathways and 2,619 reactions from over 300 species. RESD (version 1.0) contains 14,187 literature-supported enzyme sequences from across all kingdoms. We used RESD, PlantCyc, and MetaCyc (an all-species reference metabolic pathway database), in conjunction with the pathway prediction software Pathway Tools, to reconstruct a metabolic pathway database, PoplarCyc, from the recently sequenced genome of Populus trichocarpa. PoplarCyc (version 1.0) contains 321 pathways with 1,807 assigned enzymes. Comparing PoplarCyc (version 1.0) with AraCyc (version 6.0, Arabidopsis [Arabidopsis thaliana]) showed comparable numbers of pathways distributed across all domains of metabolism in both databases, except for a higher number of AraCyc pathways in secondary metabolism and a 1.5-fold increase in carbohydrate metabolic enzymes in PoplarCyc. Here, we introduce these new resources and demonstrate the feasibility of using them to identify candidate enzymes for specific pathways and to analyze metabolite profiling data through concrete examples. These resources can be searched by text or BLAST, browsed, and downloaded from our project Web site (http://plantcyc.org).

  6. Inhibitory pathways and the inhibition of luteinizing hormone-releasing hormone release by alcohol

    PubMed Central

    Lomniczi, Alejandro; Mastronardi, Claudio A.; Faletti, Alicia G.; Seilicovich, Adriana; De Laurentiis, Andrea; McCann, Samuel M.; Rettori, Valeria

    2000-01-01

    In this research we examined the mechanisms by which ethanol (EtOH) inhibits luteinizing hormone-releasing hormone (LHRH) release from incubated medial basal hypothalamic explants. EtOH (100 mM) stimulated the release of two inhibitory neurotransmitters: γ-aminobutyric acid (GABA) and β-endorphin. EtOH also inhibited NO production, indicative of a suppression of nitric oxide synthase (NOS) activity. This inhibition was reversed by naltroxone (10−8 M), a μ-opioid receptor blocker, indicating that the inhibition of NOS by EtOH is mediated by β-endorphin. EtOH also blocked N-methyl-d-aspartic acid-induced LHRH release, but the blockade could not be reversed by either the GABA receptor blocker, bicuculline (10−5 M), naltroxone (10−8 M), or both inhibitors added together. However, increasing the concentration of naltrexone (10−6 M) but not bicuculline (10−4 M) reversed the inhibition. When we lowered the concentration of EtOH (50 mM), the EtOH-induced blockade of LHRH release could be reversed by either bicuculline (10−5 M), naltroxone (10−8 M), or the combination of the two blockers. Therefore, GABA is partially responsible for the blockade of N-methyl-d-aspartic acid-induced LHRH release. The block by GABA was exerted by inhibiting the activation of cyclooxygenase by NO, because it was reversed by prostaglandin E2, the product of activation of cyclooxygenase. Because the inhibition caused by the higher concentration of EtOH could not be reduced by bicuculline (10−4 M) but was blocked by naltroxone (10−6 M), the action of alcohol can be accounted for by stimulation of β-endorphin neurons that inhibit LHRH release by inhibition of activation of NOS and stimulation of GABA release. PMID:10688896

  7. Strategies for metabolic pathway engineering with multiple transgenes.

    PubMed

    Bock, Ralph

    2013-09-01

    The engineering of metabolic pathways in plants often requires the concerted expression of more than one gene. While with traditional transgenic approaches, the expression of multiple transgenes has been challenging, recent progress has greatly expanded our repertoire of powerful techniques making this possible. New technological options include large-scale co-transformation of the nuclear genome, also referred to as combinatorial transformation, and transformation of the chloroplast genome with synthetic operon constructs. This review describes the state of the art in multigene genetic engineering of plants. It focuses on the methods currently available for the introduction of multiple transgenes into plants and the molecular mechanisms underlying successful transgene expression. Selected examples of metabolic pathway engineering are used to illustrate the attractions and limitations of each method and to highlight key factors that influence the experimenter's choice of the best strategy for multigene engineering.

  8. Cardiovascular, metabolic, and hormonal parameters in professional tennis players.

    PubMed

    König, D; Huonker, M; Schmid, A; Halle, M; Berg, A; Keul, J

    2001-04-01

    During the past decade, the physical and mental stress in professional tennis has been constantly increasing. The overall intensity in tennis ranges between 60 and 70% of maximum oxygen uptake and the energy requirements are mainly provided by aerobic energy metabolism. Therefore, particularly with respect to the duration of the tournaments and the length of the matches, a good aerobic capacity promotes continuous success in professional tennis. During frequent periods of high intensity, however, muscular energy is derived from anaerobic glycolysis. Therefore, sports-specific conditioning programs in tennis should improve both glycolytic and oxidative muscular metabolism. Years of training and competition induce a number of cardiovascular and metabolic adaptations: an increase in heart size in terms of an athlete's heart, higher oxygen uptake capacity, improved muscular oxidative enzyme activities, reduced baseline catecholamine levels, and a lower resting heart rate. In addition, tennis induces side-specific increments in bone density, bone diameter, and bone length of the upper extremity. Furthermore, structural and functional adaptations of the conducting arteries in the preferred arm could be demonstrated in professional tennis players. In conclusion, tennis is a very complex sport involving strength, power, speed, agility and explosiveness, as well as endurance components. Scientific data on exercise-related cardiovascular and metabolic parameters in professional tennis are important to evaluate the players individual fitness level and will help to improve sports-specific conditioning programs. This in turn will not only enhance performance but also prevent overstrain and burnout syndromes.

  9. Chemical modulation of glycerolipid signaling and metabolic pathways

    PubMed Central

    Scott, Sarah A.; Mathews, Thomas P.; Ivanova, Pavlina T.; Lindsley, Craig W.; Brown, H. Alex

    2014-01-01

    Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields—ranging from neuroscience and cancer to diabetes and obesity—have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems. PMID:24440821

  10. Chemical modulation of glycerolipid signaling and metabolic pathways.

    PubMed

    Scott, Sarah A; Mathews, Thomas P; Ivanova, Pavlina T; Lindsley, Craig W; Brown, H Alex

    2014-08-01

    Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields-ranging from neuroscience and cancer to diabetes and obesity-have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems. This article is part of a Special Issue entitled Tools to study lipid functions.

  11. Metabolic Pathways for Degradation of Aromatic Hydrocarbons by Bacteria.

    PubMed

    Ladino-Orjuela, Guillermo; Gomes, Eleni; da Silva, Roberto; Salt, Christopher; Parsons, John R

    2016-01-01

    The aim of this review was to build an updated collection of information focused on the mechanisms and elements involved in metabolic pathways of aromatic hydrocarbons by bacteria. Enzymes as an expression of the genetic load and the type of electron acceptor available, as an environmental factor, were highlighted. In general, the review showed that both aerobic routes and anaerobic routes for the degradation of aromatic hydrocarbons are divided into two pathways. The first, named the upper pathways, entails the route from the original compound to central intermediate compounds still containing the aromatic ring but with the benzene nucleus chemically destabilized. The second, named the lower pathway, begins with ring de-aromatization and subsequent cleavage, resulting in metabolites that can be used by bacteria in the production of biomass. Under anaerobic conditions the five mechanisms of activation of the benzene ring described show the diversity of chemical reactions that can take place. Obtaining carbon and energy from an aromatic hydrocarbon molecule is a process that exhibits the high complexity level of the metabolic apparatus of anaerobic microorganisms. The ability of these bacteria to express enzymes that catalyze reactions, known only in non-biological conditions, using final electron acceptors with a low redox potential, is a most interesting topic. The discovery of phylogenetic and functional characteristics of cultivable and noncultivable hydrocarbon degrading bacteria has been made possible by improvements in molecular research techniques such as SIP (stable isotope probing) tracing the incorporation of (13)C, (15)N and (18)O into nucleic acids and proteins. Since many metabolic pathways in which enzyme and metabolite participants are still unknown, much new research is required. Therefore, it will surely allow enhancing the known and future applications in practice.

  12. Metabolic regulation of the plant hormone indole-3-acetic acid

    SciTech Connect

    Jerry D. Cohen

    2009-11-01

    The phytohormone indole-3-acetic acid (IAA, auxin) is important for many aspects of plant growth, development and responses to the environment yet the routes to is biosynthesis and mechanisms for regulation of IAA levels remain important research questions. A critical issue concerning the biosynthesis if IAA in plants is that redundant pathways for IAA biosynthesis exist in plants. We showed that these redundant pathways and their relative contribution to net IAA production are under both developmental and environmental control. We worked on three fundamental problems related to how plants get their IAA: 1) An in vitro biochemical approach was used to define the tryptophan dependent pathway to IAA using maize endosperm, where relatively large amounts of IAA are produced over a short developmental period. Both a stable isotope dilution and a protein MS approach were used to identify intermediates and enzymes in the reactions. 2) We developed an in vitro system for analysis of tryptophan-independent IAA biosynthesis in maize seedlings and we used a metabolite profiling approach to isolate intermediates in this reaction. 3) Arabidopsis contains a small family of genes that encode potential indolepyruvate decarboxylase enzymes. We cloned these genes and studied plants that are mutant in these genes and that over-express each member in the family in terms of the level and route of IAA biosynthesis. Together, these allowed further development of a comprehensive picture of the pathways and regulatory components that are involved in IAA homeostasis in higher plants.

  13. Effect of Tumour Necrosis Factor-Alpha on Estrogen Metabolic Pathways in Breast Cancer Cells

    PubMed Central

    Kamel, Marwa; Shouman, Samia; El-Merzebany, Mahmoud; Kilic, Gokhan; Veenstra, Timothy; Saeed, Muhammad; Wagih, Mohamed; Diaz-Arrastia, Concepcion; Patel, Deepa; Salama, Salama

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that has been linked to breast cancer development. Estrogen metabolic pathway is also involved in breast carcinogenesis and DNA adducts formation. In this study we investigated the effect of TNF-α on the estrogen metabolic pathway in MCF-7, a breast cancer cell line. Capillary liquid chromatography/mass spectrometry (LC/MS) and High performance liquid chromatography (HPLC) were used for analysis of estrogen metabolites and estrogen-DNA adducts levels respectively. Reporter gene assay, Real time reverse transcription polymerase chain reaction (real time RT-PCR) and Western blot were used to assess the expression of estrogen metabolizing genes and enzymes. TNF-α significantly increased the total EM and decreased the estrone (E1) / 17-β estradiol (E2) ratio. Moreover, it altered the expression of genes and enzymes involved in E2 activation and deactivation pathways e.g. Cytochrome P-450 1A1 (CYP1A1), Cytochrome P-450 1B1 (CYP1B1), Catechol-O-methyl transferase (COMT) and Nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1 (NQO1). In addition, there were increased levels of some catechol estrogens e.g. 4-hydroxy-estrone (4-OHE1) and 2-hydroxyestradiol (2-OHE2) with decreased levels of methylated catechols e.g. 2-methoxy estradiol (2-MeOE2). DNA adducts especially 4-OHE1-[2]-1-N3 Adenine was significantly increased. TNF-α directs the estrogen metabolism into more hormonally active and carcinogenic products in MCF-7. This may implicate a new possible explanation for inflammation associated breast cancer. PMID:22866165

  14. Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer

    PubMed Central

    Diergaarde, Brenda; Potter, John D.; Jupe, Eldon R.; Manjeshwar, Sharmila; Shimasaki, Craig D.; Pugh, Thomas W.; DeFreese, Daniele C.; Gramling, Bobby A.; Evans, Ilonka; White, Emily

    2009-01-01

    Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (≥10 years versus never, odds ratio: 1.9; 95% confidence interval: 1.3–2.8; Ptrend: 0.0002). Statistically significant interactions between CYP1A1 Ile462Val (Pinteraction: 0.04), CYP1A1 MspI (Pinteraction: 0.003), CYP1B1 Val432Leu (Pinteraction: 0.007), CYP1B1 Asn453Ser (Pinteraction: 0.04) and PGR Val660Leu (Pinteraction: 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile462Val, CYP1A1 MspI, CYP1B1 Asn453Ser and PGR Val660Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val432 allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu432. Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk. PMID:18628428

  15. Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways.

    PubMed

    DeLoache, William C; Russ, Zachary N; Dueber, John E

    2016-03-30

    Compartmentalization of enzymes into organelles is a promising strategy for limiting metabolic crosstalk and improving pathway efficiency, but improved tools and design rules are needed to make this strategy available to more engineered pathways. Here we focus on the Saccharomyces cerevisiae peroxisome and develop a sensitive high-throughput assay for peroxisomal cargo import. We identify an enhanced peroxisomal targeting signal type 1 (PTS1) for rapidly sequestering non-native cargo proteins. Additionally, we perform the first systematic in vivo measurements of nonspecific metabolite permeability across the peroxisomal membrane using a polymer exclusion assay. Finally, we apply these new insights to compartmentalize a two-enzyme pathway in the peroxisome and characterize the expression regimes where compartmentalization leads to improved product titre. This work builds a foundation for using the peroxisome as a synthetic organelle, highlighting both promise and future challenges on the way to realizing this goal.

  16. Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways

    SciTech Connect

    DeLoache, William C.; Russ, Zachary N.; Dueber, John E.

    2016-03-30

    Compartmentalization of enzymes into organelles is a promising strategy for limiting metabolic crosstalk and improving pathway efficiency, but improved tools and design rules are needed to make this strategy available to more engineered pathways. Here we focus on the Saccharomyces cerevisiae peroxisome and develop a sensitive high-throughput assay for peroxisomal cargo import. We identify an enhanced peroxisomal targeting signal type 1 (PTS1) for rapidly sequestering non-native cargo proteins. Additionally, we perform the first systematic in vivo measurements of nonspecific metabolite permeability across the peroxisomal membrane using a polymer exclusion assay. Finally, we apply these new insights to compartmentalize a two-enzyme pathway in the peroxisome and characterize the expression regimes where compartmentalization leads to improved product titre. Lastly, this work builds a foundation for using the peroxisome as a synthetic organelle, highlighting both promise and future challenges on the way to realizing this goal.

  17. Towards repurposing the yeast peroxisome for compartmentalizing heterologous metabolic pathways

    DOE PAGES

    DeLoache, William C.; Russ, Zachary N.; Dueber, John E.

    2016-03-30

    Compartmentalization of enzymes into organelles is a promising strategy for limiting metabolic crosstalk and improving pathway efficiency, but improved tools and design rules are needed to make this strategy available to more engineered pathways. Here we focus on the Saccharomyces cerevisiae peroxisome and develop a sensitive high-throughput assay for peroxisomal cargo import. We identify an enhanced peroxisomal targeting signal type 1 (PTS1) for rapidly sequestering non-native cargo proteins. Additionally, we perform the first systematic in vivo measurements of nonspecific metabolite permeability across the peroxisomal membrane using a polymer exclusion assay. Finally, we apply these new insights to compartmentalize a two-enzymemore » pathway in the peroxisome and characterize the expression regimes where compartmentalization leads to improved product titre. Lastly, this work builds a foundation for using the peroxisome as a synthetic organelle, highlighting both promise and future challenges on the way to realizing this goal.« less

  18. Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

    PubMed Central

    Jansen, S. W.; Akintola, A. A.; Roelfsema, F.; van der Spoel, E.; Cobbaert, C. M.; Ballieux, B. E.; Egri, P.; Kvarta-Papp, Z.; Gereben, B.; Fekete, C.; Slagboom, P. E.; van der Grond, J.; Demeneix, B. A.; Pijl, H.; Westendorp, R. G. J.; van Heemst, D.

    2015-01-01

    Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism. PMID:26089239

  19. Evolutionary Rate Heterogeneity of Primary and Secondary Metabolic Pathway Genes in Arabidopsis thaliana.

    PubMed

    Mukherjee, Dola; Mukherjee, Ashutosh; Ghosh, Tapash Chandra

    2015-11-10

    Primary metabolism is essential to plants for growth and development, and secondary metabolism helps plants to interact with the environment. Many plant metabolites are industrially important. These metabolites are produced by plants through complex metabolic pathways. Lack of knowledge about these pathways is hindering the successful breeding practices for these metabolites. For a better knowledge of the metabolism in plants as a whole, evolutionary rate variation of primary and secondary metabolic pathway genes is a prerequisite. In this study, evolutionary rate variation of primary and secondary metabolic pathway genes has been analyzed in the model plant Arabidopsis thaliana. Primary metabolic pathway genes were found to be more conserved than secondary metabolic pathway genes. Several factors such as gene structure, expression level, tissue specificity, multifunctionality, and domain number are the key factors behind this evolutionary rate variation. This study will help to better understand the evolutionary dynamics of plant metabolism.

  20. Hormone therapy in acne.

    PubMed

    Lakshmi, Chembolli

    2013-01-01

    Underlying hormone imbalances may render acne unresponsive to conventional therapy. Relevant investigations followed by initiation of hormonal therapy in combination with regular anti-acne therapy may be necessary if signs of hyperandrogenism are present. In addition to other factors, androgen-stimulated sebum production plays an important role in the pathophysiology of acne in women. Sebum production is also regulated by other hormones, including estrogens, growth hormone, insulin, insulin-like growth factor-1, glucocorticoids, adrenocorticotropic hormone, and melanocortins. Hormonal therapy may also be beneficial in female acne patients with normal serum androgen levels. An understanding of the sebaceous gland and the hormonal influences in the pathogenesis of acne would be essential for optimizing hormonal therapy. Sebocytes form the sebaceous gland. Human sebocytes express a multitude of receptors, including receptors for peptide hormones, neurotransmitters and the receptors for steroid and thyroid hormones. Various hormones and mediators acting through the sebocyte receptors play a role in the orchestration of pathogenetic lesions of acne. Thus, the goal of hormonal treatment is a reduction in sebum production. This review shall focus on hormonal influences in the elicitation of acne via the sebocyte receptors, pathways of cutaneous androgen metabolism, various clinical scenarios and syndromes associated with acne, and the available therapeutic armamentarium of hormones and drugs having hormone-like actions in the treatment of acne.

  1. Role of intracellular carbon metabolism pathways in Shigella flexneri virulence.

    PubMed

    Waligora, E A; Fisher, C R; Hanovice, N J; Rodou, A; Wyckoff, E E; Payne, S M

    2014-07-01

    Shigella flexneri, which replicates in the cytoplasm of intestinal epithelial cells, can use the Embden-Meyerhof-Parnas, Entner-Doudoroff, or pentose phosphate pathway for glycolytic carbon metabolism. To determine which of these pathways is used by intracellular S. flexneri, mutants were constructed and tested in a plaque assay for the ability to invade, replicate intracellularly, and spread to adjacent epithelial cells. Mutants blocked in the Embden-Meyerhof-Parnas pathway (pfkAB and pykAF mutants) invaded the cells but formed very small plaques. Loss of the Entner-Doudoroff pathway gene eda resulted in small plaques, but the double eda edd mutant formed normal-size plaques. This suggested that the plaque defect of the eda mutant was due to buildup of the toxic intermediate 2-keto-3-deoxy-6-phosphogluconic acid rather than a specific requirement for this pathway. Loss of the pentose phosphate pathway had no effect on plaque formation, indicating that it is not critical for intracellular S. flexneri. Supplementation of the epithelial cell culture medium with pyruvate allowed the glycolysis mutants to form larger plaques than those observed with unsupplemented medium, consistent with data from phenotypic microarrays (Biolog) indicating that pyruvate metabolism was not disrupted in these mutants. Interestingly, the wild-type S. flexneri also formed larger plaques in the presence of supplemental pyruvate or glucose, with pyruvate yielding the largest plaques. Analysis of the metabolites in the cultured cells showed increased intracellular levels of the added compound. Pyruvate increased the growth rate of S. flexneri in vitro, suggesting that it may be a preferred carbon source inside host cells.

  2. Improving Metabolic Pathway Efficiency by Statistical Model-Based Multivariate Regulatory Metabolic Engineering.

    PubMed

    Xu, Peng; Rizzoni, Elizabeth Anne; Sul, Se-Yeong; Stephanopoulos, Gregory

    2017-01-20

    Metabolic engineering entails target modification of cell metabolism to maximize the production of a specific compound. For empowering combinatorial optimization in strain engineering, tools and algorithms are needed to efficiently sample the multidimensional gene expression space and locate the desirable overproduction phenotype. We addressed this challenge by employing design of experiment (DoE) models to quantitatively correlate gene expression with strain performance. By fractionally sampling the gene expression landscape, we statistically screened the dominant enzyme targets that determine metabolic pathway efficiency. An empirical quadratic regression model was subsequently used to identify the optimal gene expression patterns of the investigated pathway. As a proof of concept, our approach yielded the natural product violacein at 525.4 mg/L in shake flasks, a 3.2-fold increase from the baseline strain. Violacein production was further increased to 1.31 g/L in a controlled benchtop bioreactor. We found that formulating discretized gene expression levels into logarithmic variables (Linlog transformation) was essential for implementing this DoE-based optimization procedure. The reported methodology can aid multivariate combinatorial pathway engineering and may be generalized as a standard procedure for accelerating strain engineering and improving metabolic pathway efficiency.

  3. Understanding specificity in metabolic pathways--structural biology of human nucleotide metabolism.

    PubMed

    Welin, Martin; Nordlund, Pär

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  4. Understanding specificity in metabolic pathways-Structural biology of human nucleotide metabolism

    SciTech Connect

    Welin, Martin; Nordlund, Paer

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  5. Effects of hormonal contraception on systemic metabolism: cross-sectional and longitudinal evidence

    PubMed Central

    Wang, Qin; Würtz, Peter; Auro, Kirsi; Morin-Papunen, Laure; Kangas, Antti J; Soininen, Pasi; Tiainen, Mika; Tynkkynen, Tuulia; Joensuu, Anni; Havulinna, Aki S; Aalto, Kristiina; Salmi, Marko; Blankenberg, Stefan; Zeller, Tanja; Viikari, Jorma; Kähönen, Mika; Lehtimäki, Terho; Salomaa, Veikko; Jalkanen, Sirpa; Järvelin, Marjo-Riitta; Perola, Markus; Raitakari, Olli T; Lawlor, Debbie A; Kettunen, Johannes; Ala-Korpela, Mika

    2016-01-01

    Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24–49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and

  6. Increased Metabolic Flexibility and Complexity in a Long-Lived Growth Hormone Insensitive Mouse Model

    PubMed Central

    2014-01-01

    The goal of this study was to test whether the “loss of the complexity” hypothesis can be applied to compare the metabolic patterns of mouse models with known differences in metabolic and endocrine function as well as life span. Here, we compare the complexity of locomotor activity and metabolic patterns (energy expenditure, VO2, and respiratory quotient) of the long-lived growth hormone receptor gene deleted mice (GHR− /−) and their wild-type littermates. Using approximate entropy as a measure of complexity, we observed greater metabolic complexity, as indicated by greater irregularity in the physiological fluctuations of the GHR− /− mice. Further analysis of the data also revealed lower energy costs of locomotor activity and a stronger relationship between locomotor activity and respiratory quotient in the GHR− /− mice relative to controls. These findings suggest underlying differences in metabolic modulation in the GHR− /− mice revealed especially through measures of complexity of their time-dependent fluctuations. PMID:23788654

  7. Polycystic ovary syndrome: a common hormonal condition with major metabolic sequelae that physicians should know about.

    PubMed

    Shorakae, S; Boyle, J; Teede, H

    2014-08-01

    Polycystic ovary syndrome (PCOS) is a prevalent, chronic and heterogeneous endocrine condition, with reproductive, metabolic and psychological features. Insulin resistance and hyperandrogenaemia are the key pathophysiological hormonal abnormalities. Insulin resistance is a significant contributor to the reproductive and metabolic complications of PCOS, both independently and in the setting of excess bodyweight. While the diagnostic criteria are now internationally uniformly accepted, individual components of the criteria are ill-defined, making diagnosis challenging. This, along with low awareness of PCOS, has resulted in a significant proportion of women remaining undiagnosed. While reproductive features are best recognised in PCOS and form the basis of the diagnostic criteria, awareness of psychological and metabolic features, recommended screening protocols, and management strategies to prevent metabolic complications are important. In this review, we focus on diagnostic criteria, and reproductive, metabolic and psychological features of PCOS, as well as recommended screening and management strategies suggested by national and international evidence-based guidelines.

  8. Genetic, hormonal and metabolic aspects of PCOS: an update.

    PubMed

    De Leo, V; Musacchio, M C; Cappelli, V; Massaro, M G; Morgante, G; Petraglia, F

    2016-07-16

    Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting 5-10 % of women of reproductive age. It generally manifests with oligo/anovulatory cycles, hirsutism and polycystic ovaries, together with a considerable prevalence of insulin resistance. Although the aetiology of the syndrome is not completely understood yet, PCOS is considered a multifactorial disorder with various genetic, endocrine and environmental abnormalities. Moreover, PCOS patients have a higher risk of metabolic and cardiovascular diseases and their related morbidity, if compared to the general population.

  9. Modeling the flux of metabolites in the juvenile hormone biosynthesis pathway using generalized additive models and ordinary differential equations.

    PubMed

    Martínez-Rincón, Raúl O; Rivera-Pérez, Crisalejandra; Diambra, Luis; Noriega, Fernando G

    2017-01-01

    Juvenile hormone (JH) regulates development and reproductive maturation in insects. The corpora allata (CA) from female adult mosquitoes synthesize fluctuating levels of JH, which have been linked to the ovarian development and are influenced by nutritional signals. The rate of JH biosynthesis is controlled by the rate of flux of isoprenoids in the pathway, which is the outcome of a complex interplay of changes in precursor pools and enzyme levels. A comprehensive study of the changes in enzymatic activities and precursor pool sizes have been previously reported for the mosquito Aedes aegypti JH biosynthesis pathway. In the present studies, we used two different quantitative approaches to describe and predict how changes in the individual metabolic reactions in the pathway affect JH synthesis. First, we constructed generalized additive models (GAMs) that described the association between changes in specific metabolite concentrations with changes in enzymatic activities and substrate concentrations. Changes in substrate concentrations explained 50% or more of the model deviances in 7 of the 13 metabolic steps analyzed. Addition of information on enzymatic activities almost always improved the fitness of GAMs built solely based on substrate concentrations. GAMs were validated using experimental data that were not included when the model was built. In addition, a system of ordinary differential equations (ODE) was developed to describe the instantaneous changes in metabolites as a function of the levels of enzymatic catalytic activities. The results demonstrated the ability of the models to predict changes in the flux of metabolites in the JH pathway, and can be used in the future to design and validate experimental manipulations of JH synthesis.

  10. Modeling the flux of metabolites in the juvenile hormone biosynthesis pathway using generalized additive models and ordinary differential equations

    PubMed Central

    Martínez-Rincón, Raúl O.; Rivera-Pérez, Crisalejandra; Diambra, Luis; Noriega, Fernando G.

    2017-01-01

    Juvenile hormone (JH) regulates development and reproductive maturation in insects. The corpora allata (CA) from female adult mosquitoes synthesize fluctuating levels of JH, which have been linked to the ovarian development and are influenced by nutritional signals. The rate of JH biosynthesis is controlled by the rate of flux of isoprenoids in the pathway, which is the outcome of a complex interplay of changes in precursor pools and enzyme levels. A comprehensive study of the changes in enzymatic activities and precursor pool sizes have been previously reported for the mosquito Aedes aegypti JH biosynthesis pathway. In the present studies, we used two different quantitative approaches to describe and predict how changes in the individual metabolic reactions in the pathway affect JH synthesis. First, we constructed generalized additive models (GAMs) that described the association between changes in specific metabolite concentrations with changes in enzymatic activities and substrate concentrations. Changes in substrate concentrations explained 50% or more of the model deviances in 7 of the 13 metabolic steps analyzed. Addition of information on enzymatic activities almost always improved the fitness of GAMs built solely based on substrate concentrations. GAMs were validated using experimental data that were not included when the model was built. In addition, a system of ordinary differential equations (ODE) was developed to describe the instantaneous changes in metabolites as a function of the levels of enzymatic catalytic activities. The results demonstrated the ability of the models to predict changes in the flux of metabolites in the JH pathway, and can be used in the future to design and validate experimental manipulations of JH synthesis. PMID:28158248

  11. OsERF2 controls rice root growth and hormone responses through tuning expression of key genes involved in hormone signaling and sucrose metabolism.

    PubMed

    Xiao, Guiqing; Qin, Hua; Zhou, Jiahao; Quan, Ruidang; Lu, Xiangyang; Huang, Rongfeng; Zhang, Haiwen

    2016-02-01

    Root determines plant distribution, development progresses, stress response, as well as crop qualities and yields, which is under the tight control of genetic programs and environmental stimuli. Ethylene responsive factor proteins (ERFs) play important roles in plant growth and development. Here, the regulatory function of OsERF2 involved in root growth was investigated using the gain-function mutant of OsERF2 (nsf2857) and the artificial microRNA-mediated silenced lines of OsERF2 (Ami-OsERF2). nsf2857 showed short primary roots compared with the wild type (WT), while the primary roots of Ami-OsERF2 lines were longer than those of WT. Consistent with this phenotype, several auxin/cytokinin responsive genes involved in root growth were downregulated in nsf2857, but upregulated in Ami-OsERF2. Then, we found that nsf2857 seedlings exhibited decreased ABA accumulation and sensitivity to ABA and reduced ethylene-mediated root inhibition, while those were the opposite in Ami-ERF2 plants. Moreover, several key genes involved in ABA synthesis were downregulated in nsf2857, but unregulated in Ami-ERF2 lines. In addition, OsERF2 affected the accumulation of sucrose and UDPG by mediating expression of key genes involved in sucrose metabolism. These results indicate that OsERF2 is required for the control of root architecture and ABA- and ethylene-response by tuning expression of series genes involved in sugar metabolism and hormone signaling pathways.

  12. Enkephalins and hormonal-metabolic reactions in experimental stress depending on its severity

    SciTech Connect

    Lishmanov, Y.B.; Alekminskaya, L.A.; Lasukova, T.V.

    1985-08-01

    The aim of this investigation was to study the action of enkephalins on changes in hormonal-metabolic constants in stress of varied severity. Catecholamine excretion with the urine was determined fluorometrically, serum cortisol and insulin concentrations were measured radioimmunologically and glucose was determined by the standard orthotoluidine method. The results of the investigation indicate that enkephalins have a modulating effect on various hormonal mechanisms of adaptation stress. The results confirm that the physiological action of the peptide regulator depends on the functional state of the biological systems and it may differ sharply, even to the extent of diametrically opposite effects.

  13. Hormonal status and fluid electrolyte metabolism in motion sickness

    SciTech Connect

    Grigoriev, A.I.; Nichiporuk, I.A.; Yasnetsov, V.V.; Shashkov, V.S.

    1988-04-01

    In the first experimental series, 10 healthy male test subjects with a high susceptibility to motion sickness showed a significant increase of ACTH, cortisol, STH, prolactin, ADH, aldosterone concentrations, and plasma renin activity after vestibular tests. The 10 subjects with a moderate susceptibility exhibited a still higher increase of the hormones, except plasma renin. The 8 test subjects with a low susceptibility displayed a considerable increase in ACTH, cortisol, and STH after vestibular stimulation. In the second experimental series, the increase of STH, cortisol, ADH, aldosterone and renin occurred immediately after rotation in the moderate susceptibility subjects and an hour after exposure in the high susceptibility subjects. This may be indicative of specific immediate adaptation mechanisms or excitation transfer in the CNS in high susceptibility persons. In the third experimental animal series, the permeability of the blood-brain barrier for /sup 125/I and IgG increased after rotation. Greater concentrations of potassium, chloride, and urea in CSF are suggestive of an inhibition process activation in the CNS and, probably, of an active urea transport by the vascular plexus epithelium which maintains constant osmotic pressure of cerebral extracellular fluid and prevents hyper-hydration of CNS neurons.

  14. Down regulation of gene related sex hormone synthesis pathway in mouse testes by miroestrol and deoxymiroestrol.

    PubMed

    Udomsuk, Latiporn; Juengwatanatrakul, Thaweesak; Putalun, Waraporn; Jarukamjorn, Kanokwan

    2011-12-01

    Miroestrol and deoxymiroestrol are phytoestrogens isolated from tuberous root of Pueraria candollei var. mirifica. Modulatory effects of miroestrol and deoxymiroestrol on enzymes involved in sex-hormone synthesis pathway in male C57BL/6 mice were investigated using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). Miroestrol and deoxymiroestrol suppressed the expressions of 3β-HSD, 17β-HSD1, and CYP17 while CYP19 mRNA expression was slightly decreased. In addition, the expression of 17β-HSD2 was induced in correlation with those did by estradiol. These observations supported that miroestrol and deoxymiroestrol could exhibit the same effect as estradiol regarding regulation of testicular gene related sex hormone synthesis pathway.

  15. Photorespiration: metabolic pathways and their role in stress protection.

    PubMed Central

    Wingler, A; Lea, P J; Quick, W P; Leegood, R C

    2000-01-01

    Photorespiration results from the oxygenase reaction catalysed by ribulose-1,5-bisphosphate carboxylase/oxygenase. In this reaction glycollate-2-phosphate is produced and subsequently metabolized in the photorespiratory pathway to form the Calvin cycle intermediate glycerate-3-phosphate. During this metabolic process, CO2 and NH3 are produced and ATP and reducing equivalents are consumed, thus making photorespiration a wasteful process. However, precisely because of this inefficiency, photorespiration could serve as an energy sink preventing the overreduction of the photosynthetic electron transport chain and photoinhibition, especially under stress conditions that lead to reduced rates of photosynthetic CO2 assimilation. Furthermore, photorespiration provides metabolites for other metabolic processes, e.g. glycine for the synthesis of glutathione, which is also involved in stress protection. In this review we describe the use of photorespiratory mutants to study the control and regulation of photorespiratory pathways. In addition, we discuss the possible role of photorespiration under stress conditions, such as drought, high salt concentrations and high light intensities encountered by alpine plants. PMID:11128005

  16. Effects of pituitary hormone deficiency on growth and glucose metabolism of the sheep fetus.

    PubMed

    Fowden, A L; Forhead, A J

    2007-10-01

    Pituitary hormones are essential for normal growth and metabolic responsiveness after birth, but their role before birth remains unclear. This study examined the effects of hypophysectomizing fetal sheep on their growth and glucose metabolism during the late normal and extended periods of gestation, and on their metabolic response to maternal fasting for 48 h near term. Fetal hypophysectomy reduced crown rump length (CRL), limb lengths, and body weight but increased ponderal index relative to controls near normal term. It also lowered the daily rate of crown rump length increment uniformly from 35 d before, to 20 d after normal term. Hypophysectomized (HX) fetuses had normal weight-specific rates of umbilical uptake, utilization, and oxidation of glucose but lower rates of umbilical oxygen uptake than controls near term. All these metabolic rates were significantly less in HX fetuses during the extended period of gestation than in HX and intact fetuses near normal term. In contrast to controls, glucogenesis was negligible in HX fetuses during maternal fasting. Consequently, the rate of glucose utilization decreased significantly in fasted HX but not intact fetuses. Conversely, the rate of CO(2) production from glucose carbon decreased in fasted intact but not HX fetuses. Fetal hypophysectomy also prevented the fasting-induced increases in plasma cortisol and norepinephrine concentrations seen in controls. These findings demonstrate that the pituitary hormones are important in regulating the growth rate and adaptive responses of glucose metabolism to undernutrition in fetal sheep. They also suggest that fetal metabolism is altered when gestational length is extended.

  17. A safer method for studying hormone metabolism in an Asian elephant (Elephas maximus): accelerator mass spectrometry.

    PubMed

    Yon, Lisa; Faulkner, Brian; Kanchanapangka, Sumolya; Chaiyabutr, Narongsak; Meepan, Sompast; Lasley, Bill

    2010-01-01

    Noninvasive hormone assays provide a way to determine an animal's health or reproductive status without the need for physical or chemical restraint, both of which create unnecessary stress for the animal, and can potentially alter the hormones being measured. Because hormone metabolism is highly species-specific, each assay must be validated for use in the species of interest. Validation of noninvasive steroid hormone assays has traditionally required the administration of relatively high doses of radiolabelled compounds (100 µCi or more of (14)C labeled hormone) to permit subsequent detection of the excreted metabolites in the urine and feces. Accelerator mass spectrometry (AMS) is sensitive to extremely low levels of rare isotopes such as (14)C, and provides a way to validate hormone assays using much lower levels of radioactivity than those traditionally employed. A captive Asian bull elephant was given 1 µCi of (14)C-testosterone intravenously, and an opportunistic urine sample was collected 2 hr after the injection. The sample was separated by HPLC and the (14)C in the fractions was detected by AMS to characterize the metabolites present in the urine. A previously established HPLC protocol was used, which permitted the identification of fractions into which testosterone sulfate, testosterone glucuronide, and the parent compound testosterone elute. Results from this study indicate that the majority of testosterone excreted in the urine of the Asian bull elephant is in the form of testosterone sulfate. A small amount of testosterone glucuronide is also excreted, but there is no parent compound present in the urine at all. These results underscore the need for enzymatic hydrolysis to prepare urine samples for hormone assay measurement. Furthermore, they highlight the importance of proper hormone assay validation in order to ensure accurate measurement of the desired hormone. Although this study demonstrated the utility of AMS for safer validation of

  18. [Lipoprotein metabolism in menopause. Effect of hormonal substitution therapy].

    PubMed

    Heckers, H; Platt, D

    1991-06-20

    Oral administration of conjugated estrogens, estradiol valerate and micronized estradiol--but not the percutaneous application--in the postmenopause modifies the plasmic lipoprotein profile by lowering, dose-dependently, LDL and elevating HDL (HDL2). In parallel, the cardiovascular mortality is decreased by 50-66%, with smokers also benefiting to the same extent. On account of the increased risk for endometrial carcinoma associated with postmenopausal estrogen monotherapy, combination with a lowest-dose gestagen is imperative. However, the very numerous synthetic gestagens can antagonize the favorable effects of the estrogen on lipoprotein metabolism. This applies in particular to the gestagens of the 19-nortestosterone type, such as norethisterone acetate and, in particular, levonorgestrel, but less so the 17-hydroxyprogesterone derivatives medroxyprogesterone acetate and medrogestone with their very low androgenic effect.

  19. The insulin/TOR signal transduction pathway is involved in the nutritional regulation of juvenile hormone synthesis in Aedes aegypti.

    PubMed

    Pérez-Hedo, Meritxell; Rivera-Perez, Crisalejandra; Noriega, Fernando G

    2013-06-01

    Juvenile hormone (JH) levels must be modulated to permit the normal progress of development and reproductive maturation in mosquitoes. JH is part of a transduction system that assesses nutritional information and controls reproduction in mosquitoes. Adult female Aedes aegypti show nutritionally-dependent dynamic changes in corpora allata (CA) JH biosynthetic activities. A coordinated expression of most JH biosynthetic enzymes has been described in female pupae and adult mosquitoes; increases or decreases in transcript levels for all the enzymes were concurrent with increases or decreases in JH synthesis; suggesting that transcriptional changes are at least partially responsible for the dynamic changes of JH biosynthesis. The goal of the present study is to identify signaling network components responsible for the nutritional-dependent changes of JH synthesis in the CA of mosquitoes. The insulin/TOR signaling network plays a central role in the transduction of nutritional signals that regulate cell growth and metabolism in insects. These pathways have also been suggested as a link between nutritional signals and JH synthesis regulation in the CA of cockroaches and flies. We used a combination of in vitro studies and in vivo genetic knockdown experiments to explore nutritional signaling pathways in the CA. Our results suggest that the insulin/TOR pathway plays a role in the transduction of the nutritional information that regulates JH synthesis in mosquitoes. Transcriptional regulation of the genes encoding JH biosynthetic enzymes is at least partially responsible for these nutritionally modulated changes of JH biosynthesis.

  20. Do the Interactions between Glucocorticoids and Sex Hormones Regulate the Development of the Metabolic Syndrome?

    PubMed Central

    Alemany, Marià

    2012-01-01

    The metabolic syndrome is basically a maturity-onset disease. Typically, its manifestations begin to flourish years after the initial dietary or environmental aggression began. Since most hormonal, metabolic, or defense responses are practically immediate, the procrastinated response do not seem justified. Only in childhood, the damages of the metabolic syndrome appear with minimal delay. Sex affects the incidence of the metabolic syndrome, but this is more an effect of timing than absolute gender differences, females holding better than males up to menopause, when the differences between sexes tend to disappear. The metabolic syndrome is related to an immune response, countered by a permanent increase in glucocorticoids, which keep the immune system at bay but also induce insulin resistance, alter the lipid metabolism, favor fat deposition, mobilize protein, and decrease androgen synthesis. Androgens limit the operation of glucocorticoids, which is also partly blocked by estrogens, since they decrease inflammation (which enhances glucocorticoid release). These facts suggest that the appearance of the metabolic syndrome symptoms depends on the strength (i.e., levels) of androgens and estrogens. The predominance of glucocorticoids and the full manifestation of the syndrome in men are favored by decreased androgen activity. Low androgens can be found in infancy, maturity, advanced age, or because of their inhibition by glucocorticoids (inflammation, stress, medical treatment). Estrogens decrease inflammation and reduce the glucocorticoid response. Low estrogen (infancy, menopause) again allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. It is postulated that the equilibrium between sex hormones and glucocorticoids may be a critical element in the timing of the manifestation of metabolic syndrome-related pathologies. PMID:22649414

  1. Coexistence of competing metabolic pathways in well-mixed populations

    NASA Astrophysics Data System (ADS)

    Fernández, Lenin; Amado, André; Campos, Paulo R. A.; Ferreira, Fernando Fagundes

    2016-05-01

    Understanding why strains with different metabolic pathways that compete for a single limiting resource coexist is a challenging issue within a theoretical perspective. Previous investigations rely on mechanisms such as group or spatial structuring to achieve a stable coexistence between competing metabolic strategies. Nevertheless, coexistence has been experimentally reported even in situations where it cannot be attributed to spatial effects [Heredity 100, 471 (2008), 10.1038/sj.hdy.6801073]. According to that study a toxin expelled by one of the strains can be responsible for the stable maintenance of the two strain types. We propose a resource-based model in which an efficient strain with a slow metabolic rate competes with a second strain type which presents a fast but inefficient metabolism. Moreover, the model assumes that the inefficient strain produces a toxin as a by-product. This toxin affects the growth rate of both strains with different strength. Through an extensive exploration of the parameter space we determine the situations at which the coexistence of the two strains is possible. Interestingly, we observe that the resource influx rate plays a key role in the maintenance of the two strain types. In a scenario of resource scarcity the inefficient is favored, though as the resource influx rate is augmented the coexistence becomes possible and its domain is enlarged.

  2. Cerulenin-mediated apoptosis is involved in adenine metabolic pathway

    SciTech Connect

    Chung, Kyung-Sook; Sun, Nam-Kyu; Lee, Seung-Hee; Lee, Hyun-Jee; Choi, Shin-Jung; Kim, Sun-Kyung; Song, Ju-Hyun; Jang, Young-Joo; Song, Kyung-Bin; Yoo, Hyang-Sook; Simon, Julian . E-mail: jsimon@fhcrc.org; Won, Misun . E-mail: misun@kribb.re.kr

    2006-10-27

    Cerulenin, a fatty acid synthase (FAS) inhibitor, induces apoptosis of variety of tumor cells. To elucidate mode of action by cerulenin, we employed the proteomics approach using Schizosaccharomyces pombe. The differential protein expression profile of S. pombe revealed that cerulenin modulated the expressions of proteins involved in stresses and metabolism, including both ade10 and adk1 proteins. The nutrient supplementation assay demonstrated that cerulenin affected enzymatic steps transferring a phosphoribosyl group. This result suggests that cerulenin accumulates AMP and p-ribosyl-s-amino-imidazole carboxamide (AICAR) and reduces other necessary nucleotides, which induces feedback inhibition of enzymes and the transcriptional regulation of related genes in de novo and salvage adenine metabolic pathway. Furthermore, the deregulation of adenine nucleotide synthesis may interfere ribonucleotide reductase and cause defects in cell cycle progression and chromosome segregation. In conclusion, cerulenin induces apoptosis through deregulation of adenine nucleotide biosynthesis resulting in nuclear division defects in S. pombe.

  3. Brain areas and pathways in the regulation of glucose metabolism.

    PubMed

    Diepenbroek, Charlene; Serlie, Mireille J; Fliers, Eric; Kalsbeek, Andries; la Fleur, Susanne E

    2013-01-01

    Glucose is the most important source of fuel for the brain and its concentration must be kept within strict boundaries to ensure the organism's optimal fitness. To maintain glucose homeostasis, an optimal balance between glucose uptake and glucose output is required. Besides managing acute changes in plasma glucose concentrations, the brain controls a daily rhythm in glucose concentrations. The various nuclei within the hypothalamus that are involved in the control of both these processes are well known. However, novel studies indicate an additional role for brain areas that are originally appreciated in other processes than glucose metabolism. Therefore, besides the classic hypothalamic pathways, we will review cortico-limbic brain areas and their role in glucose metabolism.

  4. Expression data on liver metabolic pathway genes and proteins

    PubMed Central

    Raja Gopal Reddy, Mooli; Pavan Kumar, Chodisetti; Mahesh, Malleswarapu; Sravan Kumar, Manchiryala; Jeyakumar, Shanmugam M.

    2016-01-01

    Here, we present the expression data on various metabolic pathways of liver with special emphasize on lipid and carbohydrate metabolism and long chain polyunsaturated fatty acid (PUFA) synthesis, both at gene and protein levels. The data were obtained to understand the effect of vitamin A deficiency on the expression status (both gene and protein levels) of some of the key factors involved in lipogenesis, fatty acid oxidation, triglyceride secretion, long chain PUFA, resolvin D1 synthesis, glucose transport and glycogen synthesis of liver, using modern biology tools, such as quantitative real-time PCR (RT-PCR) and immunoblotting techniques. This data article provides the supporting evidence to the article “Vitamin A deficiency suppresses high fructose-induced triglyceride synthesis and elevates resolvin D1 levels” [1] and therefore, these data may be referred back, for comprehensive understanding and interpretations and for future studies. PMID:26909377

  5. Engineering of a xylose metabolic pathway in Rhodococcus strains.

    PubMed

    Xiong, Xiaochao; Wang, Xi; Chen, Shulin

    2012-08-01

    The two metabolically versatile actinobacteria Rhodococcus opacus PD630 and R. jostii RHA1 can efficiently convert diverse organic substrates into neutral lipids mainly consisting of triacylglycerol (TAG), the precursor of energy-rich hydrocarbon. Neither, however, is able to utilize xylose, the important component present in lignocellulosic biomass, as the carbon source for growth and lipid accumulation. In order to broaden their substrate utilization range, the metabolic pathway of d-xylose utilization was introduced into these two strains. This was accomplished by heterogenous expression of two well-selected genes, xylA, encoding xylose isomerase, and xylB, encoding xylulokinase from Streptomyces lividans TK23, under the control of the tac promoter with an Escherichia coli-Rhodococcus shuttle vector. The recombinant R. jostii RHA1 bearing xylA could grow on xylose as the sole carbon source, and additional expression of xylB further improved the biomass yield. The recombinant could consume both glucose and xylose in the sugar mixture, although xylose metabolism was still affected by the presence of glucose. The xylose metabolic pathway was also introduced into the high-lipid-producing strain R. opacus PD630 by expression of xylA and xylB. Under nitrogen-limited conditions, the fatty acid composition was determined, and lipid produced from xylose by recombinants of R. jostii RHA1 and R. opacus PD630 carrying xylA and xylB represented up to 52.5% and 68.3% of the cell dry weight (CDW), respectively. This work demonstrates that it is feasible to produce lipid from the sugars, including xylose, derived from renewable feedstock by genetic modification of rhodococcus strains.

  6. Metabolite Valves: Dynamic Control of Metabolic Flux for Pathway Engineering

    NASA Astrophysics Data System (ADS)

    Prather, Kristala

    2015-03-01

    Microbial strains have been successfully engineered to produce a wide variety of chemical compounds, several of which have been commercialized. As new products are targeted for biological synthesis, yield is frequently considered a primary driver towards determining feasibility. Theoretical yields can be calculated, establishing an upper limit on the potential conversion of starting substrates to target compounds. Such yields typically ignore loss of substrate to byproducts, with the assumption that competing reactions can be eliminated, usually by deleting the genes encoding the corresponding enzymes. However, when an enzyme encodes an essential gene, especially one involved in primary metabolism, deletion is not a viable option. Reducing gene expression in a static fashion is possible, but this solution ignores the metabolic demand needed for synthesis of the enzymes required for the desired pathway. We have developed Metabolite valves to address this challenge. The valves are designed to allow high flux through the essential enzyme during an initial period where growth is favored. Following an external perturbation, enzyme activity is then reduced, enabling a higher precursor pool to be diverted towards the pathway of interest. We have designed valves with control at both the transcriptional and post-translational levels. In both cases, key enzymes in glucose metabolism are regulated, and two different compounds are targeted for heterologous production. We have measured increased concentrations of intracellular metabolites once the valve is closed, and have demonstrated that these increased pools lead to increased product yields. These metabolite valves should prove broadly useful for dynamic control of metabolic flux, resulting in improvements in product yields.

  7. Identifying Differentially Abundant Metabolic Pathways in Metagenomic Datasets

    NASA Astrophysics Data System (ADS)

    Liu, Bo; Pop, Mihai

    Enabled by rapid advances in sequencing technology, metagenomic studies aim to characterize entire communities of microbes bypassing the need for culturing individual bacterial members. One major goal of such studies is to identify specific functional adaptations of microbial communities to their habitats. Here we describe a powerful analytical method (MetaPath) that can identify differentially abundant pathways in metagenomic data-sets, relying on a combination of metagenomic sequence data and prior metabolic pathway knowledge. We show that MetaPath outperforms other common approaches when evaluated on simulated datasets. We also demonstrate the power of our methods in analyzing two, publicly available, metagenomic datasets: a comparison of the gut microbiome of obese and lean twins; and a comparison of the gut microbiome of infant and adult subjects. We demonstrate that the subpathways identified by our method provide valuable insights into the biological activities of the microbiome.

  8. Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk

    PubMed Central

    Reding, Kerryn W.; Weiss, Noel S.; Chen, Chu; Li, Christopher I.; Carlson, Christopher S.; Wilkerson, Hui-Wen; Farin, Federico M.; Thummel, Kenneth E.; Daling, Janet R.; Malone, Kathleen E.

    2009-01-01

    Background This study investigated whether single nucleotide polymorphisms (SNPs) in genes within the catechol estrogen metabolism pathway altered the risk of breast cancer alone or in combination, as well as whether menopausal hormone therapy (HT) modified the effect of these SNPs on breast cancer risk. Methods In a population-based case-control study of breast cancer, 891 cases and 878 controls were genotyped for six functional SNPs in the COMT, CYP1B1, GSTM1, GSTP1, and GSTT1 genes. Results Women homozygous with the T allele in CYP1B1*2 (Ser119; rs1056827) were at 1.69 (95% confidence interval [CI]: 1.17–2.46) times the risk of women homozygous with the G allele; women homozygous with the G allele in GSTP1 (Val105; rs1695) were at 0.73 (95% CI: 0.54–0.99) times the risk of breast cancer compared to women homozygous with the A allele. No other SNPs tested were associated with breast cancer to any appreciable degree. Potential gene-gene and gene-HT interactions were investigated. Conclusion With the exception of GSTP1 and possibly CYP1B1*2, our findings do not provide support for the role of genetic variation in the catechol estrogen metabolism pathway and breast cancer risk in post-menopausal women. PMID:19383894

  9. Methodology of the thyroid gland disease decision-making using profiling in steroid hormone pathway.

    PubMed

    Kim, Young Sun; Yoon, Chang No

    2007-02-19

    To find out the genetic factors of outbreak of thyroid gland disease, we developed the thyroid gland decision-making system, which processes the metabolic profile in steroid hormone map using a statistical method. Metabolic profile is a measured data of lots of mixed materials that includes not only known metabolites, but also unknown ones, which is estimated to have an influence on the thyroid gland disease. Therefore, to develop thyroid gland disease decision-making system, analyzing metabolic profile containing multi-materials would be useful for diagnosing thyroid gland disease. Because experimental values used for system construction are area values for the retention time, the observations are preprocessed through variable transition and t-test to use the area values concurrently and the highly correlated materials are estimated by principal component analysis. The thyroid gland decision-making system developed through the logistic regression is an excellent system demonstrating 98.7% accuracy in the classification table.

  10. Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer.

    PubMed

    Cerne, Jasmina Ziva; Novakovic, Srdjan; Frkovic-Grazio, Snjezana; Pohar-Perme, Maja; Stegel, Vida; Gersak, Ksenija

    2011-08-01

    Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan® allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.

  11. A binary classifier for prediction of the types of metabolic pathway of chemicals.

    PubMed

    Fang, Yemin; Chen, Lei

    2016-12-15

    The study of metabolic pathway is one of the most important fields in biochemistry. Good comprehension of the metabolic pathway system is helpful to uncover the mechanism of some fundamental biological processes. Because chemicals are part of the main components of the metabolic pathway, correct identification of which metabolic pathways a given chemical can participate in is an important step for understanding the metabolic pathway system. Most previous methods only considered the chemical information, which tried to deal with a multi-label classification problem of assigning chemicals to proper metabolic pathways. In this study, the pathway information was also employed, thereby transforming the problem into a binary classification problem of identifying the pair of chemicals and metabolic pathways, i.e., a chemical and a metabolic pathway was paired as a sample to be considered in this study. To construct the prediction model, the association between chemical pathway type pairs was evaluated by integrating the association between chemicals and association between pathway types. The support vector machine was adopted as the prediction engine. The extensive tests show that the constructed model yields good performance with total prediction accuracy around 0.878. Furthermore, the comparison results indicate that our model is quite effective and suitable for the identification of whether a given chemical can participate in a given metabolic pathway.

  12. Formate Assimilation: The Metabolic Architecture of Natural and Synthetic Pathways.

    PubMed

    Bar-Even, Arren

    2016-07-19

    Formate may become an ideal mediator between the physicochemical and biological realms, as it can be produced efficiently from multiple available sources, such as electricity and biomass, and serve as one of the simplest organic compounds for providing both carbon and energy to living cells. However, limiting the realization of formate as a microbial feedstock is the low diversity of formate-fixing enzymes and thereby the small number of naturally occurring formate-assimilation pathways. Here, the natural enzymes and pathways supporting formate assimilation are presented and discussed together with proposed synthetic routes that could permit growth on formate via existing as well as novel formate-fixing reactions. By considering such synthetic routes, the diversity of metabolic solutions for formate assimilation can be expanded dramatically, such that different host organisms, cultivation conditions, and desired products could be matched with the most suitable pathway. Astute application of old and new formate-assimilation pathways may thus become a cornerstone in the development of sustainable strategies for microbial production of value-added chemicals.

  13. Adjuvant diet to improve hormonal and metabolic factors affecting breast cancer prognosis.

    PubMed

    Berrino, Franco; Villarini, Anna; De Petris, Michela; Raimondi, Milena; Pasanisi, Patrizia

    2006-11-01

    Western lifestyle, characterized by reduced physical activity and a diet rich in fat, refined carbohydrates, and animal protein is associated with high prevalence of overweight, metabolic syndrome, insulin resistance, and high plasma levels of several growth factors and sex hormones. Most of these factors are associated with breast cancer risk and, in breast cancer patients, with increased risk of recurrences. Recent trials have proven that such a metabolic and endocrine imbalance can be favorably modified through comprehensive dietary modification, shifting from Western to Mediterranean and macrobiotic diet.

  14. Quantitative analysis of energy metabolic pathways in MCF-7 breast cancer cells by selected reaction monitoring assay.

    PubMed

    Drabovich, Andrei P; Pavlou, Maria P; Dimitromanolakis, Apostolos; Diamandis, Eleftherios P

    2012-08-01

    To investigate the quantitative response of energy metabolic pathways in human MCF-7 breast cancer cells to hypoxia, glucose deprivation, and estradiol stimulation, we developed a targeted proteomics assay for accurate quantification of protein expression in glycolysis/gluconeogenesis, TCA cycle, and pentose phosphate pathways. Cell growth conditions were selected to roughly mimic the exposure of cells in the cancer tissue to the intermittent hypoxia, glucose deprivation, and hormonal stimulation. Targeted proteomics assay allowed for reproducible quantification of 76 proteins in four different growth conditions after 24 and 48 h of perturbation. Differential expression of a number of control and metabolic pathway proteins in response to the change of growth conditions was found. Elevated expression of the majority of glycolytic enzymes was observed in hypoxia. Cancer cells, as opposed to near-normal MCF-10A cells, exhibited significantly increased expression of key energy metabolic pathway enzymes (FBP1, IDH2, and G6PD) that are known to redirect cellular metabolism and increase carbon flux through the pentose phosphate pathway. Our quantitative proteomic protocol is based on a mass spectrometry-compatible acid-labile detergent and is described in detail. Optimized parameters of a multiplex selected reaction monitoring (SRM) assay for 76 proteins, 134 proteotypic peptides, and 401 transitions are included and can be downloaded and used with any SRM-compatible mass spectrometer. The presented workflow is an integrated tool for hypothesis-driven studies of mammalian cells as well as functional studies of proteins, and can greatly complement experimental methods in systems biology, metabolic engineering, and metabolic transformation of cancer cells.

  15. Yeast Pathway Kit: A Method for Metabolic Pathway Assembly with Automatically Simulated Executable Documentation.

    PubMed

    Pereira, Filipa; Azevedo, Flávio; Parachin, Nadia Skorupa; Hahn-Hägerdal, Bärbel; Gorwa-Grauslund, Marie F; Johansson, Björn

    2016-05-20

    We have developed the Yeast Pathway Kit (YPK) for rational and random metabolic pathway assembly in Saccharomyces cerevisiae using reusable and redistributable genetic elements. Genetic elements are cloned in a suicide vector in a rapid process that omits PCR product purification. Single-gene expression cassettes are assembled in vivo using genetic elements that are both promoters and terminators (TP). Cassettes sharing genetic elements are assembled by recombination into multigene pathways. A wide selection of prefabricated TP elements makes assembly both rapid and inexpensive. An innovative software tool automatically produces detailed self-contained executable documentation in the form of pydna code in the narrative Jupyter notebook format to facilitate planning and sharing YPK projects. A d-xylose catabolic pathway was created using YPK with four or eight genes that resulted in one of the highest growth rates reported on d-xylose (0.18 h(-1)) for recombinant S. cerevisiae without adaptation. The two-step assembly of single-gene expression cassettes into multigene pathways may improve the yield of correct pathways at the cost of adding overall complexity, which is offset by the supplied software tool.

  16. Nutritional and Hormonal Regulation of Citrate and Carnitine/Acylcarnitine Transporters: Two Mitochondrial Carriers Involved in Fatty Acid Metabolism

    PubMed Central

    Giudetti, Anna M.; Stanca, Eleonora; Siculella, Luisa; Gnoni, Gabriele V.; Damiano, Fabrizio

    2016-01-01

    The transport of solutes across the inner mitochondrial membrane is catalyzed by a family of nuclear-encoded membrane-embedded proteins called mitochondrial carriers (MCs). The citrate carrier (CiC) and the carnitine/acylcarnitine transporter (CACT) are two members of the MCs family involved in fatty acid metabolism. By conveying acetyl-coenzyme A, in the form of citrate, from the mitochondria to the cytosol, CiC contributes to fatty acid and cholesterol synthesis; CACT allows fatty acid oxidation, transporting cytosolic fatty acids, in the form of acylcarnitines, into the mitochondrial matrix. Fatty acid synthesis and oxidation are inversely regulated so that when fatty acid synthesis is activated, the catabolism of fatty acids is turned-off. Malonyl-CoA, produced by acetyl-coenzyme A carboxylase, a key enzyme of cytosolic fatty acid synthesis, represents a regulator of both metabolic pathways. CiC and CACT activity and expression are regulated by different nutritional and hormonal conditions. Defects in the corresponding genes have been directly linked to various human diseases. This review will assess the current understanding of CiC and CACT regulation; underlining their roles in physio-pathological conditions. Emphasis will be placed on the molecular basis of the regulation of CiC and CACT associated with fatty acid metabolism. PMID:27231907

  17. Thyroid Hormones Correlate with Basal Metabolic Rate but Not Field Metabolic Rate in a Wild Bird Species

    PubMed Central

    Welcker, Jorg; Chastel, Olivier; Gabrielsen, Geir W.; Guillaumin, Jerome; Kitaysky, Alexander S.; Speakman, John R.; Tremblay, Yann; Bech, Claus

    2013-01-01

    Thyroid hormones (TH) are known to stimulate in vitro oxygen consumption of tissues in mammals and birds. Hence, in many laboratory studies a positive relationship between TH concentrations and basal metabolic rate (BMR) has been demonstrated whereas evidence from species in the wild is scarce. Even though basal and field metabolic rates (FMR) are often thought to be intrinsically linked it is still unknown whether a relationship between TH and FMR exists. Here we determine the relationship between the primary thyroid hormone triiodothyronine (T3) with both BMR and FMR in a wild bird species, the black-legged kittiwake (Rissa tridactyla). As predicted we found a strong and positive relationship between plasma concentrations of T3 and both BMR and mass-independent BMR with coefficients of determination ranging from 0.36 to 0.60. In contrast there was no association of T3 levels with either whole-body or mass-independent FMR (R2 = 0.06 and 0.02, respectively). In accordance with in vitro studies our data suggests that TH play an important role in modulating BMR and may serve as a proxy for basal metabolism in wild birds. However, the lack of a relationship between TH and FMR indicates that levels of physical activity in kittiwakes are largely independent of TH concentrations and support recent studies that cast doubt on a direct linkage between BMR and FMR. PMID:23437096

  18. Differential Effects of Hormones on Cellular Metabolism in Keratoconus In Vitro

    PubMed Central

    McKay, Tina B.; Hjortdal, Jesper; Sejersen, Henrik; Karamichos, Dimitrios

    2017-01-01

    Keratoconus (KC) is a corneal thinning disease with an onset commonly immediately post-puberty and stabilization by 40 to 50 years of age. The role of hormones in regulating corneal tissue structure in homeostatic and pathological conditions is unknown. Our group recently linked altered hormone levels to KC. Our current study sought to investigate and delineate the effects of exogenous hormones, such as androgen, luteotropin, and estrogen, on corneal stroma bioenergetics. We utilized our established 3D in vitro model to characterize the effects of DHEA, prolactin, 17β-estradiol on insulin-growth factor-1 and -2 (IGF-1, -2) signaling and metabolic function in primary corneal fibroblasts from healthy controls (HCFs) and KC patients (HKCs). Our data showed that exogenous DHEA significantly downregulated IGF-1 and its receptor in both HCFs and HKCs with HKCs showing consistently lower basal pentose phosphate flux. Prolactin caused no significant change in IGF-1 levels and an increase in IGF-2 in HKCs correlating with an increase in ATP and NADH levels. 17β-estradiol led to a significant upregulation in pentose phosphate flux and glycolytic intermediates in HCFs. Our results identified hormone-specific responses regulated in HKCs compared to HCFs revealing a novel role for hormones on bioenergetics in KC. PMID:28211546

  19. [Hormonal regulation of metabolism in the human body in microgravity and during simulation of its physiological effects].

    PubMed

    Larina, I M

    2003-01-01

    The paper presents results of investigations into the effects of space flight and simulation experiments of various length on the hormonal regulation of metabolism in the human body. Microgravity was shown to instigate shifts on different levels of the hormonal regulation and consequent adjustment of metabolism to this new environment. For instance, adaptation occurs on the level of basal secretory activity resulting in altered metabolism and formation of a pool of hormones. Metabolism readaptation to the Earth's gravity is dependent on polymorphic processes in the system of hormonal regulation developing in the course of time. Trends in the hormonal regulation of water-electrolyte metabolism during early adaptation point to inequality of contributions of the antidiuretic hormone, natriuretic peptide, and the renin-angiotensin-aldosterone system. In the ground-based simulations responses of the hormonal regulation of water-electrolyte metabolism differ in intensity and types of hormones involved. Temperature variation can modify reactions of the comosis and volume regulating hormones at the beginning of adaptation. Physical-chemical regulation of calcium homeostasis in microgravity reveals itself by a rapid decline of the calcium-binding ability of blood buffers and, later on, degradation of the relative ability of extraplasmic structures to bind calcium. Qualitative and quantitative changes in the diurnal rhythm of the suprarenal steroidogenesis are indicative of modification of intensity of reactions of the main biosynthetic sequences. Countermeasures used by test-subjects in these investigations loosened significantly the aldosterone-secreting biosynthetic sequences but were favorable to the synthesis of testosterone and hydrocortisone. Some of the highly variable processes of hormonal regulation were mute to the diurnal rhythms in the pre-flight and preexperimental periods.

  20. A novel metabolic pathway of melatonin: oxidation by cytochrome C.

    PubMed

    Semak, Igor; Naumova, Marya; Korik, Elena; Terekhovich, Victorya; Wortsman, Jacobo; Slominski, Andrzej

    2005-07-05

    The indoleamine melatonin is ubiquitously distributed, and because of its small size and amphiphilic nature, it is able to reach easily all cellular compartments. The highest intracellular melatonin concentrations are found in the mitochondria, suggestive of local metabolism and/or direct participation in organelle function. In mitochondria cytochrome c (cyt c) could represent a melatonin target since it has the capability to oxidize organic molecules in the presence of H2O2, and mitochondria are the main site of H2O2 production in nonphagocytic cells. Therefore, we investigated oxidation of melatonin by cyt c/H2O2 couple as a potential pathway for its metabolism in the mitochondria. We found melatonin conversion into N(1)-acetyl-N(2)-formyl-5-methoxykynuramine via sequential steps that generate the intermediates 2-hydroxymelatonin and 2,3-dihydroxymelatonin. We experimentally excluded mediation by a Fenton/Haber-Weiss-type reaction and documented the dependence on oxoferryl heme for melatonin oxidation. Given the high mitochondrial concentrations of both melatonin and cyt c as well as the continuous generation of H2O2 during respiration, it is entirely possible that mitochondrial cyt c-mediated oxidation of melatonin may be a plausible pathway of its biotransformation in vivo.

  1. Proteomic Analysis of Hylocereus polyrhizus Reveals Metabolic Pathway Changes.

    PubMed

    Hua, Qingzhu; Zhou, Qianjun; Gan, Susheng; Wu, Jingyu; Chen, Canbin; Li, Jiaqiang; Ye, Yaoxiong; Zhao, Jietang; Hu, Guibing; Qin, Yonghua

    2016-09-28

    Red dragon fruit or red pitaya (Hylocereus polyrhizus) is the only edible fruit that contains betalains. The color of betalains ranges from red and violet to yellow in plants. Betalains may also serve as an important component of health-promoting and disease-preventing functional food. Currently, the biosynthetic and regulatory pathways for betalain production remain to be fully deciphered. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analyses were used to reveal the molecular mechanism of betalain biosynthesis in H. polyrhizus fruits at white and red pulp stages, respectively. A total of 1946 proteins were identified as the differentially expressed between the two samples, and 936 of them were significantly highly expressed at the red pulp stage of H. polyrhizus. RNA-seq and iTRAQ analyses showed that some transcripts and proteins were positively correlated; they belonged to "phenylpropanoid biosynthesis", "tyrosine metabolism", "flavonoid biosynthesis", "ascorbate and aldarate metabolism", "betalains biosynthesis" and "anthocyanin biosynthesis". In betalains biosynthesis pathway, several proteins/enzymes such as polyphenol oxidase, CYP76AD3 and 4,5-dihydroxy-phenylalanine (DOPA) dioxygenase extradiol-like protein were identified. The present study provides a new insight into the molecular mechanism of the betalain biosynthesis at the posttranscriptional level.

  2. Putting The Plant Metabolic Network pathway databases to work: going offline to gain new capabilities.

    PubMed

    Dreher, Kate

    2014-01-01

    Metabolic databases such as The Plant Metabolic Network/MetaCyc and KEGG PATHWAY are publicly accessible resources providing organism-specific information on reactions and metabolites. KEGG PATHWAY depicts metabolic networks as wired, electronic circuit-like maps, whereas the MetaCyc family of databases uses a canonical textbook-like representation. The first MetaCyc-based database for a plant species was AraCyc, which describes metabolism in the model plant Arabidopsis. This database was created over 10 years ago and has since then undergone extensive manual curation to reflect updated information on enzymes and pathways in Arabidopsis. This chapter describes accessing and using AraCyc and its underlying Pathway Tools software. Specifically, methods for (1) navigating Pathway Tools, (2) visualizing omics data and superimposing the data on a metabolic pathway map, and (3) creating pathways and pathway components are discussed.

  3. Pancreatic tumor cell metabolism: focus on glycolysis and its connected metabolic pathways.

    PubMed

    Guillaumond, Fabienne; Iovanna, Juan Lucio; Vasseur, Sophie

    2014-03-01

    Because of lack of effective treatment, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with a very weak improvement of survival rate over the last 40years. Defeat of numerous conventional therapies to cure this cancer makes urgent to develop new tools usable by clinicians for a better management of the disease. Aggressiveness of pancreatic cancer relies on its own hallmarks: a low vascular network as well as a prominent stromal compartment (desmoplasia), which creates a severe hypoxic environment impeding correct oxygen and nutrients diffusion to the tumoral cells. To survive and proliferate in those conditions, pancreatic cancer cells set up specific metabolic pathways to meet their tremendous energetic and biomass demands. However, as PDAC is a heterogenous tumor, a complex reprogramming of metabolic processes is engaged by cancer cells according to their level of oxygenation and nutrients supply. In this review, we focus on the glycolytic activity of PDAC and the glucose-connected metabolic pathways which contribute to the progression and dissemination of this disease. We also discuss possible therapeutic strategies targeting these pathways in order to cure this disease which still until now is resistant to numerous conventional treatments.

  4. Hormone-Related Pathways and Risk of Breast Cancer Subtypes in African American Women

    PubMed Central

    Haddad, Stephen A.; Lunetta, Kathryn L.; Ruiz-Narváez, Edward A.; Bensen, Jeannette T.; Hong, Chi-Chen; Sucheston-Campbell, Lara E.; Yao, Song; Bandera, Elisa V.; Rosenberg, Lynn; Haiman, Christopher A.; Troester, Melissa A.; Ambrosone, Christine B.; Palmer, Julie R.

    2016-01-01

    Purpose We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Methods Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER-, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women's Circle of Health Study, the Black Women's Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single SNP tests were run for the top genes. Results There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p ≤0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p ≤0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER- disease (p ≤0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r2 <0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER- disease. Conclusion We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing. PMID:26458823

  5. Hormone-related pathways and risk of breast cancer subtypes in African American women.

    PubMed

    Haddad, Stephen A; Lunetta, Kathryn L; Ruiz-Narváez, Edward A; Bensen, Jeannette T; Hong, Chi-Chen; Sucheston-Campbell, Lara E; Yao, Song; Bandera, Elisa V; Rosenberg, Lynn; Haiman, Christopher A; Troester, Melissa A; Ambrosone, Christine B; Palmer, Julie R

    2015-11-01

    We sought to investigate genetic variation in hormone pathways in relation to risk of overall and subtype-specific breast cancer in women of African ancestry (AA). Genotyping and imputation yielded data on 143,934 SNPs in 308 hormone-related genes for 3663 breast cancer cases (1098 ER-, 1983 ER+, 582 ER unknown) and 4687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. AMBER includes data from four large studies of AA women: the Carolina Breast Cancer Study, the Women's Circle of Health Study, the Black Women's Health Study, and the Multiethnic Cohort Study. Pathway- and gene-based analyses were conducted, and single-SNP tests were run for the top genes. There were no strong associations at the pathway level. The most significantly associated genes were GHRH, CALM2, CETP, and AKR1C1 for overall breast cancer (gene-based nominal p ≤ 0.01); NR0B1, IGF2R, CALM2, CYP1B1, and GRB2 for ER+ breast cancer (p ≤ 0.02); and PGR, MAPK3, MAP3K1, and LHCGR for ER- disease (p ≤ 0.02). Single-SNP tests for SNPs with pairwise linkage disequilibrium r (2) < 0.8 in the top genes identified 12 common SNPs (in CALM2, CETP, NR0B1, IGF2R, CYP1B1, PGR, MAPK3, and MAP3K1) associated with overall or subtype-specific breast cancer after gene-level correction for multiple testing. Rs11571215 in PGR (progesterone receptor) was the SNP most strongly associated with ER- disease. We identified eight genes in hormone pathways that contain common variants associated with breast cancer in AA women after gene-level correction for multiple testing.

  6. Steroid and metabolic hormonal profile of porcine serum vis-à-vis ovarian follicular fluid

    PubMed Central

    Naskar, Soumen; Borah, S.; Vashi, Y.; Thomas, R.; Sarma, D. K.; Goswami, J.; Dhara, S. K.

    2016-01-01

    Aim: This study was conducted to understand whether serum level of the steroid and metabolic hormones may be indicative of their level in ovarian follicular fluid (FF) in porcine, and its influence on fertility. Materials and Methods: Ovaries from pigs (n=32) of two genetic groups, namely, native (Ghungroo; n=16) and crossbred (Hampshire × Ghungroo; n=16) were collected. Both the genetic groups comprised gilts (n=8) and sows (n=8), and sows were in luteal phase of estrus cycle. FF was aspirated from small, medium and large follicles, and centrifuged for the collection of supernatant for further analysis. Blood samples were collected from the same animals, and serum was separated. Hormones, namely, cortisol, T3, T4 and testosterone were estimated by radioimmunoassay. Two-way ANOVA was used for analysis of data considering genetic background (native or crossbred), stage of reproductive life (gilt or sow), and source of sample (serum or FF) as fixed effects. Results: It was observed that all the hormones except cortisol differed significantly (p<0.01) based on genetic background. Stage of reproductive life and source of sample did not affect the studied hormonal level. Within the genetic groups, stage of reproductive life influenced T3 (p<0.01), cortisol (p<0.05) and testosterone (p<0.01) level in crossbred pigs as compared to T3 (p<0.01) only in native pigs. The level of T3 in serum, as well as FF, was higher (p<0.01) in Ghungroo gilts compared to sows. However, a reverse of this was observed in the case of crossbred pigs. The level of cortisol (p<0.05) and testosterone (p<0.01) was higher in crossbred sows than gilts in both serum and FF. Conclusion: The study revealed that serum level of the steroid and metabolic hormones is indicative of their level in the ovarian FF. Further, varying level of steroid and metabolic hormones in pigs based on genetic background may be due to variation in body size, rate of energy metabolism and stage of (re)productive life. PMID

  7. Stress, metabolism and cancer: integrated pathways contributing to immune suppression.

    PubMed

    Repasky, Elizabeth A; Eng, Jason; Hylander, Bonnie L

    2015-01-01

    The potential for immune cells to control cancers has been recognized for many decades, but only recently has real excitement begun to spread through the oncology community following clear evidence that therapeutic blockade of specific immune-suppressive mechanisms is enough to make a real difference in survival for patients with several different advanced cancers. However, impressive and encouraging as these new clinical data are, it is clear that more effort should be devoted toward understanding the full spectrum of factors within cancer patients, which have the potential to block or weaken antitumor activity by immune cells. The goal of this brief review is to highlight recent literature revealing interactive stress and metabolic pathways, particularly those mediated by the sympathetic nervous system, which may conspire to block immune cells from unleashing their full killing potential. There is exciting new information regarding the role of neurogenesis by tumors and adrenergic signaling in cancer progression (including metabolic changes associated with cachexia and lipolysis) and in regulation of immune cell function and differentiation. However, much more work is needed to fully understand how the systemic metabolic effects mediated by the brain and nervous system can be targeted for therapeutic efficacy in the setting of immunotherapy and other cancer therapies.

  8. Glucuronidation, a new metabolic pathway for pyrrolizidine alkaloids.

    PubMed

    He, Yu-Qi; Yang, Li; Liu, Hui-Xin; Zhang, Jiang-Wei; Liu, Yong; Fong, Alan; Xiong, Ai-Zhen; Lu, Yan-Liu; Yang, Ling; Wang, Chang-Hong; Wang, Zheng-Tao

    2010-03-15

    Pyrrolizidine alkaloids (PAs) possess significant hepatotoxicity to humans and animals after metabolic activation by liver P450 enzymes. Metabolism pathways of PAs have been studied for several decades, including metabolic activation, hydroxylation, N-oxidation, and hydrolysis. However, the glucuronidation of intact PAs has not been investigated, although glucuronidation plays an important role in the elimination and detoxication of xenobiotics. In this study, PAs glucuronidation was investigated, and three important points were found. First, we demonstrated that senecionine (SEN)-a representative hepatotoxic PA-could be conjugated by glucuronic acid via an N-glucuronidation reaction catalyzed by uridine diphosphate glucuronosyl transferase in human liver microsomes. Second, glucuronidation of SEN was catalyzed not only by human but also other animal species and showed significant species differences. Rabbits, cattle, sheep, pigs, and humans showed the significantly higher glucuronidation activity than mice, rats, dogs, and guinea pigs on SEN. Kinetics of SEN glucuronidation in humans, pigs, and rabbits followed the one-site binding model of the Michaelis-Menten equation, while cattle and sheep followed the two-sites binding model of the Michaelis-Menten equation. Third, besides SEN, other hepatotoxic PAs including monocrotaline, adonifoline, and isoline also underwent N-glucuronidation in humans and several animal species such as rabbits, cattle, sheep, and pigs.

  9. Metabolism of cysteine by cyteinesulfinate-independent pathway(s) in rat hepatocytes

    SciTech Connect

    Stipanuk, M.H.; De La Rosa, J.; Drake, M.R.

    1986-05-01

    The metabolism of cysteine (CYS) and that of cysteinesulfinate (CSA) were studied in freshly isolated hepatocytes from fed rats. In incubations of rat hepatocytes with either 1 or 25 mM CSA, over 90% of the /sup 14/CO/sub 2/ formed from (1-/sup 14/C)CSA could be accounted for by production of hypotaurine plus taurine. In similar incubations with 1 or 25 mM CYS, only 4% of /sup 14/CO/sub 2/ evolution from (1-/sup 14/C)CYS could be accounted for by production of hypotaurine plus taurine. Addition of unlabeled CSA inhibited recovery of label from (1-/sup 14/C)CYS as /sup 14/CO/sub 2/ by 33%. Metabolism of CYS and of CSA were affected differently by addition of ..cap alpha..-ketoglutarate, a cosubstrate for transamination, or of propargylglycine, an inhibitor of cystathionase activity. These data suggest that a substantial proportion of CYS is catabolized by CSA-independent pathways in the rat hepatocyte. Although addition of ..cap alpha..-ketoglutarate to incubations of hepatocytes with CSA resulted in a marked increase in CSA catabolism via the transamination pathway, addition of keto acids to incubation systems had little or no effect on production of any metabolite from CYS. Thus, CYS transamination does not appear to be a major pathway of CYS metabolism in the hepatocyte. Inhibition of cystathionase with propargylglycine reduced both /sup 14/CO/sub 2/ production from (1-/sup 14/C)CYS and ammonia plus urea nitrogen production from CYS by about 50%; CSA catabolism was not affected. Thus, cleavage of cyst(e)ine by cystathionase may be an important physiological pathway for CYS catabolism in the liver.

  10. Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy.

    PubMed

    Rasgon, Natalie L; Kenna, Heather A; Wroolie, Tonita E; Williams, Katherine E; DeMuth, Bevin N; Silverman, Daniel H S

    2014-07-30

    Insulin resistance (IR) is a putative risk factor for cognitive decline and dementia, and has been shown to impede neuronal glucose metabolism in animal models. This post hoc study focused on metabolic changes in the medial prefrontal region, a brain region exhibiting decline years before documented cognitive changes, relative to high or low IR status in a cohort of postmenopausal women at risk for dementia who were randomized to continue or discontinue existing stable hormone therapy (HT) for 2 years. Subjects were dichotomized into high and low IR groups based on the homeostatic model assessment of insulin resistance, which was within clinically normal limits for the group as a whole at both baseline and 2-year follow-up. Results showed that high and low IR groups showed significant differences in metabolic decline of the medial prefrontal gyrus, regardless of HT randomization group. However, HT randomization was predictive of metabolic decline only in women with low HOMA (homeostatic assessment of insulin resistance). Performance in working memory was consistent with observed metabolic changes. These results suggest IR may be an independent moderator of regional metabolic changes, while protective metabolic effects of HT are most apparent in those at low-end range of IR. If replicated in future studies, these findings will help to better understand the interaction between putative risk and protective factors, and further delineate cohort postmenopausal women who may benefit from HT.

  11. Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

    PubMed Central

    Kim, Seong M.; Roy, Saurabh G.; Chen, Bin; Nguyen, Tiffany M.; McMonigle, Ryan J.; McCracken, Alison N.; Kofuji, Satoshi; Hou, Jue; Selwan, Elizabeth; Finicle, Brendan T.; Nguyen, Tricia T.; Ravi, Archna; Ramirez, Manuel U.; Wiher, Tim; Guenther, Garret G.; Kono, Mari; Sasaki, Atsuo T.; Weisman, Lois S.; Potma, Eric O.; Tromberg, Bruce J.; Edwards, Robert A.; Hanessian, Stephen; Edinger, Aimee L.

    2016-01-01

    Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene Ras in vitro and in vivo. However, slower-growing, autochthonous PTEN-deficient prostate tumors that did not exhibit a classic Warburg phenotype were equally sensitive. Remarkably, normal proliferative tissues were unaffected by doses of SH-BC-893 that profoundly inhibited tumor growth. These studies demonstrate that simultaneously blocking parallel nutrient access pathways with sphingolipid-based drugs is broadly effective and cancer selective, suggesting a potential strategy for overcoming the resistance conferred by tumor heterogeneity. PMID:27669461

  12. The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia.

    PubMed

    Du, X; Hill, R A

    2016-11-01

    Dementia is an ever-expanding problem facing an ageing society. Currently, there is a sharp paucity of treatment strategies. It has long been known that sex hormones, namely 17β-estradiol and testosterone, possess neuroprotective- and cognitive-enhancing qualities. However, certain lacunae in the knowledge underlying their molecular mechanisms have delayed their use as treatment strategies in dementia. With recent advancements in pharmacology and molecular biology, especially in the development of safer selective oestrogen receptor modulators and the recent discovery of the small-molecule brain-derived neurotrophic factor receptor agonist, 7,8-dihydroxyflavone, the exploitation of these signalling pathways for clinical use has become possible. This review aims to adumbrate the evidence and hurdles underscoring the use of sex hormones in the treatment of dementia as well as discussing some direction that is required to advance the translation of evidence into practise.

  13. Pentachlorophenol disrupts steroid hormone metabolism at concentrations that reduce survival and fecundity of Daphnia magna

    SciTech Connect

    Parks, L.G.; LeBlanc, G.A.

    1995-12-31

    Alterations in steroid metabolism by environmental endocrine disrupters can significantly affect steroid hormone-dependent processes such as growth and reproduction. Exposure to pentachlorophenol (PCP) has been shown to elicit a variety of endocrine-related adverse effects. The present study was undertaken to establish whether concentrations of PCP that adversely affect survival, growth, or reproduction of Daphnia magna during chronic exposure also elicit changes in steroid hormone metabolism. Survival and/or reproduction of daphnids was significantly reduced from exposure to 1.0, 0.50 and 0.25 mg/L PCP. Following chronic exposure to PCP, daphnids were incubated with [{sup 14}C]testosterone and the testosterone metabolites eliminated were identified and quantified. The rate of testosterone hydroxyl-metabolite elimination was not significantly different from controls. However, elimination of two of the glucose-conjugated metabolites of testosterone decreased in a PCP concentration-dependent manner. Adult daphnids were next exposed to these concentrations of PCP for only 48 hours and effects on steroid metabolism assessed. As observed following chronic exposure, PCP had no effect on the elimination of hydroxyl-metabolites. However, elimination of glucose and sulfate conjugates of testosterone were inhibited in a concentration-dependent manner. These results demonstrate that, (1) PCP alters steroid biotransformation activities at concentrations that affect survival and reproduction, and (2) effects on steroid metabolism can be detected following short-term exposure to PCP. Thus, this biochemical parameter may serve as a biomarker of chronic toxicity associated with PCP.

  14. Growth hormone activity in mitochondria depends on GH receptor Box 1 and involves caveolar pathway targeting

    SciTech Connect

    Perret-Vivancos, Cecile; Abbate, Aude; Ardail, Dominique; Raccurt, Mireille; Usson, Yves; Lobie, Peter E.; Morel, Gerard . E-mail: gerard.morel@univ-lyon1.fr

    2006-02-01

    Growth hormone (GH) binding to its receptor (GHR) initiates GH-dependent signal transduction and internalization pathways to generate the biological effects. The precise role and way of action of GH on mitochondrial function are not yet fully understood. We show here that GH can stimulate cellular oxygen consumption in CHO cells transfected with cDNA coding for the full-length GHR. By using different GHR cDNA constructs, we succeeded in determining the different parts of the GHR implicated in the mitochondrial response to GH. Polarography and two-photon excitation fluorescence microscopy analysis showed that the Box 1 of the GHR intracellular domain was required for an activation of the mitochondrial respiration in response to a GH exposure. However, confocal laser scanning microscopy demonstrated that cells lacking the GHR Box 1 could efficiently internalize the hormone. We demonstrated that internalization mediated either by clathrin-coated pits or by caveolae was able to regulate GH mitochondrial effect: these two pathways are both essential to obtain the GH stimulatory action on mitochondrial function. Moreover, electron microscopic and biochemical approaches allowed us to identify the caveolar pathway as essential for targeting GH and GHR to mitochondria.

  15. Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3-iodothyronamine on the cardiovascular system.

    PubMed

    Axelband, F; Dias, J; Ferrão, F M; Einicker-Lamas, M

    2011-01-01

    Thyroid hormones play a wide range of important physiological activities in almost all organism. As changes in these hormones levels-observed in hypothyroidism and hyperthyroidism-promote serious derangements of the cardiovascular system, it is important to know their mechanisms of action. Although the classic genomic actions which are dependent on interaction with nuclear receptors to modulate cardiac myocytes genes expression, there is growing evidence about T(3) and T(4)-triggered nongenomic pathways, resulted from their binding to plasma membrane, cytoplasm, or mitocondrial receptors that leads to a rapidly regulation of cardiac functions. Interestingly both actions converge to amplify thyroid hormone effects on cardiovascular system. T(3) and T(4) nongenomic actions modify inotropic and chronotropic effects, cardiac action potential duration, cardiac growth, and myocyte shape by protein translation through protein kinases-dependent signaling cascades, which include PKA, PKC, PI3K, and MAPK, and changes on ion channels and pumps activity. In respect to the decreased systemic vascular resistance seen in hyperthyroidism, T(3) appears to activate NOS or ATP-sensitive K(+) channels. In addition, a novel biologically active T(4)-derived metabolite has been described, 3-iodothyronamine, T(1)AM, which also acts through membrane receptors to mediate nongenomic cardiac effects. This metabolite influences the physiological manifestations of thyroid hormone actions by inducing opposite effects from those stimulated by T(3) and T(4), such as negative inotropic and chronotropic effects. Therefore, beyond genomic and nongenomic effects of thyroid hormones, it is crucial for there to be an equilibrium between T(3) or T(4) and T(1)AM levels for maintaining cardiac homeostasis.

  16. Effects of growth hormone, insulin-like growth factor I, triiodothyronine, thyroxine, and cortisol on gene expression of carbohydrate metabolic enzymes in sea bream hepatocytes.

    PubMed

    Leung, L Y; Woo, Norman Y S

    2010-11-01

    The present study investigated the regulatory effects of growth hormone (GH), human insulin-like growth factor I (hIGF-I), thyroxine (T(4)), triiodothyronine (T(3)) and cortisol, on mRNA expression of key enzymes involved in carbohydrate metabolism, including glucokinase (GK), glucose-6-phosphatase (G6Pase), glycogen synthase (GS), glycogen phosphorylase (GP) and glucose-6-phosphate dehydrogenase (G6PDH) in hepatocytes isolated from silver sea bream. Genes encoding GK, G6Pase, GS and GP were partially cloned and characterized from silver sea bream liver and real-time PCR assays were developed for the quantification of the mRNA expression profiles of these genes in order to evaluate the potential of these carbohydrate metabolic pathways. GK mRNA level was elevated by GH and hIGF-I, implying that GH-induced stimulation of GK expression may be mediated via IGF-I. GH was found to elevate GS and G6Pase expression, but reduce G6PDH mRNA expression. However, hIGF-I did not affect mRNA levels of GS, G6Pase and G6PDH, suggesting that GH-induced modulation of GS, G6Pase and G6PDH expression levels is direct, and occurs independently of the action of IGF-I. T(3) and T(4) directly upregulated transcript abundance of GK, G6Pase, GS and GP. Cortisol significantly increased transcript amounts of G6Pase and GS but markedly decreased transcript abundance of GK and G6PDH. These changes in transcript abundance indicate that (1) the potential of glycolysis is stimulated by GH and thyroid hormones, but attenuated by cortisol, (2) gluconeogenic and glycogenic potential are augmented by GH, thyroid hormones and cortisol, (3) glycogenolytic potential is upregulated by thyroid hormones but not affected by GH or cortisol, and (4) the potential of the pentose phosphate pathway is attenuated by GH and cortisol but unaffected by thyroid hormones.

  17. The CHH-superfamily of multifunctional peptide hormones controlling crustacean metabolism, osmoregulation, moulting, and reproduction.

    PubMed

    Webster, Simon George; Keller, Rainer; Dircksen, Heinrich

    2012-01-15

    Apart from providing an up-to-date review of the literature, considerable emphasis was placed in this article on the historical development of the field of "crustacean eyestalk hormones". A role of the neurosecretory eyestalk structures of crustaceans in endocrine regulation was recognized about 80 years ago, but it took another half a century until the first peptide hormones were identified. Following the identification of crustacean hyperglycaemic hormone (CHH) and moult-inhibiting hormone (MIH), a large number of homologous peptides have been identified to this date. They comprise a family of multifunctional peptides which can be divided, according to sequences and precursor structure, into two subfamilies, type-I and -II. Recent results on peptide sequences, structure of genes and precursors are described here. The best studied biological activities include metabolic control, moulting, gonad maturation, ionic and osmotic regulation and methyl farnesoate synthesis in mandibular glands. Accordingly, the names CHH, MIH, and GIH/VIH (gonad/vitellogenesis-inhibiting hormone), MOIH (mandibular organ-inhibiting hormone) were coined. The identification of ITP (ion transport peptide) in insects showed, for the first time, that CHH-family peptides are not restricted to crustaceans, and data mining has recently inferred their occurrence in other ecdysozoan clades as well. The long-held tenet of exclusive association with the eyestalk X-organ-sinus gland tract has been challenged by the finding of several extra nervous system sites of expression of CHH-family peptides. Concerning mode of action and the question of target tissues, second messenger mechanisms are discussed, as well as binding sites and receptors. Future challenges are highlighted.

  18. Consequences of monocarboxylate transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice.

    PubMed

    Trajkovic-Arsic, Marija; Visser, Theo J; Darras, Veerle M; Friesema, Edith C H; Schlott, Bernhard; Mittag, Jens; Bauer, Karl; Heuer, Heike

    2010-02-01

    Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T(3) and low-serum T(4) levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T(3) and T(4) content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T(4) and T(3) into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T(4) in the kidneys of MCT8 null mice together with the increased renal conversion of T(4) into T(3) by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T(4) and the increase in circulating T(3) levels, a hallmark of MCT8 deficiency.

  19. Traditional and novel aspects of the metabolic actions of growth hormone.

    PubMed

    Sperling, Mark A

    2016-06-01

    Growth hormone has been known to be diabetogenic for almost a century and it's diabetogenic properties fostered consideration of excessive and abnormal GH secretion as a cause of diabetes, as well as a role in the microvascular complications, especially retinopathy. However, besides inducing insulin resistance, GH also is lipolytic and a major anabolic hormone for nitrogen retention and protein synthesis. These actions are best illustrated at the extremes of GH secretion: Gigantism/acromegaly is characterized by excessive growth, CHO intolerance, hyperplasia of bone, little body fat and prominent muscle development, whereas total deficiency of GH secretion or action is associated with adiposity, poor growth, and poor muscle development. These actions also become apparent during puberty and pregnancy, times when GH secretion is increased and account for the characteristic changes in body composition and tendency to diabetes. More recently, tissue specific deletions of the GH receptor (GHR), have uncovered newer metabolic effects including it's essential role in triglyceride export from the liver when GHR is deleted in the liver, leading to hepatic steatosis and ultimately to hepatic adenoma formation, effects which may explain these findings in obesity, a state of diminished GH secretion and action. In addition deletion of GH action in muscle and fat is associated with specific patterns of disturbed phenotype and metabolic effects in CHO, fat, and protein metabolism affecting the specific tissue and whole body function. This chapter provides an overview of these classic and newer metabolic functions of GH, placing this hormone and its actions in a central role of body fuel economy in health and disease.

  20. Acute metabolic, hormonal, and psychological responses to different endurance training protocols.

    PubMed

    Wahl, P; Mathes, S; Köhler, K; Achtzehn, S; Bloch, W; Mester, J

    2013-10-01

    In the last years, mainly 2 high-intensity-training (HIT) protocols became common: first, a Wingate-based "all-out" protocol and second, a 4×4 min protocol. However, no direct comparison between these protocols exists, and also a comparison with high-volume-training (HVT) is missing. Therefore, the aim of the present study was to compare these 3 endurance training protocols on metabolic, hormonal, and psychological responses. Twelve subjects performed: 1) HVT [130 min at 55% peak power output (PPO)]; 2) 4×4 min at 95% PPO; 3) 4×30 s all-out. Human growth hormone (hGH), testosterone, and cortisol were determined before (pre) and 0', 30', 60', 180' after each intervention. Metabolic stimuli and perturbations were characterized by lactate, blood gas (pH, BE, HCO₃⁻, pO₂, PCO₂), and spirometric analysis. Furthermore, changes of the person's perceived physical state were determined. The 4×30 s training caused the highest increases in cortisol and hGH, followed by 4 × 4 min and HVT. Testosterone levels were significantly increased by all 3 exercise protocols. Metabolic stress was highest during and after 4×30 s, followed by 4×4 min and HVT. The 4×30 s training was also the most demanding intervention from an athlete's point of view. In conclusion, the results suggest that 4×30 s and 4×4 min promote anabolic processes more than HVT, due to higher increases of hGH, testosterone, and the T/C ratio. It can be speculated that the acute hormonal increase and the metabolic perturbations might play a positive role in optimizing training adaptation and in eliciting health benefits as it has been shown by previous long term training studies using similar exercise protocols.

  1. Flower abscission in Vitis vinifera L. triggered by gibberellic acid and shade discloses differences in the underlying metabolic pathways

    PubMed Central

    Domingos, Sara; Scafidi, Pietro; Cardoso, Vania; Leitao, Antonio E.; Di Lorenzo, Rosario; Oliveira, Cristina M.; Goulao, Luis F.

    2015-01-01

    Understanding abscission is both a biological and an agronomic challenge. Flower abscission induced independently by shade and gibberellic acid (GAc) sprays was monitored in grapevine (Vitis vinifera L.) growing under a soilless greenhouse system during two seasonal growing conditions, in an early and late production cycle. Physiological and metabolic changes triggered by each of the two distinct stimuli were determined. Environmental conditions exerted a significant effect on fruit set as showed by the higher natural drop rate recorded in the late production cycle with respect to the early cycle. Shade and GAc treatments increased the percentage of flower drop compared to the control, and at a similar degree, during the late production cycle. The reduction of leaf gas exchanges under shade conditions was not observed in GAc treated vines. The metabolic profile assessed in samples collected during the late cycle differently affected primary and secondary metabolisms and showed that most of the treatment-resulting variations occurred in opposite trends in inflorescences unbalanced in either hormonal or energy deficit abscission-inducing signals. Particularly concerning carbohydrates metabolism, sucrose, glucose, tricarboxylic acid metabolites and intermediates of the raffinose family oligosaccharides pathway were lower in shaded and higher in GAc samples. Altered oxidative stress remediation mechanisms and indolacetic acid (IAA) concentration were identified as abscission signatures common to both stimuli. According to the global analysis performed, we report that grape flower abscission mechanisms triggered by GAc application and C-starvation are not based on the same metabolic pathways. PMID:26157448

  2. Metabolic and hormonal responses to long-distance swimming in cold water.

    PubMed

    Dulac, S; Quirion, A; DeCarufel, D; LeBlanc, J; Jobin, M; Côte, J; Brisson, G R; Lavoie, J M; Diamond, P

    1987-10-01

    The acute effects of long-distance swimming in cold water on selected hormonal and metabolic variables were evaluated on 22 long-distance swimmers (16 males and 6 females) during a 32-km swimming competition (La Traversée Internationale du Lac St-Jean). The water temperature was 18.5 degrees C and the mean performance times were 8 h and 32 min for men (M) and 9 h and 1 min for women (F). The blood samples were withdrawn in the fasting state during the week preceding the event and within 30 min after completion of the race. A positive correlation was obtained, for both groups, between percent body fat and rectal temperature measured at the end of the competition. After the competition, an increase in plasma epinephrine, norepinephrine, cortisol, thyroxine, free fatty acids, lactate, a decrease in glucose and insulin and no change in growth hormone, triiodothyronine, triglycerides, and cholesterol concentrations were observed in both groups. The increase in plasma thyroxine was more pronounced in the slower swimmers while the change in blood cortisol concentrations was higher in the subjects having the most acute decrease in body temperature. Male and female swimmers have a similar metabolic and hormonal response to a long-distance swimming competition in cold water.

  3. Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells.

    PubMed

    Li, Huika; Pham, Thy; McWhinney, Brett C; Ungerer, Jacobus P; Pretorius, Carel J; Richard, Derek J; Mortimer, Robin H; d'Emden, Michael C; Richard, Kerry

    2016-01-01

    Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.

  4. Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells

    PubMed Central

    Li, Huika; Ungerer, Jacobus P.; Pretorius, Carel J.; Mortimer, Robin H.; d'Emden, Michael C.

    2016-01-01

    Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease. PMID:27990161

  5. Gene expression analysis reveals the dysregulation of immune and metabolic pathways in Alzheimer's disease

    PubMed Central

    Li, Zhiyan; Xu, Panpan; Yao, Lifen

    2016-01-01

    In recent years, several pathway analyses of genome-wide association studies reported the involvement of metabolic and immune pathways in Alzheimer's disease (AD). Until now, the exact mechanisms of these pathways in AD are still unclear. Here, we conducted a pathway analysis of a whole genome AD case-control expression dataset (n=41, 25 AD cases and 16 controls) from the human temporal cortex tissue. Using the differently expressed AD genes, we identified significant KEGG pathways related to metabolism and immune processes. Using the up- and down- regulated AD gene list, we further found up-regulated AD gene were significantly enriched in immune and metabolic pathways. We further compare the immune and metabolic KEGG pathways from the expression dataset with those from previous GWAS datasets, and found that most of these pathways are shared in both GWAS and expression datasets. PMID:27732949

  6. Role of bile acids in the regulation of the metabolic pathways

    PubMed Central

    Taoka, Hiroki; Yokoyama, Yoko; Morimoto, Kohkichi; Kitamura, Naho; Tanigaki, Tatsuya; Takashina, Yoko; Tsubota, Kazuo; Watanabe, Mitsuhiro

    2016-01-01

    Recent studies have revealed that bile acids (BAs) are not only facilitators of dietary lipid absorption but also important signaling molecules exerting multiple physiological functions. Some major signaling pathways involving the nuclear BAs receptor farnesoid X receptor and the G protein-coupled BAs receptor TGR5/M-BAR have been identified to be the targets of BAs. BAs regulate their own homeostasis via signaling pathways. BAs also affect diverse metabolic pathways including glucose metabolism, lipid metabolism and energy expenditure. This paper suggests the mechanism of controlling metabolism via BA signaling and demonstrates that BA signaling is an attractive therapeutic target of the metabolic syndrome. PMID:27433295

  7. Serum Metabolic Profiling Reveals Altered Metabolic Pathways in Patients with Post-traumatic Cognitive Impairments.

    PubMed

    Yi, Lunzhao; Shi, Shuting; Wang, Yang; Huang, Wei; Xia, Zi-an; Xing, Zhihua; Peng, Weijun; Wang, Zhe

    2016-02-17

    Cognitive impairment, the leading cause of traumatic brain injury (TBI)-related disability, adversely affects the quality of life of TBI patients, and exacts a personal and economic cost that is difficult to quantify. The underlying pathophysiological mechanism is currently unknown, and an effective treatment of the disease has not yet been identified. This study aimed to advance our understanding of the mechanism of disease pathogenesis; thus, metabolomics based on gas chromatography/mass spectrometry (GC-MS), coupled with multivariate and univariate statistical methods were used to identify potential biomarkers and the associated metabolic pathways of post-TBI cognitive impairment. A biomarker panel consisting of nine serum metabolites (serine, pyroglutamic acid, phenylalanine, galactose, palmitic acid, arachidonic acid, linoleic acid, citric acid, and 2,3,4-trihydroxybutyrate) was identified to be able to discriminate between TBI patients with cognitive impairment, TBI patients without cognitive impairment and healthy controls. Furthermore, associations between these metabolite markers and the metabolism of amino acids, lipids and carbohydrates were identified. In conclusion, our study is the first to identify several serum metabolite markers and investigate the altered metabolic pathway that is associated with post-TBI cognitive impairment. These markers appear to be suitable for further investigation of the disease mechanisms of post-TBI cognitive impairment.

  8. Serum Metabolic Profiling Reveals Altered Metabolic Pathways in Patients with Post-traumatic Cognitive Impairments

    PubMed Central

    Yi, Lunzhao; Shi, Shuting; Wang, Yang; Huang, Wei; Xia, Zi-an; Xing, Zhihua; Peng, Weijun; Wang, Zhe

    2016-01-01

    Cognitive impairment, the leading cause of traumatic brain injury (TBI)-related disability, adversely affects the quality of life of TBI patients, and exacts a personal and economic cost that is difficult to quantify. The underlying pathophysiological mechanism is currently unknown, and an effective treatment of the disease has not yet been identified. This study aimed to advance our understanding of the mechanism of disease pathogenesis; thus, metabolomics based on gas chromatography/mass spectrometry (GC-MS), coupled with multivariate and univariate statistical methods were used to identify potential biomarkers and the associated metabolic pathways of post-TBI cognitive impairment. A biomarker panel consisting of nine serum metabolites (serine, pyroglutamic acid, phenylalanine, galactose, palmitic acid, arachidonic acid, linoleic acid, citric acid, and 2,3,4-trihydroxybutyrate) was identified to be able to discriminate between TBI patients with cognitive impairment, TBI patients without cognitive impairment and healthy controls. Furthermore, associations between these metabolite markers and the metabolism of amino acids, lipids and carbohydrates were identified. In conclusion, our study is the first to identify several serum metabolite markers and investigate the altered metabolic pathway that is associated with post-TBI cognitive impairment. These markers appear to be suitable for further investigation of the disease mechanisms of post-TBI cognitive impairment. PMID:26883691

  9. Metabolism

    MedlinePlus

    ... and intestines. Several of the hormones of the endocrine system are involved in controlling the rate and direction ... For Kids For Parents MORE ON THIS TOPIC Endocrine System What Can I Do About My High Metabolism? ...

  10. Race and sex differences in small-molecule metabolites and metabolic hormones in overweight and obese adults.

    PubMed

    Patel, Mahesh J; Batch, Bryan C; Svetkey, Laura P; Bain, James R; Turer, Christy Boling; Haynes, Carol; Muehlbauer, Michael J; Stevens, Robert D; Newgard, Christopher B; Shah, Svati H

    2013-12-01

    In overweight/obese individuals, cardiometabolic risk factors differ by race and sex categories. Small-molecule metabolites and metabolic hormone levels might also differ across these categories and contribute to risk factor heterogeneity. To explore this possibility, we performed a cross-sectional analysis of fasting plasma levels of 69 small-molecule metabolites and 13 metabolic hormones in 500 overweight/obese adults who participated in the Weight Loss Maintenance trial. Principal-components analysis (PCA) was used for reduction of metabolite data. Race and sex-stratified comparisons of metabolite factors and metabolic hormones were performed. African Americans represented 37.4% of the study participants, and females 63.0%. Of thirteen metabolite factors identified, three differed by race and sex: levels of factor 3 (branched-chain amino acids and related metabolites, p<0.0001), factor 6 (long-chain acylcarnitines, p<0.01), and factor 2 (medium-chain dicarboxylated acylcarnitines, p<0.0001) were higher in males vs. females; factor 6 levels were higher in Caucasians vs. African Americans (p<0.0001). Significant differences were also observed in hormones regulating body weight homeostasis. Among overweight/obese adults, there are significant race and sex differences in small-molecule metabolites and metabolic hormones; these differences may contribute to risk factor heterogeneity across race and sex subgroups and should be considered in future investigations with circulating metabolites and metabolic hormones.

  11. The transcription factor AREB1 regulates primary metabolic pathways in tomato fruits.

    PubMed

    Bastías, Adriana; Yañez, Mónica; Osorio, Sonia; Arbona, Vicent; Gómez-Cadenas, Aurelio; Fernie, Alisdair R; Casaretto, José A

    2014-06-01

    Tomato fruit development is regulated both by the action of plant hormones and by tight genetic control. Recent studies suggest that abscisic acid (ABA) signalling may affect different aspects of fruit maturation. Previously, it was shown that SlAREB1, an ABA-regulated transcription factor involved in stress-induced responses, is expressed in seeds and in fruit tissues in tomato. Here, the role of SlAREB1 in regulating the expression of genes relevant for primary metabolic pathways and affecting the metabolic profile of the fruit was investigated using transgenic tomato lines. Metabolite profiling using gas chromatography-time of flight mass spectrometry (GC-TOF-MS) and non-targeted liquid chromatography-mass spectrometry (LC-MS) was performed on pericarp tissue from fruits harvested at three stages of fruit development. Principal component analysis of the data could distinguish the metabolite profiles of non-transgenic fruits from those that overexpress and down-regulate SlAREB1. Overexpression of SlAREB1 resulted in increased content of organic acids, hexoses, hexose-phosphates, and amino acids in immature green, mature green, and red ripe fruits, and these modifications correlated with the up-regulation of enzyme-encoding genes involved in primary carbohydrate and amino acid metabolism. A non-targeted LC-MS analysis indicated that the composition of secondary metabolites is also affected in transgenic lines. In addition, gene expression data revealed that some genes associated with fruit ripening are also up-regulated in SlAREB1-overexpressing lines compared with wild-type and antisense lines. Taken together, the results suggest that SlAREB1 participates in the regulation of the metabolic programming that takes place during fruit ripening and that may explain part of the role of ABA in fruit development in tomato.

  12. The transcription factor AREB1 regulates primary metabolic pathways in tomato fruits

    PubMed Central

    Bastías, Adriana; Osorio, Sonia; Casaretto, José A.

    2014-01-01

    Tomato fruit development is regulated both by the action of plant hormones and by tight genetic control. Recent studies suggest that abscisic acid (ABA) signalling may affect different aspects of fruit maturation. Previously, it was shown that SlAREB1, an ABA-regulated transcription factor involved in stress-induced responses, is expressed in seeds and in fruit tissues in tomato. Here, the role of SlAREB1 in regulating the expression of genes relevant for primary metabolic pathways and affecting the metabolic profile of the fruit was investigated using transgenic tomato lines. Metabolite profiling using gas chromatography–time of flight mass spectrometry (GC-TOF-MS) and non-targeted liquid chromatography–mass spectrometry (LC-MS) was performed on pericarp tissue from fruits harvested at three stages of fruit development. Principal component analysis of the data could distinguish the metabolite profiles of non-transgenic fruits from those that overexpress and down-regulate SlAREB1. Overexpression of SlAREB1 resulted in increased content of organic acids, hexoses, hexose-phosphates, and amino acids in immature green, mature green, and red ripe fruits, and these modifications correlated with the up-regulation of enzyme-encoding genes involved in primary carbohydrate and amino acid metabolism. A non-targeted LC-MS analysis indicated that the composition of secondary metabolites is also affected in transgenic lines. In addition, gene expression data revealed that some genes associated with fruit ripening are also up-regulated in SlAREB1-overexpressing lines compared with wild-type and antisense lines. Taken together, the results suggest that SlAREB1 participates in the regulation of the metabolic programming that takes place during fruit ripening and that may explain part of the role of ABA in fruit development in tomato. PMID:24659489

  13. BioPAXViz: a cytoscape application for the visual exploration of metabolic pathway evolution.

    PubMed

    Psomopoulos, Fotis E; Vitsios, Dimitrios M; Baichoo, Shakuntala; Ouzounis, Christos A

    2017-01-25

    BioPAXViz is a Cytoscape (version 3) application, providing a comprehensive framework for metabolic pathway visualization. Beyond the basic parsing, viewing and browsing roles, the main novel function that BioPAXViz provides is a visual comparative analysis of metabolic pathway topologies across pre-computed pathway phylogenomic profiles given a species phylogeny. Furthermore, BioPAXViz supports the display of hierarchical trees that allow efficient navigation through sets of variants of a single reference pathway. Thus, BioPAXViz can significantly facilitate, and contribute to, the study of metabolic pathway evolution and engineering.

  14. Metabolic pathways of benzimidazole anthelmintics in harebell (Campanula rotundifolia).

    PubMed

    Stuchlíková, Lucie; Jirásko, Robert; Skálová, Lenka; Pavlík, František; Szotáková, Barbora; Holčapek, Michal; Vaněk, Tomáš; Podlipná, Radka

    2016-08-01

    Benzimidazoles anthelmintics, which enter into environment primarily through excretion in the feces or urine of treated animals, can affect various organisms and disrupt ecosystem balance. The present study was designed to test the phytotoxicity and biotransformation of the three benzimidazole anthelmintics albendazole (ABZ), fenbendazole (FBZ) and flubendazole (FLU) in the harebell (Campanula rotundifolia). This meadow plant commonly grows in pastures and comes into contact with anthelmintics through the excrements of treated animals. Suspensions of harebell cells in culture medium were used as an in vitro model system. ABZ, FLU and FBZ were not found to be toxic for harebell cells, which were able to metabolize ABZ, FLU and FBZ via the formation of a wide scale of metabolites. Ultrahigh-performance liquid chromatography coupled with high mass accuracy tandem mass spectrometry (UHPLC-MS/MS) led to the identification of 24, 18 and 29 metabolites of ABZ, FLU and FBZ, respectively. Several novel metabolites were identified for the first time. Based on the obtained results, the schemes of the metabolic pathways of these anthelmintics were proposed. Most of these metabolites can be considered deactivation products, but a substantial portion of them may readily be decomposed to biologically active substances which could negatively affect ecosystems.

  15. Phospholipase Cγ1 Connects the Cell Membrane Pathway to the Nuclear Receptor Pathway in Insect Steroid Hormone Signaling*

    PubMed Central

    Liu, Wen; Cai, Mei-Juan; Zheng, Chuan-Chuan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2014-01-01

    In addition to the classical nuclear receptor pathway, there is a nongenomic pathway in the cell membrane that regulates gene expression in animal steroid hormone signaling; however, this mechanism is unclear. Here, we report that the insect steroid hormone 20-hydroxyecdysone (20E) regulates calcium influx via phospholipase Cγ1 (PLCG1) to modulate the protein kinase C phosphorylation of the transcription factor ultraspiracle (USP1) in the lepidopteran insect Helicoverpa armigera. The PLCG1 mRNA levels are increased during the molting and metamorphic stages. The depletion of PLCG1 by RNA interference can block 20E-enhanced pupation, cause larvae death and pupation defects, and repress 20E-induced gene expression. 20E may induce the tyrosine phosphorylation of PLCG1 at the cytosolic tyrosine kinase (Src) homology 2 domains and then determine the migration of PLCG1 toward the plasma membrane. The G-protein-coupled receptor (GPCR) inhibitor suramin, Src family kinase inhibitor PP2, and the depletions of ecdysone-responsible GPCR (ErGPCR) and Gαq restrain the 20E-induced tyrosine phosphorylation of PLCG1. PLCG1 participates in the 20E-induced Ca2+ influx. The inhibition of GPCR, PLC, inositol 1,4,5-trisphosphate receptor, and calcium channels represses the 20E-induced Ca2+ influx. Through calcium signaling, PLCG1 mediates the transcriptional activation driven by the ecdysone-response element. Through PLCG1 and calcium signaling, 20E regulates PKC phosphorylation of USP1 at Ser-21 to determine its ecdysone-response element binding activity. These results suggest that 20E activates PLCG1 via the ErGPCR and Src family kinases to regulate Ca2+ influx and PKC phosphorylation of USP1 to subsequently modulate gene transcription for metamorphosis. PMID:24692553

  16. The effect of alterations in total coenzyme A on metabolic pathways in the liver and heart

    SciTech Connect

    Schlosser, C.A.S.

    1989-01-01

    The first set of experiments involved in vitro experiments using primary cultures of rat hepatocytes. A range of conditions were developed which resulted in cell cultures with variations in total CoA over a range of 1.3 to 2.9 nmol/mg protein with identical hormonal activation which simulated metabolic stress. Elevations of total CoA levels above that of controls due to preincubation with cyanamide plus pantothenate were correlated with diminished rates of total ketone body production, 3-hydroxybutyrate production and ratios of 3 hydroxybutyrate/acetoactetate with palmitate as substrate. In contrast, cells with elevated total CoA levels had higher rates of ({sup 14}C) CO{sub 2} production from radioactive palmitate which implied greater flux of acetyl CoA units into the TCA cycle and less to the pathway of ketogenesis. The second set of experiments were designed to alter total CoA levels in vivo by maintaining rats on a chronic ethanol diet with or without pantothenate-supplementation. The effect of alterations of CoA on mitochondrial metabolism was evaluated by measuring substrate oxidation rates in liver and heat mitochondria as well as ketone body production with palmitoyl-1-carnitine as substrate.

  17. APL-1, the Alzheimer's Amyloid precursor protein in Caenorhabditis elegans, modulates multiple metabolic pathways throughout development.

    PubMed

    Ewald, Collin Y; Raps, Daniel A; Li, Chris

    2012-06-01

    Mutations in the amyloid precursor protein (APP) gene or in genes that process APP are correlated with familial Alzheimer's disease (AD). The biological function of APP remains unclear. APP is a transmembrane protein that can be sequentially cleaved by different secretases to yield multiple fragments, which can potentially act as signaling molecules. Caenorhabditis elegans encodes one APP-related protein, APL-1, which is essential for viability. Here, we show that APL-1 signaling is dependent on the activity of the FOXO transcription factor DAF-16 and the nuclear hormone receptor DAF-12 and influences metabolic pathways such as developmental progression, body size, and egg-laying rate. Furthermore, apl-1(yn5) mutants, which produce high levels of the extracellular APL-1 fragment, show an incompletely penetrant temperature-sensitive embryonic lethality. In a genetic screen to isolate mutants in which the apl-1(yn5) lethality rate is modified, we identified a suppressor mutation in MOA-1/R155.2, a receptor-protein tyrosine phosphatase, and an enhancer mutation in MOA-2/B0495.6, a protein involved in receptor-mediated endocytosis. Knockdown of apl-1 in an apl-1(yn5) background caused lethality and molting defects at all larval stages, suggesting that apl-1 is required for each transitional molt. We suggest that signaling of the released APL-1 fragment modulates multiple metabolic states and that APL-1 is required throughout development.

  18. Text mining for metabolic pathways, signaling cascades, and protein networks.

    PubMed

    Hoffmann, Robert; Krallinger, Martin; Andres, Eduardo; Tamames, Javier; Blaschke, Christian; Valencia, Alfonso

    2005-05-10

    The complexity of the information stored in databases and publications on metabolic and signaling pathways, the high throughput of experimental data, and the growing number of publications make it imperative to provide systems to help the researcher navigate through these interrelated information resources. Text-mining methods have started to play a key role in the creation and maintenance of links between the information stored in biological databases and its original sources in the literature. These links will be extremely useful for database updating and curation, especially if a number of technical problems can be solved satisfactorily, including the identification of protein and gene names (entities in general) and the characterization of their types of interactions. The first generation of openly accessible text-mining systems, such as iHOP (Information Hyperlinked over Proteins), provides additional functions to facilitate the reconstruction of protein interaction networks, combine database and text information, and support the scientist in the formulation of novel hypotheses. The next challenge is the generation of comprehensive information regarding the general function of signaling pathways and protein interaction networks.

  19. Olanzapine-induced changes in glucose metabolism are independent of the melanin-concentrating hormone system.

    PubMed

    Girault, Elodie M; Toonen, Pim W; Eggels, Leslie; Foppen, Ewout; Ackermans, Mariëtte T; la Fleur, Susanne E; Fliers, Eric; Kalsbeek, Andries

    2013-11-01

    Atypical antipsychotic drugs such as Olanzapine (Ola) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. Chagnon et al. showed that the common allele rs7973796 of the prepro-melanin-concentrating hormone (PMCH) gene is associated with a greater body mass index in Ola-treated schizophrenic patients. As PMCH encodes for the orexigenic neuropeptide melanin-concentrating hormone (MCH), it was hypothesized that MCH is involved in Ola-induced metabolic changes. We have recently reported that the intragastric infusion of Ola results in hyperglycaemia and insulin resistance in male rats. In order to test in vivo the possible involvement of the PMCH gene in the pathogenesis of Ola side-effects, we administered Ola intragastrically in wild-type (WT) and PMCH knock-out (KO) rats. Our results show that glucose and corticosterone levels, as well as endogenous glucose production, are elevated by the infusion of Ola in both WT and KO animals. Thus, the lack of MCH does not seem to affect the acute effects of Ola on glucose metabolism. On the other hand, these effects might be obliterated by compensatory changes in other hypothalamic systems. In addition, possible modulatory effects of the MCH KO on the long term effects of Ola, i.e. increased adiposity, body weight gain, have not been investigated yet.

  20. Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats.

    PubMed

    Mizoguchi, Toshihide; Nagasawa, Sakae; Takahashi, Naoyuki; Yagasaki, Hiroshi; Ito, Michio

    2005-01-01

    Dolomite, a mineral composed of calcium magnesium carbonate (CaMg (CO3)2), is used as a food supplement that supplies calcium and magnesium. However, the effect of magnesium supplementation on bone metabolism in patients with osteoporosis is a matter of controversy. We examined the effects of daily supplementation with dolomite on calcium metabolism in ovariectomized (OVX) rats. Dolomite was administered daily to OVX rats for 9 weeks. The same amount of magnesium chloride as that supplied by the dolomite was given to OVX rats as a positive control. Histological examination revealed that ovariectomy decreased trabecular bone and increased adipose tissues in the femoral metaphysis. Dolomite or magnesium supplementation failed to improve these bone histological features. Calcium content in the femora was decreased in OVX rats. Neither calcium nor magnesium content in the femora in OVX rats was significantly increased by dolomite or magnesium administration. Urinary deoxypyridinoline excretion was significantly increased in OVX rats, and was not affected by the magnesium supplementation. Serum concentrations of magnesium were increased, and those of calcium were decreased, in OVX rats supplemented with dolomite or magnesium. However, there was a tendency toward decreased parathyroid hormone secretion and increased calcitonin secretion in OVX rats supplemented with dolomite or magnesium. Serum 1,25-dihydroxyvitamin D(3) and osteocalcin levels were significantly increased in the supplemented OVX rats. These results suggest that increased magnesium intake improves calcium metabolism in favor of increasing bone formation, through the modulation of calcium-regulating hormone secretion.

  1. Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations.

    PubMed

    Hu, Fang; Liu, Feng

    2014-01-01

    It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging.

  2. Review of metabolic pathways activated in cancer cells as determined through isotopic labeling and network analysis.

    PubMed

    Dong, Wentao; Keibler, Mark A; Stephanopoulos, Gregory

    2017-02-10

    Cancer metabolism has emerged as an indispensable part of contemporary cancer research. During the past 10 years, the use of stable isotopic tracers and network analysis have unveiled a number of metabolic pathways activated in cancer cells. Here, we review such pathways along with the particular tracers and labeling observations that led to the discovery of their rewiring in cancer cells. The list of such pathways comprises the reductive metabolism of glutamine, altered glycolysis, serine and glycine metabolism, mutant isocitrate dehydrogenase (IDH) induced reprogramming and the onset of acetate metabolism. Additionally, we demonstrate the critical role of isotopic labeling and network analysis in identifying these pathways. The alterations described in this review do not constitute a complete list, and future research using these powerful tools is likely to discover other cancer-related pathways and new metabolic targets for cancer therapy.

  3. Exploring metabolic pathways and regulation through functional chemoproteomic and metabolomic platforms.

    PubMed

    Medina-Cleghorn, Daniel; Nomura, Daniel K

    2014-09-18

    Genome sequencing efforts have revealed a strikingly large number of uncharacterized genes, including poorly or uncharacterized metabolic enzymes, metabolites, and metabolic networks that operate in normal physiology, and those enzymes and pathways that may be rewired under pathological conditions. Although deciphering the functions of the uncharacterized metabolic genome is a challenging prospect, it also presents an opportunity for identifying novel metabolic nodes that may be important in disease therapy. In this review, we will discuss the chemoproteomic and metabolomic platforms used in identifying, characterizing, and targeting nodal metabolic pathways important in physiology and disease, describing an integrated workflow for functional mapping of metabolic enzymes.

  4. Vitamin D Metabolic Pathway Genes and Pancreatic Cancer Risk

    PubMed Central

    Arem, Hannah; Yu, Kai; Xiong, Xiaoqin; Moy, Kristin; Freedman, Neal D.; Mayne, Susan T.; Albanes, Demetrius; Arslan, Alan A.; Austin, Melissa; Bamlet, William R.; Beane-Freeman, Laura; Bracci, Paige; Canzian, Federico; Cotterchio, Michelle; Duell, Eric J.; Gallinger, Steve; Giles, Graham G.; Goggins, Michael; Goodman, Phyllis J.; Hartge, Patricia; Hassan, Manal; Helzlsouer, Kathy; Henderson, Brian; Holly, Elizabeth A.; Hoover, Robert; Jacobs, Eric J.; Kamineni, Aruna; Klein, Alison; Klein, Eric; Kolonel, Laurence N.; Li, Donghui; Malats, Núria; Männistö, Satu; McCullough, Marjorie L.; Olson, Sara H.; Orlow, Irene; Peters, Ulrike; Petersen, Gloria M.; Porta, Miquel; Severi, Gianluca; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Yu, Herbert; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Tobias, Geoffrey S.; Maeder, Dennis; Brotzman, Michelle; Risch, Harvey; Sampson, Joshua N.; Stolzenberg-Solomon, Rachael Z.

    2015-01-01

    Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008–0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk. PMID:25799011

  5. Metabolomic analysis reveals altered metabolic pathways in a rat model of gastric carcinogenesis

    PubMed Central

    Gu, Jinping; Hu, Xiaomin; Shao, Wei; Ji, Tianhai; Yang, Wensheng; Zhuo, Huiqin; Jin, Zeyu; Huang, Huiying; Chen, Jiacheng; Huang, Caihua; Lin, Donghai

    2016-01-01

    Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression. PMID:27527852

  6. An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk

    DTIC Science & Technology

    2008-04-01

    breast cancer risk to be modestly associated with one SNPs in each GSTP1 (rs1695: OR = 1.4 [95% CI: 1.02-1.9] for carriers of A allele); CYP1B1 ...In a multi-gene model including two genes with single gene effects within the estrogen pathway ( CYP1B1 *2 and GSTP1), breast cancer risk was 1.6 (95...pathways. 15. SUBJECT TERMS Genetic polymorphisms , epidemiology, exogenous risk factors, gene-environment interactions, hormonal pathway, estrogen

  7. How type of parturition and health status influence hormonal and metabolic profiles in newborn foals.

    PubMed

    Panzani, S; Comin, A; Galeati, G; Romano, G; Villani, M; Faustini, M; Veronesi, M C

    2012-04-01

    Thyroid hormones, insulin growth factor I (IGF-I) and non-esterified fatty acids (NEFA) represent important hormonal and metabolic factors associated with perinatal growth and maturation. Their action could be influenced by the type of parturition and the health status of the foal and therefore the aim of this work is to evaluate their plasma concentrations in newborn foals during the first 2 wks of life. Three groups of subjects were enrolled: 15 healthy foals born by spontaneous parturition, 24 healthy foals born by induced parturition and 26 pathologic foals. From each of the healthy foals, blood was collected at 10, 20 and 30 minutes, 3 and 12 hours from birth, daily from Day 1 to Day 7, and at Day 10 and 14 of life. In pathologic foals samples were collected twice a day from the day of admission at the hospital until the day of discharge or death. Thyroid hormones (T3 and T4) and IGF-I were analyzed by radioimmunoassay and NEFA by enzymatic-colorimetric methods. In all the three groups a declining trend of T3 and T4 plasma concentrations was detectable, with lower levels in the pathologic group compared to healthy foals. Spontaneous foals showed higher levels of T3 at 7 d compared to induced foals, while T4 levels were higher in spontaneous vs. induced foals before 6 h of life, at three and seven days. IGF-I showed increasing plasma concentrations in all three considered groups. No differences were found between healthy and pathologic foals. NEFA in spontaneous and induced healthy foals showed a declining trend with higher levels during the first hours of life. Pathologic foals presented higher levels compared to spontaneous foals only at 24 h and 10 d. These data suggest that the type of foaling could influence the reference ranges for thyroid hormones. Moreover, pathologic foals showed some hormonal and metabolic differences related to their health status. Above all changes of thyroid hormones levels, early in postnatal life, could be a cause, and not only a

  8. The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency.

    PubMed

    Ferrara, Alfonso Massimiliano; Liao, Xiao-Hui; Ye, Honggang; Weiss, Roy E; Dumitrescu, Alexandra M; Refetoff, Samuel

    2015-11-01

    Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

  9. The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency

    PubMed Central

    Ferrara, Alfonso Massimiliano; Liao, Xiao-Hui; Ye, Honggang; Weiss, Roy E.; Dumitrescu, Alexandra M.

    2015-01-01

    Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials. PMID:26322373

  10. Thyroid hormone receptor alpha1 follows a cooperative CRM1/calreticulin-mediated nuclear export pathway.

    PubMed

    Grespin, Matthew E; Bonamy, Ghislain M C; Roggero, Vincent R; Cameron, Nicole G; Adam, Lindsay E; Atchison, Andrew P; Fratto, Victoria M; Allison, Lizabeth A

    2008-09-12

    The thyroid hormone receptor alpha1 (TRalpha) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T(3)). Previously, we have shown that TRalpha, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TRalpha is its ability to exit the nucleus through the nuclear pore complex. TRalpha export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TRalpha. We show that, in addition to shuttling in heterokaryons, TRalpha shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TRalpha directly interacts with calreticulin, and point to the intriguing possibility that TRalpha follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRalpha from the nucleus to cytoplasm.

  11. Thyroid Hormone Receptor α1 Follows a Cooperative CRM1/Calreticulin-mediated Nuclear Export Pathway*

    PubMed Central

    Grespin, Matthew E.; Bonamy, Ghislain M. C.; Roggero, Vincent R.; Cameron, Nicole G.; Adam, Lindsay E.; Atchison, Andrew P.; Fratto, Victoria M.; Allison, Lizabeth A.

    2008-01-01

    The thyroid hormone receptor α1 (TRα) exhibits a dual role as an activator or repressor of its target genes in response to thyroid hormone (T3). Previously, we have shown that TRα, formerly thought to reside solely in the nucleus bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. An important aspect of the shuttling activity of TRα is its ability to exit the nucleus through the nuclear pore complex. TRα export is not sensitive to treatment with the CRM1-specific inhibitor leptomycin B (LMB) in heterokaryon assays, suggesting a role for an export receptor other than CRM1. Here, we have used a combined approach of in vivo fluorescence recovery after photobleaching experiments, in vitro permeabilized cell nuclear export assays, and glutathione S-transferase pull-down assays to investigate the export pathway used by TRα. We show that, in addition to shuttling in heterokaryons, TRα shuttles rapidly in an unfused monokaryon system as well. Furthermore, our data show that TRα directly interacts with calreticulin, and point to the intriguing possibility that TRα follows a cooperative export pathway in which both calreticulin and CRM1 play a role in facilitating efficient translocation of TRα from the nucleus to cytoplasm. PMID:18641393

  12. Carboxypeptidase Z (CPZ) links thyroid hormone and Wnt signaling pathways in growth plate chondrocytes.

    PubMed

    Wang, Lai; Shao, Yvonne Y; Ballock, R Tracy

    2009-02-01

    Carboxypeptidase Z (CPZ) removes carboxyl-terminal basic amino acid residues, particularly arginine residues, from proteins. CPZ contains a cysteine-rich domain (CRD) similar to the CRD found in the frizzled family of Wnt receptors. We have previously shown that thyroid hormone regulates terminal differentiation of growth plate chondrocytes through activation of Wnt-4 expression and Wnt/beta-catenin signaling. The Wnt-4 protein contains a C-terminal arginine residue and binds to CPZ through the CRD. The objective of this study was to determine whether CPZ modulates Wnt/beta-catenin signaling and terminal differentiation of growth plate chondrocytes. Our results show that CPZ and Wnt-4 mRNA are co-expressed throughout growth plate cartilage. In primary pellet cultures of rat growth plate chondrocytes, thyroid hormone increases both Wnt-4 and CPZ expression, as well as CPZ enzymatic activity. Knockdown of either Wnt-4 or CPZ mRNA levels using an RNA interference technique or blocking CPZ enzymatic activity with the carboxypeptidase inhibitor GEMSA reduces the thyroid hormone effect on both alkaline phosphatase activity and Col10a1 mRNA expression. Adenoviral overexpression of CPZ activates Wnt/beta-catenin signaling and promotes the terminal differentiation of growth plate cells. Overexpression of CPZ in growth plate chondrocytes also removes the C-terminal arginine residue from a synthetic peptide consisting of the carboxyl-terminal 16 amino acids of the Wnt-4 protein. Removal of the C-terminal arginine residue of Wnt-4 by site-directed mutagenesis enhances the positive effect of Wnt-4 on terminal differentiation. These data indicate that thyroid hormone may regulate terminal differentiation of growth plate chondrocytes in part by modulating Wnt signaling pathways through the induction of CPZ and subsequent CPZ-enhanced activation of Wnt-4.

  13. Comparative metabolic pathway analysis with special reference to nucleotide metabolism-related genes in chicken primordial germ cells.

    PubMed

    Rengaraj, Deivendran; Lee, Bo Ram; Jang, Hyun-Jun; Kim, Young Min; Han, Jae Yong

    2013-01-01

    Metabolism provides energy and nutrients required for the cellular growth, maintenance, and reproduction. When compared with genomics and proteomics, metabolism studies provide novel findings in terms of cellular functions. In this study, we examined significant and differentially expressed genes in primordial germ cells (PGCs), gonadal stromal cells, and chicken embryonic fibroblasts compared with blastoderms using microarray. All upregulated genes (1001, 1118, and 974, respectively) and downregulated genes (504, 627, and 1317, respectively) in three test samples were categorized into functional groups according to gene ontology. Then all selected genes were tested to examine their involvement in metabolic pathways through Kyoto Encyclopedia of Genes and Genomes pathway database using overrepresentation analysis. In our results, most of the upregulated and downregulated genes were involved in at least one subcategory of seven major metabolic pathways. The main objective of this study is to compare the PGC expressed genes and their metabolic pathways with blastoderms, gonadal stromal cells, and chicken embryonic fibroblasts. Among the genes involved in metabolic pathways, a higher number of PGC upregulated genes were identified in retinol metabolism, and a higher number of PGC downregulated genes were identified in sphingolipid metabolism. In terms of the fold change, acyl-CoA synthetase medium-chain family member 3 (ACSM3), which is involved in butanoate metabolism, and N-acetyltransferase, pineal gland isozyme NAT-10 (PNAT10), which is involved in energy metabolism, showed higher expression in PGCs. To validate these gene changes, the expression of 12 nucleotide metabolism-related genes in chicken PGCs was examined by real-time polymerase chain reaction. The results of this study provide new information on the expression of genes associated with metabolism function of PGCs and will facilitate more basic research on animal PGC differentiation and function.

  14. Nosema ceranae alters a highly conserved hormonal stress pathway in honeybees.

    PubMed

    Mayack, C; Natsopoulou, M E; McMahon, D P

    2015-12-01

    Nosema ceranae, an emerging pathogen of the western honeybee (Apis mellifera), is implicated in recent pollinator losses and causes severe energetic stress. However, whether precocious foraging and accelerated behavioural maturation in infected bees are caused by the infection itself or via indirect energetic stress remains unknown. Using a combination of nutritional and infection treatments, we investigated how starvation and infection alters the regulation of adipokinetic hormone (AKH) and octopamine, two highly conserved physiological pathways that respond to energetic stress by mobilizing fat stores and increasing search activity for food. Although there was no response from AKH when bees were experimentally infected with N. ceranae or starved, supporting the notion that honeybees have lost this pathway, there were significant regulatory changes in the octopamine pathway. Significantly, we found no evidence of acute energetic stress being the only cause of symptoms associated with N. ceranae infection. Therefore, the parasite itself appears to alter regulatory components along a highly conserved physiological pathway in an infection-specific manner. This indicates that pathogen-induced behavioural alteration of chronically infected bees should not just be viewed as a coincidental short-term by-product of pathogenesis (acute energetic stress) and may be a result of a generalist manipulation strategy to obtain energy for reproduction.

  15. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.

    PubMed

    Suarez-Bregua, Paula; Torres-Nuñez, Eva; Saxena, Ankur; Guerreiro, Pedro; Braasch, Ingo; Prober, David A; Moran, Paloma; Cerda-Reverter, Jose Miguel; Du, Shao Jun; Adrio, Fatima; Power, Deborah M; Canario, Adelino V M; Postlethwait, John H; Bronner, Marianne E; Cañestro, Cristian; Rotllant, Josep

    2017-02-01

    Regulation of bone development, growth, and remodeling traditionally has been thought to depend on endocrine and autocrine/paracrine modulators. Recently, however, brain-derived signals have emerged as key regulators of bone metabolism, although their mechanisms of action have been poorly understood. We reveal the existence of an ancient parathyroid hormone (Pth)4 in zebrafish that was secondarily lost in the eutherian mammals' lineage, including humans, and that is specifically expressed in neurons of the hypothalamus and appears to be a central neural regulator of bone development and mineral homeostasis. Transgenic fish lines enabled mapping of axonal projections leading from the hypothalamus to the brainstem and spinal cord. Targeted laser ablation demonstrated an essential role for of pth4-expressing neurons in larval bone mineralization. Moreover, we show that Runx2 is a direct regulator of pth4 expression and that Pth4 can activate cAMP signaling mediated by Pth receptors. Finally, gain-of-function experiments show that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Based on our discovery and characterization of Pth4, we propose a model for evolution of bone homeostasis in the context of the vertebrate transition from an aquatic to a terrestrial lifestyle.-Suarez-Bregua, P., Torres-Nuñez, E., Saxena, A., Guerreiro, P., Braasch, I., Prober, D. A., Moran, P., Cerda-Reverter, J. M., Du, S. J., Adrio, F., Power, D. M., Canario, A. V. M., Postlethwait, J. H., Bronner, M E., Cañestro, C., Rotllant, J. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.

  16. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion.

    PubMed

    Sangiao-Alvarellos, Susana; Vázquez, María J; Varela, Luis; Nogueiras, Rubén; Saha, Asish K; Cordido, Fernando; López, Miguel; Diéguez, Carlos

    2009-10-01

    GH plays a major role in the regulation of lipid metabolism and alterations in GH axis elicit major changes in fat distribution and mobilization. For example, in patients with GH deficiency (GHD) or in mice lacking the GH receptor, the percentage of fat is increased. In addition to the direct actions of GH on lipid metabolism, current evidence indicates that ghrelin, a stomach-derived peptide hormone with potent GH secretagogue action, increases lipogenesis in white adipose tissue (WAT) through a hypothalamic-mediated mechanism. Still, the mechanism by which GH tone modulates ghrelin actions on WAT remains unclear. Here we investigated the effect of central ghrelin administration on lipid metabolism in lipogenic tissues (liver and WAT) in the absence of GH, by using a model for the study of GHD, namely the spontaneous dwarf rat, which shows increased body fat. Our data demonstrate that central chronic ghrelin administration regulates adipose lipid metabolism, mainly in a GH-independent fashion, as a result of increased mRNA, protein expression, and activity levels of fatty acid metabolism enzymes. On the contrary, central ghrelin regulates hepatic lipogenesis de novo in a GH-independent fashion but lipid mobilization in a GH-dependent fashion because carnitine palmitoyltransferase 1 was decreased only in wild-type Lewis rats. These findings suggest the existence of a new central nervous system-based neuroendocrine circuit, regulating metabolic homeostasis of adipose tissue. Understanding the molecular mechanism underlying the interplay between GH and ghrelin and their effects on lipid metabolism will provide new strategies for the design and development of suitable drugs for the treatment of GHD, obesity, and its comorbidities.

  17. Physiologically-based pharmacokinetic (PBPK) modeling of metabolic pathways of bromochloromethane

    EPA Science Inventory

    Bromochloromethane (BCM) is a volatile compound that if metabolized can lead to toxicity in different organs. Using a physiologically-based phannacokinetic model, we explore two hypotheses describing the metabolic pathways of BCM in rats: a two-pathway model exploiting both the e...

  18. Metabolism of 4-chloro-2-methylphenoxyacetate by a soil pseudomonad. Preliminary evidence for the metabolic pathway

    PubMed Central

    Gaunt, J. K.; Evans, W. C.

    1971-01-01

    1. A pseudomonad capable of utilizing the herbicide 4-chloro-2-methylphenoxyacetate as a sole carbon source was isolated from soil and cultured in liquid medium. 2. Analysis of induction patterns of 4-chloro-2-methylphenoxyacetate-grown cells suggests that 5-chloro-o-cresol and 5-chloro-3-methylcatechol are early intermediates in the oxidation of 4-chloro-2-methylphenoxyacetate. Cells were not adapted to oxidize 4-chloro-6-hydroxy-2-methylphenoxyacetate. 3. In culture, 4-chloro-2-methylphenoxyacetate rapidly disappeared and the chlorine in the molecule was quantitatively released as Cl− ion. 4. A lactone (γ-carboxymethylene-α-methyl-Δαβ-butenolide) was isolated from cultures and established as an intermediate. 5. The following metabolic pathway is suggested: 4-chloro-2-methylphenoxyacetate → 5-chloro-o-cresol → 5-chloro-3-methylcatechol → cis–cis-γ-chloro-α-methylmuconate → γ-carboxymethylene-α-methyl-Δαβ-butenolide → γ-hydroxy-α-methylmuconate. 6. The tentative identification of 5-chloro-o-cresol, a γ-chloro-α-methylmuconate and γ-hydroxy-α-methylmuconate in culture extracts supports this scheme. However, the catechol was never observed to accumulate in cultures. 7. The detection of 4-chloro-6-hydroxy-2-methylphenoxyacetate, 2-methyl-phenoxyacetate, a dehalogenated cresol and oxalate in culture extracts is discussed in relation to the proposed metabolic pathway. PMID:5123885

  19. Action of luteinizing hormone-releasing hormone: involvement of novel arachidonic acid metabolites.

    PubMed Central

    Snyder, G D; Capdevila, J; Chacos, N; Manna, S; Falck, J R

    1983-01-01

    Anterior pituitary cells were incubated in the presence of luteinizing hormone-releasing hormone and one of three inhibitors of arachidonic acid metabolism:indomethacin, an inhibitor of the cyclooxygenase system; nordihydroguaiaretic acid, an antioxidant that inhibits lipoxygenase; and icosatetraynoic acid, an acetylenic analogue of arachidonic acid that blocks all known pathways of arachidonic acid metabolism. Indomethacin was ineffective in blocking luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Nordihydroguaiaretic acid was only marginally capable of inhibiting luteinizing hormone-releasing hormone-stimulated luteinizing hormone secretion. Icosatetraynoic acid at 10 microM completely inhibited stimulated luteinizing hormone secretion. Addition of several epoxygenated arachidonic acid metabolites to cells in vitro resulted in secretion of luteinizing hormone equal to or greater than that induced by 10 nM luteinizing hormone-releasing hormone. The half-maximal effective dose for these compounds was approximately 50 nM. The 5,6-epoxyicosatrienoic acid was the most potent of the compounds tested. These studies suggest that luteinizing hormone-releasing hormone-stimulated luteinizing hormone release is closely coupled with the production of oxidized arachidonic acid metabolites. Moreover, one or more of the epoxygenated arachidonic acid metabolites might be a component of the cascade of reactions initiated by luteinizing hormone-releasing hormone that ultimately results in secretion of luteinizing hormone. PMID:6344087

  20. Regulation of respiration in plants: a role for alternative metabolic pathways.

    PubMed

    van Dongen, Joost T; Gupta, Kapuganti J; Ramírez-Aguilar, Santiago J; Araújo, Wagner L; Nunes-Nesi, Adriano; Fernie, Alisdair R

    2011-08-15

    Respiratory metabolism includes the reactions of glycolysis, the tricarboxylic acid cycle and the mitochondrial electron transport chain, but is also directly linked with many other metabolic pathways such as protein and lipid biosynthesis and photosynthesis via photorespiration. Furthermore, any change in respiratory activity can impact the redox status of the cell and the production of reactive oxygen species. In this review, it is discussed how respiration is regulated and what alternative pathways are known that increase the metabolic flexibility of this vital metabolic process. By looking at the adaptive responses of respiration to hypoxia or changes in the oxygen availability of a cell, the integration of regulatory responses of various pathways is illustrated.

  1. Transcriptional regulation of neurodevelopmental and metabolic pathways by NPAS3.

    PubMed

    Sha, L; MacIntyre, L; Machell, J A; Kelly, M P; Porteous, D J; Brandon, N J; Muir, W J; Blackwood, D H; Watson, D G; Clapcote, S J; Pickard, B S

    2012-03-01

    The basic helix-loop-helix PAS (Per, Arnt, Sim) domain transcription factor gene NPAS3 is a replicated genetic risk factor for psychiatric disorders. A knockout (KO) mouse model exhibits behavioral and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 etiopathology, we combined immunofluorescent, transcriptomic and metabonomic approaches. Intense Npas3 immunoreactivity was observed in the hippocampal subgranular zone-the site of adult neurogenesis--but was restricted to maturing, rather than proliferating, neuronal precursor cells. Microarray analysis of a HEK293 cell line over-expressing NPAS3 showed that transcriptional targets varied according to circadian rhythm context and C-terminal deletion. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was just one of many NPAS3 target genes also regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental function. The parallel repression of multiple glycolysis genes by NPAS3 reveals a second role in the regulation of glucose metabolism. Comparison of wild-type and Npas3 KO metabolite composition using high-resolution mass spectrometry confirmed these transcriptional findings. KO brain tissue contained significantly altered levels of NAD(+), glycolysis metabolites (such as dihydroxyacetone phosphate and fructose-1,6-bisphosphate), pentose phosphate pathway components and Kreb's cycle intermediates (succinate and α-ketoglutarate). The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of mental illness etiology, and may provide a mechanism for innate and medication-induced susceptibility to diabetes commonly reported in psychiatric patients.

  2. Neural-metabolic coupling in the central visual pathway.

    PubMed

    Freeman, Ralph D; Li, Baowang

    2016-10-05

    Studies are described which are intended to improve our understanding of the primary measurements made in non-invasive neural imaging. The blood oxygenation level-dependent signal used in functional magnetic resonance imaging (fMRI) reflects changes in deoxygenated haemoglobin. Tissue oxygen concentration, along with blood flow, changes during neural activation. Therefore, measurements of tissue oxygen together with the use of a neural sensor can provide direct estimates of neural-metabolic interactions. We have used this relationship in a series of studies in which a neural microelectrode is combined with an oxygen micro-sensor to make simultaneous co-localized measurements in the central visual pathway. Oxygen responses are typically biphasic with small initial dips followed by large secondary peaks during neural activation. By the use of established visual response characteristics, we have determined that the oxygen initial dip provides a better estimate of local neural function than the positive peak. This contrasts sharply with fMRI for which the initial dip is unreliable. To extend these studies, we have examined the relationship between the primary metabolic agents, glucose and lactate, and associated neural activity. For this work, we also use a Doppler technique to measure cerebral blood flow (CBF) together with neural activity. Results show consistent synchronously timed changes such that increases in neural activity are accompanied by decreases in glucose and simultaneous increases in lactate. Measurements of CBF show clear delays with respect to neural response. This is consistent with a slight delay in blood flow with respect to oxygen delivery during neural activation.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.

  3. A Newton Cooperative Genetic Algorithm Method for In Silico Optimization of Metabolic Pathway Production

    PubMed Central

    Mohamad, Mohd Saberi; Abdullah, Afnizanfaizal

    2015-01-01

    This paper presents an in silico optimization method of metabolic pathway production. The metabolic pathway can be represented by a mathematical model known as the generalized mass action model, which leads to a complex nonlinear equations system. The optimization process becomes difficult when steady state and the constraints of the components in the metabolic pathway are involved. To deal with this situation, this paper presents an in silico optimization method, namely the Newton Cooperative Genetic Algorithm (NCGA). The NCGA used Newton method in dealing with the metabolic pathway, and then integrated genetic algorithm and cooperative co-evolutionary algorithm. The proposed method was experimentally applied on the benchmark metabolic pathways, and the results showed that the NCGA achieved better results compared to the existing methods. PMID:25961295

  4. [Hormonal regulation of lipoprotein metabolism: the role in pathogenesis of coronary heart disease].

    PubMed

    Sokolov, E I; Metel'skaia, V A; Perova, N V; Shchukina, G N

    2006-01-01

    The character and role of hormonal dysregulation of lipoprotein metabolism during postprandial hyperlipemia were studied in patients with coronary heart disease (CHD) and hyperthyroidism as compared with healthy subjects. Pronounced hypertriglyceridemia alongside with the decreased high density lipoprotein cholesterol (HDL C) after standard fat load were associated with increased level of insulin and decreased level of cortisol. Moreover, in CHD patients fasting hyperinsulinemia becoming even stronger postprandially resulted in prevalence of antilipolytic action of insulin over lipid-mobilizing effect of cortisol; and an extended postprandial hypertriglyceridemia took place. Patients with hyperthyroidism and low cholesterol level both in atherogenic LDL and antiatherogenic HDL, demonstrated decreased level of apo AI (as in CHD patients) and apo B (three times lower than in CHD patients). Very low ratio of apo B/AI in patients with hyperthyroidism both in fasting and postprandial state was a clear indication of their lipoprotein profile antiatherogeneity. Thus, in patients with hyperthyroidism despite of low HDL C and apo AI levels, antiatherogenic properties of lipoprotein profile are probably determined by very low apo B/AI ratio induced by thyroid hormones, and might be explained by the influence of thyroid hormones on the expression of genes coding these apoproteins.

  5. Relation with HOMA-IR and thyroid hormones in obese Turkish women with metabolic syndrome.

    PubMed

    Topsakal, S; Yerlikaya, E; Akin, F; Kaptanoglu, B; Erürker, T

    2012-03-01

    The aim of this study was to investigate the relationship between insulin resistance and thyroid function in obese pre- and postmenopausal women with or without metabolic syndrome (MetS). 141 obese women were divided into two groups, HOMA-IR<2.7 and HOMA-IR>2.7, to evaluate relation with HOMA-IR and fatness, hormone and blood parameters. They were then divided into four groups as pre- and postmenopausal with or without MetS. Various fatness, hormone and blood parameters were examined. Statistically significant difference was found in weight, body mass index (BMI), waist circumference, fat%, fasting insulin, TSH, FT3, FT4, FSH, Anti-microsomal antibody (ANTIM) and triglycerides levels in HOMA-IR<2.7 and HOMA-IR>2.7 obese Turkish women. This study showed that age, weight, BMI, waist circumference, fat%, fasting insulin, FT3, ANTIM, FSH, LH, total cholesterol, triglycerides, HDL, HOMA-IR, systolic and diastolic blood pressure levels were related in preand post menopausal status in obese women with or without MetS. Obesity may influence the levels of thyroid hormones and increases the risk of MetS in women. Postmenopausal status with MetS is associated with an increased TSH, FT3 and FT4 levels and HOMA-IR in obese women. Strong relation was observed with MetS and TSH and FT3 levels.

  6. Transdermal hormone therapy in postmenopausal women: A review of metabolic effects and drug delivery technologies

    PubMed Central

    Kopper, Nathan W; Gudeman, Jennifer; Thompson, Daniel J

    2008-01-01

    Vasomotor symptoms (VMS) associated with menopause can cause significant discomfort and decrease the quality of life for women in the peri-menopausal and post-menopausal stages of life. Hormone therapy (HT) is the mainstay of treatment for menopausal symptoms and is currently the only therapy proven effective for VMS. Numerous HT options are available to treat VMS, including estrogen-only and estrogen-progestogen combination products to meet the needs of both hysterectomized and nonhysterectomized women. In addition to selecting an appropriate estrogen or estrogen-progestogen combination, consideration should be given to the route of administration to best suit the needs of the patient. Delivery systems for hormone therapy include oral tablets, transdermal patches, transdermal topical (nonpatch) products, and intravaginal preparations. Oral is currently the most commonly utilized route of administration in the United States. However, evidence suggests that oral delivery may lead to some undesirable physiologic effects caused by significant gut and hepatic metabolism. Transdermal drug delivery may mitigate some of these effects by avoiding gut and hepatic first-pass metabolism. Advantages of transdermal delivery include the ability to administer unmetabolized estradiol directly to the blood stream, administration of lower doses compared to oral products, and minimal stimulation of hepatic protein production. Several estradiol transdermal delivery technologies are available, including various types of patches, topical gels, and a transdermal spray. PMID:19920906

  7. Interrelationship between feeding level and the metabolic hormones leptin, ghrelin and obestatin in control of chicken egg laying and release of ovarian hormones.

    PubMed

    Sirotkin, Alexander V; Grossmann, Roland

    2015-06-01

    The aim of the present experiment is to examine the role of nutritional status, metabolic hormones and their interrelationships in the control of chicken ovarian ovulatory and secretory activity. For this purpose, we identified the effect of food restriction, administration of leptin, ghrelin 1-18, obestatin and combinations of food restriction with these hormones for 3days on chicken ovulation (egg laying) rate and ovarian hormone release. The release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) by isolated and cultured ovarian fragments was determined by EIA. It was observed that food restriction significantly reduced the egg-laying rate, T, E and AVT release and promoted P output by ovarian fragments. Leptin, administrated to ad libitum-fed chickens, did not change these parameters besides promoting E release. Nevertheless, administration of leptin was able to prevent the effect of food restriction on ovulation, T and E (but not P or AVT) release. Ghrelin 1-18 administration to ad libitum-fed birds did not affect the measured parameters besides a reduction in P release. Ghrelin 1-18 administration prevented the food restriction-induced decrease in ovarian T, E and AVT, but it did not change P output or egg laying. Obestatin administrated to control chicken promoted their ovarian P, E and inhibited ovarian AVT release but did not affect egg laying. It was able to promote the effect of food restriction on P, T and AVT, but not E release or egg laying. Our results (1) confirm an inhibitory effect of food restriction on chicken ovulation rate; (2) shows that food restriction-induced reduction in egg laying is associated with a decrease in ovarian T, E and AVT and an increase in ovarian P release; (3) confirm the involvement of metabolic hormones leptin, ghrelin and obestatin in the control of chicken ovarian hormones output; and (4) the ability of metabolic hormones to mimic/antagonize or prevent/promote the effects of food

  8. Thyroid hormones correlate with field metabolic rate in ponies, Equus ferus caballus.

    PubMed

    Brinkmann, Lea; Gerken, Martina; Hambly, Catherine; Speakman, John R; Riek, Alexander

    2016-08-15

    During winter, free-living herbivores are often exposed to reduced energy supply at the same time that energy needs for thermoregulation increase. Several wild herbivores as well as robust horse breeds reduce their metabolism during times of low ambient temperature and food shortage. Thyroid hormones (THs) affect metabolic intensity and a positive effect of THs on basal metabolic rate (BMR) has been demonstrated in mammals and birds. As BMR and field metabolic rate (FMR) are often assumed to be intrinsically linked, THs may represent a reliable indicator for FMR. To test this hypothesis, 10 Shetland pony mares were kept under semi-extensive central European conditions. During the winter season, one group was fed 60% and one group 100% of their maintenance energy requirements. We measured FMR, locomotor activity, resting heart rate and TH levels in summer and winter. FMR, locomotor activity, resting heart rate and total T3 concentrations decreased substantially in winter compared with summer, whereas total T4 increased. Food restriction led to a reduced FMR and resting heart rate, while THs and locomotor activity were not affected. Across both seasons, FMR, resting heart rate and locomotor activity were positively correlated with total T3 but negatively and more weakly correlated with total T4.

  9. Metabolic strategies in wild male Barbary macaques: evidence from faecal measurement of thyroid hormone

    PubMed Central

    2016-01-01

    Selection is expected to favour the evolution of flexible metabolic strategies, in response to environmental conditions. Here, we use a non-invasive index of basal metabolic rate (BMR), faecal thyroid hormone (T3) levels, to explore metabolic flexibility in a wild mammal inhabiting a highly seasonal, challenging environment. T3 levels of adult male Barbary macaques in the Atlas Mountains, Morocco, varied markedly over the year; temporal patterns of variation differed between a wild-feeding and a provisioned group. Overall, T3 levels were related to temperature, foraging time (linked to food availability) and intensity of mating activity, and were higher in the provisioned than in the wild-feeding group. In both groups, T3 levels began to increase markedly one month before the start of the mating season, peaking four to six weeks into this period, and at a higher level in the wild-feeding group. Our results suggest that while both groups demonstrate marked metabolic flexibility, responding similarly to ecological and social challenges, such flexibility is affected by food availability. This study provides new insights into the way Barbary macaques respond to the multiple demands of their environment. PMID:27095269

  10. Hormone and receptor interplay in the regulation of mosquito lipid metabolism.

    PubMed

    Wang, Xueli; Hou, Yuan; Saha, Tusar T; Pei, Gaofeng; Raikhel, Alexander S; Zou, Zhen

    2017-03-28

    Mosquitoes transmit devastating human diseases because they need vertebrate blood for egg development. Metabolism in female mosquitoes is tightly coupled with blood meal-mediated reproduction, which requires an extremely high level of energy consumption. Functional analysis has shown that major genes encoding for enzymes involved in lipid metabolism (LM) in the mosquito fat bodies are down-regulated at the end of the juvenile hormone (JH)-controlled posteclosion (PE) phase but exhibit significant elevation in their transcript levels during the post-blood meal phase (PBM), which is regulated mainly by 20-hydroxyecdysone (20E). Reductions in the transcript levels of genes encoding triacylglycerol (TAG) catabolism and β-oxidation enzymes were observed to correlate with a dramatic accumulation of lipids in the PE phase; in contrast, these transcripts were elevated significantly and lipid stores were diminished during the PBM phase. The RNAi depletion of Methoprene-tolerant (Met) and ecdysone receptor (EcR), receptors for JH and 20E, respectively, reversed the LM gene expression and the levels of lipid stores and metabolites, demonstrating the critical roles of these hormones in LM regulation. Hepatocyte nuclear factor 4 (HNF4) RNAi-silenced mosquitoes exhibited down-regulation of the gene transcripts encoding TAG catabolism and β-oxidation enzymes and an inability to use lipids effectively, as manifested by TAG accumulation. The luciferase reporter assay showed direct regulation of LM-related genes by HNF4. Moreover, HNF4 gene expression was down-regulated by Met and activated by EcR and Target of rapamycin, providing a link between nutritional and hormonal regulation of LM in female mosquitoes.

  11. Electron attachment to antipyretics: Possible implications of their metabolic pathways

    NASA Astrophysics Data System (ADS)

    Pshenichnyuk, Stanislav A.; Modelli, Alberto

    2012-06-01

    The empty-level structures and formation of negative ion states via resonance attachment of low-energy (0-15 eV) electrons into vacant molecular orbitals in a series of non-steroidal anti-inflammatory drugs (NSAIDs), namely aspirin, paracetamol, phenacetin, and ibuprofen, were investigated in vacuo by electron transmission and dissociative electron attachment (DEA) spectroscopies, with the aim to model the behavior of these antipyretic agents under reductive conditions in vivo. The experimental findings are interpreted with the support of density functional theory calculations. The negative and neutral fragments formed by DEA in the gas phase display similarities with the main metabolites of these commonly used NSAIDs generated in vivo by the action of cytochrome P450 enzymes, as well as with several known active agents. It is concluded that xenobiotic molecules which possess pronounced electron-accepting properties could in principle follow metabolic pathways which parallel the gas-phase dissociative decay channels observed in the DEA spectra at incident electron energies below 1 eV. Unwanted side effects as, e.g., hepatoxicity or carcinogenicity produced by the NSAIDs under study in human organism are discussed within the "free radical model" framework, reported earlier to describe the toxic action of the well-known model toxicant carbon tetrachloride.

  12. Metabolic engineering of cottonseed oil biosynthesis pathway via RNA interference

    PubMed Central

    Xu, Zhongping; Li, Jingwen; Guo, Xiaoping; Jin, Shuangxia; Zhang, Xianlong

    2016-01-01

    Cottonseed oil is recognized as an important oil in food industry for its unique characters: low flavor reversion and the high level of antioxidants (VitaminE) as well as unsaturated fatty acid. However, the cottonseed oil content of cultivated cotton (Gossypium hirsutum) is only around 20%. In this study, we modified the accumulation of oils by the down-regulation of phosphoenolpyruvate carboxylase 1 (GhPEPC1) via RNA interference in transgenic cotton plants. The qRT-PCR and enzyme activity assay revealed that the transcription and expression of GhPEPC1 was dramatically down-regulated in transgenic lines. Consequently, the cottonseed oil content in several transgenic lines showed a significant (P < 0.01) increase (up to 16.7%) without obvious phenotypic changes under filed condition when compared to the control plants. In order to elucidate the molecular mechanism of GhPEPC1 in the regulation of seed oil content, we quantified the expression of the carbon metabolism related genes of transgenic GhPEPC1 RNAi lines by transcriptome analysis. This analysis revealed the decrease of GhPEPC1 expression led to the increase expression of triacylglycerol biosynthesis-related genes, which eventually contributed to the lipid biosynthesis in cotton. This result provides a valuable information for cottonseed oil biosynthesis pathway and shows the potential of creating high cottonseed oil germplasm by RNAi strategy for cotton breeding. PMID:27620452

  13. Thyroid hormone inhibits the proliferation of piglet Sertoli cell via PI3K signaling pathway.

    PubMed

    Sun, Yan; Yang, WeiRong; Luo, HongLin; Wang, XianZhong; Chen, ZhongQiong; Zhang, JiaoJiao; Wang, Yi; Li, XiaoMin

    2015-01-01

    Accumulating researches show that thyroid hormone (TH) inhibits Sertoli cells (SCs) proliferation and stimulates their functional maturation in prepubertal rat testis, confirming that TH plays a key role in testicular development. However, the mechanism under the T3 regulation of piglet SC proliferation remains unclear. In the present study, in order to investigate the possible mechanism of T3 on the suppression of SC proliferation, the expression pattern of TRα1 and cell cycle-related molecules, effect of T3 on SC proliferation, and the role of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway on the T3-mediated SC proliferation in piglet testis were explored. Our results demonstrated that TRα1 was expressed in all tested stages of SCs and decreased along with the ages. T3 inhibited the proliferation of SCs in a time- and dose-dependent manner, and T3 treatment downregulated the expressions of cell cycling molecules, such as cyclinA2, cyclinD1, cyclinE1, PCNA, and Skp2, but upregulated the p27 expression in SCs. Most importantly, the suppressive effects of T3 on SC proliferation seemed dependent on the inhibition of PI3K/Akt signaling pathway, and pre-stimulation of PI3K could enhance such suppressive effects. Together, our findings demonstrate that TH inhibits the proliferation of piglet SCs via the suppression of PI3K/Akt signaling pathway.

  14. The Gustatory Signaling Pathway and Bitter Taste Receptors Affect the Development of Obesity and Adipocyte Metabolism in Mice

    PubMed Central

    Avau, Bert; Bauters, Dries; Steensels, Sandra; Vancleef, Laurien; Laermans, Jorien; Lesuisse, Jens; Buyse, Johan; Lijnen, H. Roger; Tack, Jan; Depoortere, Inge

    2015-01-01

    Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R) have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/-) mice became less obese than wild type (WT) mice when fed a high-fat diet (HFD). White adipose tissue (WAT) mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT) thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB) or quinine (Q) during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB), but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism. PMID:26692363

  15. Regulatory mechanism of protein metabolic pathway during the differentiation process of chicken male germ cell.

    PubMed

    Li, Dong; Zuo, Qisheng; Lian, Chao; Zhang, Lei; Shi, Qingqing; Zhang, Zhentao; Wang, Yingjie; Ahmed, Mahmoud F; Tang, Beibei; Xiao, Tianrong; Zhang, Yani; Li, Bichun

    2015-08-01

    We explored the regulatory mechanism of protein metabolism during the differentiation process of chicken male germ cells and provide a basis for improving the induction system of embryonic stem cell differentiation to male germ cells in vitro. We sequenced the transcriptome of embryonic stem cells, primordial germ cells, and spermatogonial stem cells with RNA sequencing (RNA-Seq), bioinformatics analysis methods, and detection of the key genes by quantitative reverse transcription PCR (qRT-PCR). Finally, we found 16 amino acid metabolic pathways enriched in the biological metabolism during the differentiation process of embryonic stem cells to primordial germ cells and 15 amino acid metabolic pathways enriched in the differentiation stage of primordial germ cells to spermatogonial stem cells. We found three pathways, arginine-proline metabolic pathway, tyrosine metabolic pathway, and tryptophan metabolic pathway, significantly enriched in the whole differentiation process of embryonic stem cells to spermatogonial stem cells. Moreover, for these three pathways, we screened key genes such as NOS2, ADC, FAH, and IDO. qRT-PCR results showed that the expression trend of these genes were the same to RNA-Seq. Our findings showed that the three pathways and these key genes play an important role in the differentiation process of embryonic stem cells to male germ cells. These results provide basic information for improving the induction system of embryonic stem cell differentiation to male germ cells in vitro.

  16. Endogenous hormone concentrations correlate with fructan metabolism throughout the phenological cycle in Chrysolaena obovata

    PubMed Central

    Rigui, Athos Poli; Gaspar, Marília; Oliveira, Vanessa F.; Purgatto, Eduardo; de Carvalho, Maria Angela Machado

    2015-01-01

    the entry into dormancy. Conclusions The results show that fructan metabolism correlates well with endogenous hormone concentrations and environmental changes, suggesting that the co-ordinated action of carbohydrate metabolism and hormone synthesis enables C. obovata to survive unfavourable field conditions. Endogenous hormone concentrations seem to be related to regulation of fructan metabolism and to the transition between phenophases, signalling for energy storage, reserve mobilization and accumulation of oligosaccharides as osmolytes. PMID:25921788

  17. Sex steroids and growth hormone interactions.

    PubMed

    Fernández-Pérez, Leandro; de Mirecki-Garrido, Mercedes; Guerra, Borja; Díaz, Mario; Díaz-Chico, Juan Carlos

    2016-04-01

    GH and sex hormones are critical regulators of body growth and composition, somatic development, intermediate metabolism, and sexual dimorphism. Deficiencies in GH- or sex hormone-dependent signaling and the influence of sex hormones on GH biology may have a dramatic impact on liver physiology during somatic development and in adulthood. Effects of sex hormones on the liver may be direct, through hepatic receptors, or indirect by modulating endocrine, metabolic, and gender-differentiated functions of GH. Sex hormones can modulate GH actions by acting centrally, regulating pituitary GH secretion, and peripherally, by modulating GH signaling pathways. The endocrine and/or metabolic consequences of long-term exposure to sex hormone-related compounds and their influence on the GH-liver axis are largely unknown. A better understanding of these interactions in physiological and pathological states will contribute to preserve health and to improve clinical management of patients with growth, developmental, and metabolic disorders.

  18. Genome-Wide Prediction of Metabolic Enzymes, Pathways, and Gene Clusters in Plants1[OPEN

    PubMed Central

    Zhang, Peifen; Kim, Taehyong; Banf, Michael; Chavali, Arvind K.; Nilo-Poyanco, Ricardo; Bernard, Thomas

    2017-01-01

    Plant metabolism underpins many traits of ecological and agronomic importance. Plants produce numerous compounds to cope with their environments but the biosynthetic pathways for most of these compounds have not yet been elucidated. To engineer and improve metabolic traits, we need comprehensive and accurate knowledge of the organization and regulation of plant metabolism at the genome scale. Here, we present a computational pipeline to identify metabolic enzymes, pathways, and gene clusters from a sequenced genome. Using this pipeline, we generated metabolic pathway databases for 22 species and identified metabolic gene clusters from 18 species. This unified resource can be used to conduct a wide array of comparative studies of plant metabolism. Using the resource, we discovered a widespread occurrence of metabolic gene clusters in plants: 11,969 clusters from 18 species. The prevalence of metabolic gene clusters offers an intriguing possibility of an untapped source for uncovering new metabolite biosynthesis pathways. For example, more than 1,700 clusters contain enzymes that could generate a specialized metabolite scaffold (signature enzymes) and enzymes that modify the scaffold (tailoring enzymes). In four species with sufficient gene expression data, we identified 43 highly coexpressed clusters that contain signature and tailoring enzymes, of which eight were characterized previously to be functional pathways. Finally, we identified patterns of genome organization that implicate local gene duplication and, to a lesser extent, single gene transposition as having played roles in the evolution of plant metabolic gene clusters. PMID:28228535

  19. Twenty-four-hour profiles of metabolic and stress hormones in sheep selected for a calm or nervous temperament.

    PubMed

    Rietema, S E; Blackberry, M A; Maloney, S K; Martin, G B; Hawken, P A R; Blache, D

    2015-10-01

    Even in the absence of stressors, temperament is associated with changes in the concentration of stress-responsive hormones and, possibly because of such changes, temperament can affect metabolism. We tested whether, in sheep bred for temperament for 14 generations, "nervous" females have greater concentrations of stress-responsive hormones in the absence of stressors than "calm" females, and whether these differences are associated with changes in the concentrations of metabolic hormones. In resting "calm" (n = 8) and "nervous" (n = 8) sheep, concentrations of cortisol, prolactin, leptin, and insulin were measured in blood plasma sampled via jugular catheter every 20 min for 24 h. The animals were individually penned, habituated to their housing and human handling over 7 wk, and fed before sampling began. Diurnal variation was evident for all hormones, but a 24-h cortisol pattern was detected in only 7 individuals. There was no effect of temperament on any aspect of concentrations of cortisol or prolactin, but "calm" animals had greater concentrations of insulin in the early afternoon than "nervous" animals (14.5 ± 1.1 vs 10.0 ± 1.6 μU/mL; P = 0.038), and a similar tendency was seen for leptin (P = 0.092). We conclude that selection for temperament affects the concentration of metabolic hormones in the absence of stressors, but this effect is independent of stress-responsive hormones.

  20. Genetic analysis of a novel pathway for D-xylose metabolism in Caulobacter crescentus.

    PubMed

    Stephens, Craig; Christen, Beat; Fuchs, Thomas; Sundaram, Vidyodhaya; Watanabe, Kelly; Jenal, Urs

    2007-03-01

    Genetic data suggest that the oligotrophic freshwater bacterium Caulobacter crescentus metabolizes D-xylose through a pathway yielding alpha-ketoglutarate, comparable to the recently described L-arabinose degradation pathway of Azospirillum brasilense. Enzymes of the C. crescentus pathway, including an NAD(+)-dependent xylose dehydrogenase, are encoded in the xylose-inducible xylXABCD operon (CC0823-CC0819).

  1. DISTURBANCES IN CALCIUM METABOLISM AND CARDIOMYOCYTE NECROSIS: THE ROLE OF CALCITROPIC HORMONES

    PubMed Central

    Yusuf, Jawwad; Khan, M. Usman; Cheema, Yaser; Bhattacharya, Syamal K.; Weber, Karl T.

    2012-01-01

    Summary A synchronized dyshomeostasis of extra- and intracellular Ca2+, expressed as plasma ionized hypocalcemia and excessive intracellular Ca2+ accumulation, respectively, represents a common pathophysiologic scenario that accompanies a number of diverse disorders. These include low-renin and salt-sensitive hypertension, primary aldosteronism and hyperparathyroidism, congestive heart failure, acute and chronic hyperadrenergic stressor states, high dietary Na+, and low dietary Ca2+ with hypovitaminosis D. Homeostatic responses are invoked to restore normal extracellular [Ca2+]o, including increased plasma levels of parathyroid hormone and 1,25(OH)2D3. However, in cardiomyocytes, these calcitropic hormones concurrently promote cytosolic free [Ca2+]i and mitochondrial [Ca2+]m overloading. The latter sets into motion organellar-based oxidative stress, in which the rate of reactive oxygen species generation overwhelms their detoxification by endogenous antioxidant defenses, including those related to intrinsically coupled increments in intracellular Zn2+. In turn, the opening potential of the mitochondrial permeability transition pore increases allowing for osmotic swelling and ensuing organellar degeneration. Collectively, these pathophysiologic events represent the major components to a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis. From necrotic cells there follows a spillage of intracellular contents, including troponins, and a subsequent wound healing response with reparative fibrosis, or scarring. Taken together the loss of terminally differentiated cardiomyocytes from this postmitotic organ and the ensuing replacement fibrosis each contribute to the adverse structural remodeling of myocardium and progressive nature of heart failure. In conclusion, hormone-induced ionized hypocalcemia and intracellular Ca2+ overloading comprise a pathophysiologic cascade common to diverse disorders and which initiates a mitochondriocentric

  2. Effect of oxytocin on serum biochemistry, liver enzymes, and metabolic hormones in lactating Nili Ravi buffaloes.

    PubMed

    Iqbal, Zafar; ur Rahman, Zia; Muhammad, Faqir; Akhtar, Masood; Awais, Mian Muhammad; Khaliq, Tanweer; Nasir, Amar; Nadeem, Muhammad; Khan, Kinza; Arshad, Hafiz Muhammad; Basit, Muhammad Abdul

    2015-01-01

    Studies reporting the effects of oxytocin on the health of lactating animals are lacking and still no such data is available on Nili Ravi buffalo, the most prominent Asian buffalo breed. The present study was conducted to investigate the effect of oxytocin on physiological and metabolic parameters of lactating Nili Ravi buffaloes. Healthy lactating buffaloes (n = 40) of recent calving were selected from a commercial dairy farm situated in the peri-urban area of district Faisalabad, Pakistan. These buffaloes were randomly allocated to two equal groups viz experimental and control, comprising 20 animals each. Twice-a-day (morning and evening) milking practice was followed. The experimental and control buffaloes were administered subcutaneously with 3 mL of oxytocin (10 IU/mL) and normal saline respectively, prior to each milking. Serum biochemical profile including glucose, total cholesterol (tChol), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), total proteins (TP), C-reactive protein (CRP), liver enzymes aspartate transaminase (AST), alanine transaminase (ALT), and metabolic hormones triiodothyronine (T₃) and thyroxine (T₄) were studied. Results revealed significantly higher (P ≤ 0.01) levels of glucose, total cholesterol, LDL-C, triglycerides, total proteins, and C-reactive protein in experimental (oxytocin-injected) lactating buffaloes compared to control group. Liver enzymes AST and ALT as well as serum T₄ concentration was significantly higher (P ≤ 0.01) in oxytocin-injected lactating buffaloes as compared to control animals. It was concluded that oxytocin had the key role in increasing the metabolic parameters and hormones, resulting in the optimization of production. But, at the same time, it may pose a threat to the animal health.

  3. Wolbachia-induced paternal defect in Drosophila is likely by interaction with the juvenile hormone pathway.

    PubMed

    Liu, Chen; Wang, Jia-Lin; Zheng, Ya; Xiong, En-Juan; Li, Jing-Jing; Yuan, Lin-Ling; Yu, Xiao-Qiang; Wang, Yu-Feng

    2014-06-01

    Wolbachia are endosymbionts that infect many insect species. They can manipulate the host's reproduction to increase their own maternal transmission. Cytoplasmic incompatibility (CI) is one such manipulation, which is expressed as embryonic lethality when Wolbachia-infected males mate with uninfected females. However, matings between males and females carrying the same Wolbachia strain result in viable progeny. The molecular mechanisms of CI are currently not clear. We have previously reported that the gene Juvenile hormone-inducible protein 26 (JhI-26) exhibited the highest upregulation in the 3rd instar larval testes of Drosophila melanogaster when infected by Wolbachia. This is reminiscent of an interaction between Wolbachia and juvenile hormone (JH) pathway in flies. Considering that Jhamt gene encodes JH acid methyltransferase, a key regulatory enzyme of JH biosynthesis, and that methoprene-tolerant (Met) has been regarded as the best JH receptor candidate, we first compared the expression of Jhamt and Met between Wolbachia-infected and uninfected fly testes to investigate whether Wolbachia infection influence the JH signaling pathway. We found that the expressions of Jhamt and Met were significantly increased in the presence of Wolbachia, suggesting an interaction of Wolbachia with the JH signaling pathway. Then, we found that overexpression of JhI-26 in Wolbachia-free transgenic male flies caused paternal-effect lethality that mimics the defects associated with CI. JhI-26 overexpressing males resulted in significantly decrease in hatch rate. Surprisingly, Wolbachia-infected females could rescue the egg hatch. In addition, we showed that overexpression of JhI-26 caused upregulation of the male accessory gland protein (Acp) gene CG10433, but not vice versa. This result suggests that JhI-26 may function at the upstream of CG10433. Likewise, overexpression of CG10433 also resulted in paternal-effect lethality. Both JhI-26 and CG10433 overexpressing males

  4. EvoMS: An evolutionary tool to find de novo metabolic pathways.

    PubMed

    Gerard, Matias F; Stegmayer, Georgina; Milone, Diego H

    2015-08-01

    The evolutionary metabolic synthesizer (EvoMS) is an evolutionary tool capable of finding novel metabolic pathways linking several compounds through feasible reactions. It allows system biologists to explore different alternatives for relating specific metabolites, offering the possibility of indicating the initial compound or allowing the algorithm to automatically select it. Searching process can be followed graphically through several plots of the evolutionary process. Metabolic pathways found are displayed in a web browser as directed graphs. In all cases, solutions are networks of reactions that produce linear or branched metabolic pathways which are feasible from the specified set of available compounds. Source code of EvoMS is available at http://sourceforge.net/projects/sourcesinc/files/evoms/. Subsets of reactions are provided, as well as four examples for searching metabolic pathways among several compounds. Available as a web service at http://fich.unl.edu.ar/sinc/web-demo/evoms/.

  5. Impaired counterregulatory hormonal and metabolic response to exhaustive exercise in obese subjects.

    PubMed

    Vettor, R; Macor, C; Rossi, E; Piemonte, G; Federspil, G

    1997-08-01

    A reduction of postprandial thermogenesis has been described in obesity; insulin resistance and/or decreased sympathetic nervous system activity seem to play the major role in its pathogenesis. On the other hand, a normal energy expenditure during exercise has been reported. At present, the response and the role of catecholamines in energy metabolism during exercise in obesity have not been well clarified yet. The aim of this work was to study the metabolic and hormonal changes caused by intense exercise in obesity. Nine obese subjects and ten normal weight controls were submitted to exhaustive exercise on a cycloergometer. Blood glucose, free fatty acids (FFA), glycerol, lactate, beta-OH-butyrate, insulin, glucagon, plasma growth hormone (HGH), catecholamine plasma levels were assayed before and at the end of exercise, and after a recovery period. The energy cost of exercise was evaluated by indirect calorimetry. In our experiment muscular exercise did not provoke any change in blood glucose and FFA plasma levels in either of our groups. In the obese subjects the insulin plasma levels were higher than in the controls. Glucagon plasma levels did not change. The exercise responses of norepinephrine (NE) (4.28 +/- 0.74 vs 8.81 +/- 1.35 nmol/l; P < 0.01), epinephrine (E) (234.21 +/- 64.18 vs 560.51 +/- 83.38 pmol/l; P < 0.01) and plasma growth hormone (HGH) (134.84 +/- 58.97 vs 825.92 +/- 195.25 pmol/l; P < 0.01) were significantly lower in obese subjects. At the end of exercise, the thermic effect of exercise did not differ between obese and control subjects (0.335 +/- 0.038 vs 0.425 +/- 0.040 kJ/min x kg fat-free mass. Our findings indicate that an impaired counterregulatory hormone response to exercise exists in obese subjects. The thermic effect of exercise does not seem to be affected by either the reduced catecholamine response nor insulin resistance.

  6. Phylogenetic sequence of metabolic pathways in Precambrian cellular life

    NASA Technical Reports Server (NTRS)

    Barnabas, J.; Schwartz, R. M.; Dayhoff, M. O.

    1981-01-01

    A sequence of major metabolic events is presented as they may have appeared during prokaryote evolution. This is based on (1) the phylogenetic schema derived from sequences of bacterial ferredoxin, 2Fe-2S ferredoxin, 5S ribosomal RNA, and c-type cytochromes; (2) metabolic settings in which these macromolecules are found; and (3) metabolic capabilities of the prokaryotes that carry these molecules.

  7. Cutting Edge: Murine Mast Cells Rapidly Modulate Metabolic Pathways Essential for Distinct Effector Functions.

    PubMed

    Phong, Binh; Avery, Lyndsay; Menk, Ashley V; Delgoffe, Greg M; Kane, Lawrence P

    2017-01-15

    There is growing appreciation that cellular metabolic and bioenergetic pathways do not play merely passive roles in activated leukocytes. Rather, metabolism has important roles in controlling cellular activation, differentiation, survival, and effector function. Much of this work has been performed in T cells; however, there is still very little information regarding mast cell metabolic reprogramming and its effect on cellular function. Mast cells perform important barrier functions and help control type 2 immune responses. In this study we show that murine bone marrow-derived mast cells rapidly alter their metabolism in response to stimulation through the FcεRI. We also demonstrate that specific metabolic pathways appear to be differentially required for the control of mast cell function. Manipulation of metabolic pathways may represent a novel point for the manipulation of mast cell activation.

  8. In vitro models for metabolic studies of small peptide hormones in sport drug testing.

    PubMed

    Esposito, Simone; Deventer, Koen; Geldof, Lore; Van Eenoo, Peter

    2015-01-01

    Peptide hormones represent an emerging class of potential doping agents. Detection of their misuse is difficult due to their short half-life in plasma and rapid elimination. Therefore, investigating their metabolism can improve detectability. Unfortunately, pharmacokinetic studies with human volunteers are often not allowed because of ethical constraints, and therefore alternative models are needed. This study was performed in order to evaluate in vitro models (human liver microsomes and S9 fraction) for the prediction of the metabolism of peptidic doping agents and to compare them with the established models. The peptides that were investigated include desmopressin, TB-500, GHRP-2, GHRP-6, hexarelin, LHRH and leuprolide. Several metabolites were detected for each peptide after incubation with human liver microsomes, S9 fraction, and serum, which all showed endopeptidase and exopeptidase activity. In vitro models from different organs (liver vs. kidney) were compared, but no significant differences were recorded. Deamidation was not observed in any of the models and was therefore evaluated by incubation with α-chymotrypsin. In conclusion, in vitro models are useful tools for forensic and clinical analysts to detect peptidic metabolic markers in biological fluids.

  9. Changes of hormones regulating electrolyte metabolism after space flight and hypokinesia

    NASA Astrophysics Data System (ADS)

    Macho, L.; Fickova, M.; Lichardus, B.; Kvetnansky, R.; Carrey, R. M.; Grigoriev, A.; Popova, I. A.; Tigranian, R. A.; Noskov, V. B.

    the urinary excretion of potassium was elevated. In rats exposed to hypokinesia for 7 and 60 days an increase of urine osmolality was observed. The results of hormone and electrolyte determination in plasma of cosmonauts after space flight and in experimental animals after hypokinesia suggested that in evaluation of relations between the changes of hormone levels and electrolyte in plasma and urine other factors like emotional stress working load; altered diurnal cycles should be considered in interpretation of homeostatic response of fluid and electrolyte metabolism to space flight conditions.

  10. Impact of hepatitis B virus infection on hepatic metabolic signaling pathway.

    PubMed

    Shi, Yi-Xian; Huang, Chen-Jie; Yang, Zheng-Gang

    2016-09-28

    A growing body of epidemiologic research has demonstrated that metabolic derangement exists in patients with hepatitis B virus (HBV) infection, indicating that there are clinical associations between HBV infection and host metabolism. In order to understand the complex interplay between HBV and hepatic metabolism in greater depth, we systematically reviewed these alterations in different metabolic signaling pathways due to HBV infection. HBV infection interfered with most aspects of hepatic metabolic responses, including glucose, lipid, nucleic acid, bile acid and vitamin metabolism. Glucose and lipid metabolism is a particular focus due to the significant promotion of gluconeogenesis, glucose aerobic oxidation, the pentose phosphate pathway, fatty acid synthesis or oxidation, phospholipid and cholesterol biosynthesis affected by HBV. These altered metabolic pathways are involved in the pathological process of not only hepatitis B, but also metabolic disorders, increasing the occurrence of complications, such as hepatocellular carcinoma and liver steatosis. Thus, a clearer understanding of the hepatic metabolic pathways affected by HBV and its pathogenesis is necessary to develop more novel therapeutic strategies targeting viral eradication.

  11. Impact of hepatitis B virus infection on hepatic metabolic signaling pathway

    PubMed Central

    Shi, Yi-Xian; Huang, Chen-Jie; Yang, Zheng-Gang

    2016-01-01

    A growing body of epidemiologic research has demonstrated that metabolic derangement exists in patients with hepatitis B virus (HBV) infection, indicating that there are clinical associations between HBV infection and host metabolism. In order to understand the complex interplay between HBV and hepatic metabolism in greater depth, we systematically reviewed these alterations in different metabolic signaling pathways due to HBV infection. HBV infection interfered with most aspects of hepatic metabolic responses, including glucose, lipid, nucleic acid, bile acid and vitamin metabolism. Glucose and lipid metabolism is a particular focus due to the significant promotion of gluconeogenesis, glucose aerobic oxidation, the pentose phosphate pathway, fatty acid synthesis or oxidation, phospholipid and cholesterol biosynthesis affected by HBV. These altered metabolic pathways are involved in the pathological process of not only hepatitis B, but also metabolic disorders, increasing the occurrence of complications, such as hepatocellular carcinoma and liver steatosis. Thus, a clearer understanding of the hepatic metabolic pathways affected by HBV and its pathogenesis is necessary to develop more novel therapeutic strategies targeting viral eradication. PMID:27688657

  12. The phytopathogen Rhodococcus fascians breaks apical dominance and activates axillary meristems by inducing plant genes involved in hormone metabolism.

    PubMed

    Simón-Mateo, Carmen; Depuydt, Stephen; DE Oliveira Manes, Carmem Lara; Cnudde, Filip; Holsters, Marcelle; Goethals, Koen; Vereecke, Danny

    2006-03-01

    SUMMARY Rhodococcus fascians is a Gram-positive bacterium that interacts with many plant species and induces multiple shoots through a combination of activation of dormant axillary meristems and de novo meristem formation. Although phenotypic analysis of the symptoms of infected plants clearly demonstrates a disturbance of the phytohormonal balance and an activation of the cell cycle, the actual mechanism of symptom development and the targets of the bacterial signals are unknown. To elucidate the molecular pathways that are responsive to R. fascians infection, differential display was performed on Nicotiana tabacum as a host. Four differentially expressed genes could be identified that putatively encode a senescence-associated protein, a gibberellin 2-oxidase, a P450 monooxygenase and a proline dehydrogenase. The differential expression of the three latter genes was confirmed on infected Arabidopsis thaliana plants by quantitative reverse transcription polymerase chain reactions, supporting their general function in R. fascians-induced symptom development. The role of these genes in hormone metabolism, especially of gibberellin and abscisic acid, in breaking apical dominance and in activating axillary meristems, which are processes associated with symptom development, is discussed.

  13. Merlin inhibits growth hormone-regulated Raf-ERKs pathways by binding to Grb2 protein

    SciTech Connect

    Lim, Jung Yeon; Kim, Hongtae; Jeun, Sin-Soo . E-mail: ssjeun@catholic.ac.kr; Kang, Seok-Gu; Lee, Kyung-Jin

    2006-02-24

    Numerous studies have suggested that the NF2 protein merlin is involved in the regulation of abnormal cell growth and proliferation. In this study, to better understand the merlin's mechanisms that contribute to the inhibition of tumorigenesis, we examined the potential action of merlin on the cell proliferative signaling pathways in response to growth hormone (GH). Merlin effectively attenuated the GH-induced serum response element (SRE) and Elk-1-mediated transcriptional activation, as well as the endogenous SRE-regulated gene c-fos expression in NIH3T3 cells. In addition, merlin prevented the Raf-1 complex activation process, which resulted in the suppression of MAP kinase/ERK, extracellular signal-regulated kinase (ERKs), and Elk-1 phosphorylation, which are the downstream signals of Raf-1. Moreover, it was shown that merlin interacted with endogenous growth factor receptor bound 2 (Grb2) protein and inhibited its expression. These results suggest that merlin contributes, via its protein-to-protein interaction with Grb2 and consequent inhibition of the MAPK pathways, to the regulation of the abnormal cell proliferation, and this provides a further mechanism underlying the tumor suppressor function of merlin.

  14. Parallel labeling experiments for pathway elucidation and (13)C metabolic flux analysis.

    PubMed

    Antoniewicz, Maciek R

    2015-12-01

    Metabolic pathway models provide the foundation for quantitative studies of cellular physiology through the measurement of intracellular metabolic fluxes. For model organisms metabolic models are well established, with many manually curated genome-scale model reconstructions, gene knockout studies and stable-isotope tracing studies. However, for non-model organisms a similar level of knowledge is often lacking. Compartmentation of cellular metabolism in eukaryotic systems also presents significant challenges for quantitative (13)C-metabolic flux analysis ((13)C-MFA). Recently, innovative (13)C-MFA approaches have been developed based on parallel labeling experiments, the use of multiple isotopic tracers and integrated data analysis, that allow more rigorous validation of pathway models and improved quantification of metabolic fluxes. Applications of these approaches open new research directions in metabolic engineering, biotechnology and medicine.

  15. Inherited defects in thyroid hormone cell-membrane transport and metabolism

    PubMed Central

    Fu, Jiao

    2013-01-01

    The description of two novel human defects in the last ten years has uncovered new aspects of thyroid hormone physiology with regard to cellular-membrane transport and intracellular metabolism. Mutations in the X-linked monocarboxylate transporter 8 (MCT8) gene result in an invalidating neurodevelopmental phenotype in males and pathognomonic thyroid functions tests with high T3, low rT3, low or low normal T4, and normal or slightly high TSH. Recessive mutations in the selenocysteine insertion sequence binding protein 2 (SBP2) gene present a variable clinical phenotype depending on the severity of the defect and its consequences on the selenoprotein hierarchy. Most characteristic is the thyroid phenotype of low serum T3, high T4, high rT3, and slightly elevated TSH levels. Herein we review all known cases of MCT8 and SBP2 deficiency and describe each disease in terms of the clinical, biochemical, genetic, and therapeutic aspects. PMID:24629861

  16. Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate

    PubMed Central

    Rafalski, Victoria A.; Mancini, Elena; Brunet, Anne

    2012-01-01

    Summary Metabolism is influenced by age, food intake, and conditions such as diabetes and obesity. How do physiological or pathological metabolic changes influence stem cells, which are crucial for tissue homeostasis? This Commentary reviews recent evidence that stem cells have different metabolic demands than differentiated cells, and that the molecular mechanisms that control stem cell self-renewal and differentiation are functionally connected to the metabolic state of the cell and the surrounding stem cell niche. Furthermore, we present how energy-sensing signaling molecules and metabolism regulators are implicated in the regulation of stem cell self-renewal and differentiation. Finally, we discuss the emerging literature on the metabolism of induced pluripotent stem cells and how manipulating metabolic pathways might aid cellular reprogramming. Determining how energy metabolism regulates stem cell fate should shed light on the decline in tissue regeneration that occurs during aging and facilitate the development of therapies for degenerative or metabolic diseases. PMID:23420198

  17. Metabolic and hormonal response to short term fasting after endurance training in the rat.

    PubMed

    Guezennec, C Y; Serrurier, B; Aymonod, M; Merino, D; Pesquies, P C

    1984-11-01

    The metabolic and hormonal response to short term fasting was studied after endurance exercise training. Rats were kept running on a motor driven rodent treadmill 5 days/wk for periods up to 1 h/day for 6 wk. Trained and untrained rats were then fasted for 24 h and 48 h. Liver and muscle glycogen, blood glucose, lactate, beta OH butyrate, glycerol, plasma insulin, testosterone and corticosterone were measured in fed and fasted trained and untrained rats. 48 h fasted trained rats show a lower level of blood lactate (1.08 +/- 0.05 vs 1.33 +/- 0.08 mmol/l-1 of blood glycerol (1 +/- 0.11 vs 0.84 +/- 0.08 mmol/l-1), and of muscle glycogen. There is a significant increase in plasma corticosterone in 48 h fasted trained rats from fed values. Plasma testosterone decreases during fasting, the values are higher in trained rats. Plasma insulin decreases during fasting without any difference between the two groups. These results show higher lipolysis, and decreased glycogenolysis in trained animals during 48 h fasting. The difference between the groups in steroid hormone response could reduce neoglucogenesis and muscle proteolysis in trained animals.

  18. Hormones, polyamines, and cell wall metabolism during oil palm fruit mesocarp development and ripening.

    PubMed

    Teh, Huey Fang; Neoh, Bee Keat; Wong, Yick Ching; Kwong, Qi Bin; Ooi, Tony Eng Keong; Ng, Theresa Lee Mei; Tiong, Soon Huat; Low, Jaime Yoke Sum; Danial, Asma Dazni; Ersad, Mohd Amiron; Kulaveerasingam, Harikrishna; Appleton, David R

    2014-08-13

    Oil palm is one of the most productive oil-producing crops and can store up to 90% oil in its fruit mesocarp. Oil palm fruit is a sessile drupe consisting of a fleshy mesocarp from which palm oil is extracted. Biochemical changes in the mesocarp cell walls, polyamines, and hormones at different ripening stages of oil palm fruits were studied, and the relationship between the structural and the biochemical metabolism of oil palm fruits during ripening is discussed. Time-course analysis of the changes in expression of polyamines, hormones, and cell-wall-related genes and metabolites provided insights into the complex processes and interactions involved in fruit development. Overall, a strong reduction in auxin-responsive gene expression was observed from 18 to 22 weeks after pollination. High polyamine concentrations coincided with fruit enlargement during lipid accumulation and latter stages of maturation. The trend of abscisic acid (ABA) concentration was concordant with GA₄ but opposite to the GA₃ profile such that as ABA levels increase the resulting elevated ABA/GA₃ ratio clearly coincides with maturation. Polygalacturonase, expansin, and actin gene expressions were also observed to increase during fruit maturation. The identification of the master regulators of these coordinated processes may allow screening for oil palm variants with altered ripening profiles.

  19. Fasting in king penguin. II. Hormonal and metabolic changes during molt.

    PubMed

    Cherel, Y; Leloup, J; Le Maho, Y

    1988-02-01

    The coincidence of fast and molt in penguins is an interesting condition for investigating the factors controlling protein metabolism; avian molt involves the utilization of amino acids for synthesis of new feathers, whereas a major factor for adaptation to fasting in birds, as for mammals, is reduction in net protein breakdown. Hormonal and biochemical changes were studied in seven molting king penguins. Their initial body mass was 18 kg. It decreased by 58% over 41 days of fasting. Feather synthesis lasted for the first 3 wk of the fast. It was marked by plasma concentrations of alanine and uric acid 1.5 to 2 times those for nonmolting fast, and plasma thyroxine was increased five times. At the completion of molt all these values returned to levels comparable to those in nonmolting fast. As indicated by high plasma levels of beta-hydroxybutyrate, lipid stores were mobilized readily during molting. The fast ended by a phase of enhancement in protein utilization that was characterized by a fivefold increase in uricacidemia and coincided with an 80% drop in plasma beta-hydroxybutyrate and a fourfold increase in plasma corticosterone. These data suggest that two different hormones control the two successive periods marked by an increased protein mobilization during the molting fast, i.e., thyroxine during feather growth and corticosterone toward the end of the fast, when the molt is completed.

  20. Neuromuscular, hormonal, and metabolic responses to different plyometric training volumes in rugby players.

    PubMed

    Cadore, Eduardo L; Pinheiro, Eraldo; Izquierdo, Mikel; Correa, Cleiton S; Radaelli, Régis; Martins, Jocelito B; Lhullier, Francisco L R; Laitano, Orlando; Cardoso, Marcelo; Pinto, Ronei S

    2013-11-01

    The purpose of this study was to investigate the effect of different volumes of plyometric exercise (i.e., 100, 200, or 300 hurdle jumps) on acute strength and jump performance and on the acute hormonal and lactate responses in rugby players. Eleven young male elite rugby players (age, 23.5 ± 0.9 years; height, 173 ± 4.8 cm) volunteered for the study. Maximal isometric peak torque (PT), maximal rate of force development (RFD), squat jump (SJ), and drop jump (DJ) performance were assessed before and 5 minutes, 8 hours, and 24 hours after 100, 200, or 300 jumps. In addition, total testosterone (TT), cortisol (COR), and lactate were measured before and after the 3 different plyometric exercise volumes. There were significant decreases in the PT (p < 0.02) and maximal RFD (p < 0.001) 5 minutes, 8 hours, and 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. Additionally, there were significant decreases in the SJ (p < 0.001) and DJ (p < 0.01) performances 24 hours after 100, 200, and 300 jumps, with no differences between the exercise volumes. However, there were significant increases in the TT (p < 0.001), COR (p < 0.05), and lactate (p < 0.001) after 100, 200, and 300 jumps, with no differences between the exercise volumes. All plyometric exercise volumes (100, 200, and 300 jumps) resulted in similar neuromuscular, metabolic, and hormonal responses.

  1. Macro- and microgeographic variation in metabolism and hormone correlates in big brown bats (Eptesicus fuscus).

    PubMed

    Richardson, Christopher S; Heeren, Tim; Widmaier, Eric P; Kunz, Thomas H

    2009-01-01

    To better understand intraspecific variation in basal metabolic rate (BMR), we examined environmental, physiological, and/or cellular bases for residual variation in BMR in big brown bats, Eptesicus fuscus. We measured BMR and plasma levels of thyroid hormone (T(3)) and leptin in bats captured in maternity colonies in eastern Massachusetts (MA; northern population) and in Alabama and Georgia (ALGA; southern population) to assess macrogeographic (between- or among-population) and microgeographic (within-population) variation in those traits. After accounting for effects of body mass, stage of pregnancy, and within-population variation, bats from the northern population did not differ significantly in BMR, T(3), or leptin values from those in the southern population. However, after accounting for the effects of body mass and stage of pregnancy, a test for differences in all traits among colonies from both populations was significant. For BMR, bats differed significantly among the northern colonies. Moreover, after removing the effects of body mass and stage of pregnancy, bats from the AL colony had significantly higher BMR than did bats from all other colonies except one in MA, and they had significantly higher T(3) levels but lower leptin levels than did bats from two other colonies. The presence of among-colony and within-population variation for these traits suggests that proximate (nonevolutionary) factors (e.g., microhabitat differences such as roost type) play an important role in shaping intraspecific variation in BMR and its hormone correlates.

  2. Rapid Optimization of Engineered Metabolic Pathways with Serine Integrase Recombinational Assembly (SIRA).

    PubMed

    Merrick, C A; Wardrope, C; Paget, J E; Colloms, S D; Rosser, S J

    2016-01-01

    Metabolic pathway engineering in microbial hosts for heterologous biosynthesis of commodity compounds and fine chemicals offers a cheaper, greener, and more reliable method of production than does chemical synthesis. However, engineering metabolic pathways within a microbe is a complicated process: levels of gene expression, protein stability, enzyme activity, and metabolic flux must be balanced for high productivity without compromising host cell viability. A major rate-limiting step in engineering microbes for optimum biosynthesis of a target compound is DNA assembly, as current methods can be cumbersome and costly. Serine integrase recombinational assembly (SIRA) is a rapid DNA assembly method that utilizes serine integrases, and is particularly applicable to rapid optimization of engineered metabolic pathways. Using six pairs of orthogonal attP and attB sites with different central dinucleotide sequences that follow SIRA design principles, we have demonstrated that ΦC31 integrase can be used to (1) insert a single piece of DNA into a substrate plasmid; (2) assemble three, four, and five DNA parts encoding the enzymes for functional metabolic pathways in a one-pot reaction; (3) generate combinatorial libraries of metabolic pathway constructs with varied ribosome binding site strengths or gene orders in a one-pot reaction; and (4) replace and add DNA parts within a construct through targeted postassembly modification. We explain the mechanism of SIRA and the principles behind designing a SIRA reaction. We also provide protocols for making SIRA reaction components and practical methods for applying SIRA to rapid optimization of metabolic pathways.

  3. Metabolic and hormonal responses during exercise at 20°, 0° and -20°C

    NASA Astrophysics Data System (ADS)

    Quirion, A.; Laurencelle, L.; Paulin, L.; Therminarias, A.; Brisson, G. R.; Audet, A.; Dulac, S.; Vogelaere, P.

    1989-12-01

    This study was designed to clarify the effects of cold air exposure on metabolic and hormonal responses during progressive incremental exercise. Eight healthy males volunteered for the study. Informed consent was obtained from every participant. The following protocol was administered to each subject on three occasions in a climatic chamber in which the temperature was 20°, 0° or -20°C with relative humidity at 60%±1%. Exercise tests were conducted on an electrically braked ergocycle, and consisted of a propressive incremental maximal exercise. Respiratory parameters were continuously monitored by an automated open-circuit sampling system Exercise blood lactate (LA), free fatty acids (FFA), glucose levels, bicarbonate concentration (HCO{3/-}), acidbase balance, plasma epinephrine (E) and norepinephrine (NE) were determined from venous blood samples obtained through an indwelling brachial catheter. Maximal oxygen uptake was significantly different between conditions: 72.0±5.4 ml kg-1 min-1 at 20°C; 68.9±5.1 ml kg-1 min-1 at 0°C and 68.5±4.6 ml kg-1 min-1 at -20°C. Workload, time to exhaustion, glucose levels and rectal Catecholamines and lactate values were not significantly altered by thermal conditions after maximal exercise but the catecholamines were decreased during rest. Bicarbonate, respiratory quotient, lactate and ventilatory thresholds increased significantly at -20°C. The data support the contention that metabolic and hormonal responses following progressive incremental exercise are altered by cold exposure and they indicate a marked decrease in maximal oxygen uptake, time to exhaustion and workload.

  4. Dietary energy source in dairy cows in early lactation: metabolites and metabolic hormones.

    PubMed

    van Knegsel, A T M; van den Brand, H; Graat, E A M; Dijkstra, J; Jorritsma, R; Decuypere, E; Tamminga, S; Kemp, B

    2007-03-01

    Negative energy balance-related metabolic disorders suggest that the balance between available lipogenic and glucogenic nutrients is important. The objectives of this study were to compare the effects of a glucogenic or a lipogenic diet on liver triacylglycerides (TAG), metabolites, and metabolic hormones in dairy cows in early lactation and to relate metabolite concentrations to the determined energy retention in body mass (ER). Sixteen dairy cows were fed either a lipogenic or glucogenic diet from wk 3 prepartum to wk 9 postpartum (pp) and were housed in climate respiration chambers from wk 2 to 9 pp. Diets were isocaloric (net energy basis). Postpartum, cows fed a lipogenic diet tended to have higher nonesterified fatty acid concentration (NEFA; 0.46 +/- 0.04 vs. 0.37 +/- 0.04 mmol/L) and lower insulin concentration (4.0 +/- 0.5 vs. 5.5 +/- 0.6 microIU/mL). No difference was found in plasma glucose, beta-hydroxybutyrate, insulin-like growth factor-I, and thyroid hormones. Liver TAG was equal between both diets in wk -2 and 2 pp. In wk 4 pp cows fed the glucogenic diet had numerically lower TAG levels, although there was no significant dietary effect. Negative relationships were detected between ER and milk fat and between ER and NEFA. A positive relationship was detected between ER and insulin concentration. Overall, results suggest that insulin plays a regulating role in altering energy partitioning between milk and body tissue. Feeding lactating dairy cows a glucogenic diet decreased mobilization of body fat compared with a lipogenic diet. The relative abundance of lipogenic nutrients, when feeding a more lipogenic diet, is related to more secretion of lipogenic nutrients in milk, lower plasma insulin, and higher plasma NEFA concentration.

  5. Combining pathway analysis with flux balance analysis for the comprehensive study of metabolic systems.

    PubMed

    Schilling, C H; Edwards, J S; Letscher, D; Palsson, B Ø

    The elucidation of organism-scale metabolic networks necessitates the development of integrative methods to analyze and interpret the systemic properties of cellular metabolism. A shift in emphasis from single metabolic reactions to systemically defined pathways is one consequence of such an integrative analysis of metabolic systems. The constraints of systemic stoichiometry, and limited thermodynamics have led to the definition of the flux space within the context of convex analysis. The flux space of the metabolic system, containing all allowable flux distributions, is constrained to a convex polyhedral cone in a high-dimensional space. From metabolic pathway analysis, the edges of the high-dimensional flux cone are vectors that correspond to systemically defined "extreme pathways" spanning the capabilities of the system. The addition of maximum flux capacities of individual metabolic reactions serves to further constrain the flux space and has led to the development of flux balance analysis using linear optimization to calculate optimal flux distributions. Here we provide the precise theoretical connections between pathway analysis and flux balance analysis allowing for their combined application to study integrated metabolic function. Shifts in metabolic behavior are calculated using linear optimization and are then interpreted using the extreme pathways to demonstrate the concept of pathway utilization. Changes to the reaction network, such as the removal of a reaction, can lead to the generation of suboptimal phenotypes that can be directly attributed to the loss of pathway function and capabilities. Optimal growth phenotypes are calculated as a function of environmental variables, such as the availability of substrate and oxygen, leading to the definition of phenotypic phase planes. It is illustrated how optimality properties of the computed flux distributions can be interpreted in terms of the extreme pathways. Together these developments are applied to an

  6. Predicting metabolic pathways of small molecules and enzymes based on interaction information of chemicals and proteins.

    PubMed

    Gao, Yu-Fei; Chen, Lei; Cai, Yu-Dong; Feng, Kai-Yan; Huang, Tao; Jiang, Yang

    2012-01-01

    Metabolic pathway analysis, one of the most important fields in biochemistry, is pivotal to understanding the maintenance and modulation of the functions of an organism. Good comprehension of metabolic pathways is critical to understanding the mechanisms of some fundamental biological processes. Given a small molecule or an enzyme, how may one identify the metabolic pathways in which it may participate? Answering such a question is a first important step in understanding a metabolic pathway system. By utilizing the information provided by chemical-chemical interactions, chemical-protein interactions, and protein-protein interactions, a novel method was proposed by which to allocate small molecules and enzymes to 11 major classes of metabolic pathways. A benchmark dataset consisting of 3,348 small molecules and 654 enzymes of yeast was constructed to test the method. It was observed that the first order prediction accuracy evaluated by the jackknife test was 79.56% in identifying the small molecules and enzymes in a benchmark dataset. Our method may become a useful vehicle in predicting the metabolic pathways of small molecules and enzymes, providing a basis for some further analysis of the pathway systems.

  7. Characterization of an isopentenyl diphosphate isomerase involved in the juvenile hormone pathway in Aedes aegypti.

    PubMed

    Diaz, Miguel E; Mayoral, Jaime G; Priestap, Horacio; Nouzova, Marcela; Rivera-Perez, Crisalejandra; Noriega, Fernando G

    2012-10-01

    Isopentenyl diphosphate isomerase (IPPI) is an enzyme involved in the synthesis of juvenile hormone (JH) in the corpora allata (CA) of insects. IPPI catalyzes the conversion of isopentenyl pyrophosphate (IPP) to dimethylallyl pyrophosphate (DMAPP); afterward IPP and DMAPP condense in a head-to-tail manner to produce geranyl diphosphate (GPP), this head-to-tail condensation can be repeated, by the further reaction of GPP with IPP, yielding the JH precursor farnesyl diphosphate. An IPPI expressed sequence tag (EST) was obtained from an Aedes aegypti corpora-allata + corpora cardiaca library. Its full-length cDNA encodes a 244-aa protein that shows a high degree of similarity with type I IPPIs from other organisms, particularly for those residues that have important roles in catalysis, metal coordination and interaction with the diphosphate moiety of the IPP. Heterologous expression produced a recombinant protein that metabolized IPP into DMAPP; treatment of DMAPP with phosphoric acid produced isoprene, a volatile compound that was measured with an assay based on a solid-phase micro extraction protocol and direct analysis by gas chromatography. A. aegypti IPPI (AaIPPI) required Mg(2+) or Mn(2+) but not Zn(2+) for full activity and it was entirely inhibited by iodoacetamide. Real time PCR experiments showed that AaIPPI is highly expressed in the CA. Changes in AaIPPI mRNA levels in the CA in the pupal and adult female mosquito corresponded well with changes in JH synthesis (Li et al., 2003). This is the first molecular and functional characterization of an isopentenyl diphosphate isomerase involved in the production of juvenile hormone in the CA of an insect.

  8. Metabolic pathways variability and sequence/networks comparisons

    PubMed Central

    Tun, Kyaw; Dhar, Pawan K; Palumbo, Maria Concetta; Giuliani, Alessandro

    2006-01-01

    Background In this work a simple method for the computation of relative similarities between homologous metabolic network modules is presented. The method is similar to classical sequence alignment and allows for the generation of phenotypic trees amenable to be compared with correspondent sequence based trees. The procedure can be applied to both single metabolic modules and whole metabolic network data without the need of any specific assumption. Results We demonstrate both the ability of the proposed method to build reliable biological classification of a set of microrganisms and the strong correlation between the metabolic network wiringand involved enzymes sequence space. Conclusion The method represents a valuable tool for the investigation of genotype/phenotype correlationsallowing for a direct comparison of different species as for their metabolic machinery. In addition the detection of enzymes whose sequence space is maximally correlated with the metabolicnetwork space gives an indication of the most crucial (on an evolutionary viewpoint) steps of the metabolic process. PMID:16420696

  9. Modelling and pathway identification involving the transport mechanism of a complex metabolic system in batch culture

    NASA Astrophysics Data System (ADS)

    Yuan, Jinlong; Zhang, Xu; Zhu, Xi; Feng, Enmin; Yin, Hongchao; Xiu, Zhilong

    2014-06-01

    The bio-dissimilation of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) can be characterized by a complex metabolic system of interactions among biochemical fluxes, metabolic compounds, key enzymes and genetic regulation. In this paper, in consideration of the fact that the transport ways of 1,3-PD and glycerol with different weights across cell membrane are still unclear in batch culture, we consider 121 possible metabolic pathways and establish a novel mathematical model which is represented by a complex metabolic system. Taking into account the difficulty in accurately measuring the concentration of intracellular substances and the absence of equilibrium point for the metabolic system of batch culture, the novel approach used here is to define quantitatively biological robustness of the intracellular substance concentrations for the overall process of batch culture. To determine the most possible metabolic pathway, we take the defined biological robustness as cost function and establish an identification model, in which 1452 system parameters and 484 pathway parameters are involved. Simultaneously, the identification model is subject to the metabolic system, continuous state constraints and parameter constraints. As such, solving the identification model by a serial program is a very complicated task. We propose a parallel migration particle swarm optimization algorithm (MPSO) capable of solving the identification model in conjunction with the constraint transcription and smoothing approximation techniques. Numerical results show that the most possible metabolic pathway and the corresponding metabolic system can reasonably describe the process of batch culture.

  10. Carbohydrate metabolism in Archaea: current insights into unusual enzymes and pathways and their regulation.

    PubMed

    Bräsen, Christopher; Esser, Dominik; Rauch, Bernadette; Siebers, Bettina

    2014-03-01

    The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many "classical" pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of "new," unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented.

  11. Soy protein diet alters expression of hepatic genes regulating fatty acid and thyroid hormone metabolism in the male rat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We determined effects of soy protein (SPI) and the isoflavone genistein (GEN) on mRNA expression of key lipid metabolism and thyroid hormone system genes in young adult, male Sprague-Dawley rats. SPI-fed rats had less retroperitoneal fat and less hepato-steatosis than casein (CAS, control protein)-...

  12. [Influence of ecdysteron-80 on the hormonal-mediator balance and lipid metabolism in rats with chronic cardiac failure].

    PubMed

    Fedorov, V N; Pynegova, N V

    2009-01-01

    Administration of ecdysteron-80 made of Serratula coronata L. to rats with experimental chronic cardiac failure partially corrects hormonal and mediator imbalance typical for this pathology. By some parameters this correction is full. By improving lipid metabolism, ecdysteron-80 reduces blood plasma atherogenicity.

  13. Hormonal regulators of muscle and metabolism in aging (HORMA): Design and conduct of a complex, double-masked, multicenter trial

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Older persons often lose muscle mass, strength, and physical function. This report describes the challenges of conducting a complex clinical investigation assessing the effects of anabolic hormones on body composition, physical function, and metabolism during aging. METHODS: HORMA is a m...

  14. The steroid hormone biosynthesis pathway as a target for endocrine-disrupting chemicals.

    PubMed

    Sanderson, J Thomas

    2006-11-01

    Various chemicals found in the human and wildlife environments have the potential to disrupt endocrine functions in exposed organisms. Increasingly, the enzymes involved in the steroid biosynthesis pathway are being recognized as important targets for the actions of various endocrine-disrupting chemicals. Interferences with steroid biosynthesis may result in impaired reproduction, alterations in (sexual) differentiation, growth, and development and the development of certain cancers. Steroid hormone synthesis is controlled by the activity of several highly substrate-selective cytochrome P450 enzymes and a number of steroid dehydrogenases and reductases. Particularly aromatase (CYP19), the enzyme that converts androgens to estrogens, has been the subject of studies into the mechanisms by which chemicals interfere with sex steroid hormone homeostasis and function, often related to (de)feminization and (de)masculinazation processes. Studies in vivo and in vitro have focussed on ovarian and testicular function, with less attention given to other steroidogenic organs, such as the adrenal cortex. This review aims to provide a comprehensive overview of the state of knowledge regarding the mechanisms by which chemicals interfere with the function of steroidogenic enzymes in various tissues and organisms. The endocrine toxicities and mechanisms of action related to steroidogenesis of a number of classes of drugs and environmental contaminants are discussed. In addition, several potential in vitro bioassays are reviewed for their usefulness as screening tools for the detection of chemicals that can interfere with steroidogenesis. Analysis of the currently scattered state of knowledge indicates that still relatively little is known about the underlying mechanisms of interference of chemicals with steroidogenesis and their potential toxicity in steroidogenic tissues, neither in humans nor in wildlife. Considerably more detailed and systematic research in this area of

  15. Sensitive cells: enabling tools for static and dynamic control of microbial metabolic pathways.

    PubMed

    Cress, Brady F; Trantas, Emmanouil A; Ververidis, Filippos; Linhardt, Robert J; Koffas, Mattheos Ag

    2015-12-01

    Natural metabolic pathways are dynamically regulated at the transcriptional, translational, and protein levels. Despite this, traditional pathway engineering has relied on static control strategies to engender changes in metabolism, most likely due to ease of implementation and perceived predictability of design outcome. Increasingly in recent years, however, metabolic engineers have drawn inspiration from natural systems and have begun to harness dynamically controlled regulatory machinery to improve design of engineered microorganisms for production of specialty and commodity chemicals. Here, we review recent enabling technologies for engineering static control over pathway expression levels, and we discuss state-of-the-art dynamic control strategies that have yielded improved outcomes in the field of microbial metabolic engineering. Furthermore, we emphasize design of a novel class of genetically encoded controllers that will facilitate automatic, transient tuning of synthetic and endogenous pathways.

  16. Hormonal and metabolic regulation of tomato fruit sink activity and yield under salinity.

    PubMed

    Albacete, Alfonso; Cantero-Navarro, Elena; Balibrea, María E; Großkinsky, Dominik K; de la Cruz González, María; Martínez-Andújar, Cristina; Smigocki, Ann C; Roitsch, Thomas; Pérez-Alfocea, Francisco

    2014-11-01

    Salinization of water and soil has a negative impact on tomato (Solanum lycopersicum L.) productivity by reducing growth of sink organs and by inducing senescence in source leaves. It has been hypothesized that yield stability implies the maintenance or increase of sink activity in the reproductive structures, thus contributing to the transport of assimilates from the source leaves through changes in sucrolytic enzymes and their regulation by phytohormones. In this study, classical and functional physiological approaches have been integrated to study the influence of metabolic and hormonal factors on tomato fruit sink activity, growth, and yield: (i) exogenous hormones were applied to plants, and (ii) transgenic plants overexpressing the cell wall invertase (cwInv) gene CIN1 in the fruits and de novo cytokinin (CK) biosynthesis gene IPT in the roots were constructed. Although salinity reduces fruit growth, sink activity, and trans-zeatin (tZ) concentrations, it increases the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) during the actively growing period (25 days after anthesis). Indeed, exogenous application of the CK analogue kinetin to salinized actively growing fruits recovered sucrolytic activities (mainly cwInv and sucrose synthase), sink strength, and fruit weight, whereas the ethylene-releasing compound ethephon had a negative effect in equivalent non-stressed fruits. Fruit yield was increased by both the constitutive expression of CIN1 in the fruits (up to 4-fold) or IPT in the root (up to 30%), owing to an increase in the fruit number (lower flower abortion) and in fruit weight. This is possibly related to a recovery of sink activity in reproductive tissues due to both (i) increase in sucrolytic activities (cwInv, sucrose synthase, and vacuolar and cytoplasmic invertases) and tZ concentration, and (ii) a decrease in the ACC levels and the activity of the invertase inhibitor. This study provides new functional evidences about the role of

  17. Control of YAP/TAZ Activity by Metabolic and Nutrient-Sensing Pathways.

    PubMed

    Santinon, Giulia; Pocaterra, Arianna; Dupont, Sirio

    2016-04-01

    Metabolism is a fundamental cellular function that can be reprogrammed by signaling pathways and oncogenes to meet cellular requirements. An emerging paradigm is that signaling and transcriptional networks can be in turn regulated by metabolism, allowing cells to coordinate their metabolism and behavior in an integrated manner. The activity of the YAP/TAZ transcriptional coactivators, downstream transducers of the Hippo cascade and powerful pro-oncogenic factors, was recently found to be regulated by metabolic pathways, such as aerobic glycolysis and mevalonate synthesis, and by the nutrient-sensing LKB1-AMPK and TSC-mTOR pathways. We discuss here current data linking YAP/TAZ to metabolism and suggest how this coupling might coordinate nutrient availability with genetic programs that sustain tissue growth, neoplastic cell proliferation, and tumor malignancy.

  18. Agmatine : metabolic pathway and spectrum of activity in brain.

    PubMed

    Halaris, Angelos; Plietz, John

    2007-01-01

    Agmatine is an endogenous neuromodulator that, based on animal studies, has the potential for new drug development. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared with other monoamines. Agmatine was long thought to be synthesised only in lower life forms, until its biosynthetic pathway (decarboxylation of arginine) was described in the mammalian brain in 1994. Human arginine decarboxylase has been cloned and shown to have 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon neuronal depolarisation. Other evidence of a neuromodulation role for agmatine is the presence of a specific cellular uptake mechanism and a specific metabolic enzyme (agmatinase; which forms putrescine).Initially, agmatine was conceptualised as an endogenous clonidine-displacing substance of imidazoline receptors; however, it has now been established to have affinity for several transmembrane receptors, such as alpha(2)-adrenergic, imidazoline I(1) and glutamatergic NMDA receptors. In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase. Endogenous agmatine is induced in response to stress and/or inflammation. Stressful conditions that induce agmatine include hypoxic-ischaemia and cold-restraint stress of ulcerogenic proportion. Induction of agmatine in the brain seems to occur in astrocytes, although neurons also synthesise agmatine. The effects of injected agmatine in animals include anticonvulsant-, antineurotoxic- and antidepressant-like actions. Intraperitoneal or intracerebroventricular injections of agmatine rapidly elicit antidepressant-like behavioural changes in the rodent forced swim test and tail suspension test. Intraperitoneal injections of agmatine into rats and mice also elicit acute anxiolytic-like behavioural changes in the elevated

  19. Parathyroid hormone-dependent signaling pathways regulating genes in bone cells

    NASA Technical Reports Server (NTRS)

    Swarthout, John T.; D'Alonzo, Richard C.; Selvamurugan, Nagarajan; Partridge, Nicola C.

    2002-01-01

    Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific

  20. Evidence of chemical stimulation of hepatic metabolism by an experimental acetanilide (FOE 5043) indirectly mediating reductions in circulating thyroid hormone levels in the male rat.

    PubMed

    Christenson, W R; Becker, B D; Wahle, B S; Moore, K D; Dass, P D; Lake, S G; Van Goethem, D L; Stuart, B P; Sangha, G K; Thyssen, J H

    1996-02-01

    N-(4-Fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3, 4-thiadiazol-2-yl]oxy]acetamide (FOE 5043) is a new acetanilide-type herbicide undergoing regulatory testing. Previous work in this laboratory suggested that FOE 5043-induced reductions in serum thyroxine (T4) levels were mediated via an extrathyroidal site of action. The possibility that the alterations in circulating T4 levels were due to chemical induction of hepatic thyroid hormone metabolism was investigated. Treatment with FOE 5043 at a rate of 1000 ppm as a dietary admixture was found to significantly increase the clearance of [125I]T4 from the serum, suggesting an enhanced excretion of the hormone. In the liver, the activity of hepatic uridine glucuronosyl transferase, a major pathway of thyroid hormone biotransformation in the rat, increased in a statistically significant and dose-dependent manner; conversely, hepatic 5'-monodeiodinase activity trended downward with dose. Bile flow as well as the hepatic uptake and biliary excretion of [125I]T4 were increased following exposure to FOE 5043. Thyroidal function, as measured by the discharge of iodide ion in response to perchlorate, and pituitary function, as measured by the capacity of the pituitary to secrete thyrotropin in response to an exogenous challenge by hypothalamic thyrotropin releasing hormone, were both unchanged from the controlled response. These data suggest that the functional status of the thyroid and pituitary glands has not been altered by treatment with FOE 5043 and that reductions in circulating levels of T4 are being mediated indirectly through an increase in the biotransformation and excretion of thyroid hormone in the liver.

  1. Tissue thyroid hormone metabolism is differentially regulated during illness in mice.

    PubMed

    Boelen, Anita; van der Spek, Anne H; Bloise, Flavia; de Vries, Emmely M; Surovtseva, Olga V; van Beeren, Mieke; Ackermans, Mariette T; Kwakkel, Joan; Fliers, Eric

    2017-04-01

    Illness induces major modifications in central and peripheral thyroid hormone (TH) metabolism, so-called nonthyroidal illness syndrome (NTIS). As a result, organ-specific changes in local TH availability occur depending on the type and severity of illness. Local TH availability is of importance for the regulation of the tissue-specific TH target genes and determined by the interplay between deiodinating enzymes, TH transport and TH receptor (TR) expression. In the present study, we evaluated changes in TH transport, deiodination and TR expression, the resulting tissue TH concentrations and the expression of TH target genes in liver and muscle in three animal models of illness. We induced (1) acute systemic inflammation by intraperitoneal injection of bacterial endotoxin (LPS), (2) chronic local inflammation by a turpentine injection in the hind limb and (3) severe pneumonia and sepsis by intranasal inoculation with Streptococcus pneumoniae We found that all aspects of peripheral TH metabolism are differentially regulated during illness, depending on the organ studied and severity of illness. In addition, tissue TH concentrations are not equally affected by the decrease in serum TH concentrations. For example, the decrease in muscle TH concentrations is less severe than the decrease observed in liver. In addition, despite lower TH concentrations in muscle in all three models, muscle T3 action is differentially affected. These observations help to understand the complex nature of the nonthyroidal illness syndrome.

  2. Disorders of water metabolism: diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion.

    PubMed

    Verbalis, Joseph G

    2014-01-01

    Disorders of body fluids are among the most commonly encountered problems in the practice of clinical medicine. This is in large part because many different disease states can potentially disrupt the finely balanced mechanisms that control the intake and output of water and solute. It therefore behooves clinicians treating such patients to have a good understanding of the pathophysiology, the differential diagnosis and the management of these disorders. Since body water is the primary determinant of the osmolality of the extracellular fluid (ECF), disorders of body water homeostasis can be divided into hypoosmolar disorders, in which there is an excess of body water relative to body solute, and hyperosmolar disorders, in which there is a deficiency of body water relative to body solute. The classical hyperosmolar disorder is diabetes insipidus (DI), and the classical hypoosmolar disorder is the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This chapter first reviews the regulatory mechanisms underlying water and sodium metabolism, the two major determinants of body fluid homeostasis. The major disorders of water metabolism causing hyperosmolality and hypoosmolality, DI and SIADH, are then discussed in detail, including the pathogenesis, differential diagnosis and treatment of these disorders.

  3. Hormonal enhancement of insecticide efficacy in Tribolium castaneum: oxidative stress and metabolic aspects.

    PubMed

    Plavšin, Ivana; Stašková, Tereza; Šerý, Michal; Smýkal, Vlastimil; Hackenberger, Branimir K; Kodrík, Dalibor

    2015-04-01

    Insect anti-stress responses, including those induced by insecticides, are controlled by adipokinetic hormones (AKHs). We examined the physiological consequences of Pyrap-AKH application on Tribolium castaneum adults (AKH-normal and AKH-deficient prepared by the RNAi technique) treated by two insecticides, pirimiphos-methyl and deltamethrin. Co-application of pirimiphos-methyl and/or deltamethrin with AKH significantly increased beetle mortality compared with application of the insecticides alone. This co-treatment was accompanied by substantial stimulation of general metabolism, as monitored by carbon dioxide production. Further, the insecticide treatment alone affected some basic markers of oxidative stress: it lowered total antioxidative capacity as well as the activity of superoxide dismutase in the beetle body; in addition, it enhanced the activity of catalase and glutathione-S-transferase. However, these discrepancies in oxidative stress markers were eliminated/reduced by co-application with Pyrap-AKH. We suggest that the elevation of metabolism, which is probably accompanied with faster turnover of toxins, might be responsible for the higher mortality that results after AKH and insecticide co-application. Changes in oxidative stress markers are probably not included in the mechanisms responsible for increased mortality.

  4. Feeding and Fasting Signals Converge on the LKB1-SIK3 Pathway to Regulate Lipid Metabolism in Drosophila.

    PubMed

    Choi, Sekyu; Lim, Dae-Sik; Chung, Jongkyeong

    2015-05-01

    LKB1 plays important roles in governing energy homeostasis by regulating AMP-activated protein kinase (AMPK) and other AMPK-related kinases, including the salt-inducible kinases (SIKs). However, the roles and regulation of LKB1 in lipid metabolism are poorly understood. Here we show that Drosophila LKB1 mutants display decreased lipid storage and increased gene expression of brummer, the Drosophila homolog of adipose triglyceride lipase (ATGL). These phenotypes are consistent with those of SIK3 mutants and are rescued by expression of constitutively active SIK3 in the fat body, suggesting that SIK3 is a key downstream kinase of LKB1. Using genetic and biochemical analyses, we identify HDAC4, a class IIa histone deacetylase, as a lipolytic target of the LKB1-SIK3 pathway. Interestingly, we found that the LKB1-SIK3-HDAC4 signaling axis is modulated by dietary conditions. In short-term fasting, the adipokinetic hormone (AKH) pathway, related to the mammalian glucagon pathway, inhibits the kinase activity of LKB1 as shown by decreased SIK3 Thr196 phosphorylation, and consequently induces HDAC4 nuclear localization and brummer gene expression. However, under prolonged fasting conditions, AKH-independent signaling decreases the activity of the LKB1-SIK3 pathway to induce lipolytic responses. We also identify that the Drosophila insulin-like peptides (DILPs) pathway, related to mammalian insulin pathway, regulates SIK3 activity in feeding conditions independently of increasing LKB1 kinase activity. Overall, these data suggest that fasting stimuli specifically control the kinase activity of LKB1 and establish the LKB1-SIK3 pathway as a converging point between feeding and fasting signals to control lipid homeostasis in Drosophila.

  5. Comparative aspects of steroid hormone metabolism and ovarian activity in felids, measured noninvasively in feces.

    PubMed

    Brown, J L; Wasser, S K; Wildt, D E; Graham, L H

    1994-10-01

    Noninvasive fecal assays were used to study steroid metabolism and ovarian activity in several felid species. Using the domestic cat (Felis catus) as model, the excretory products of injected [14C]estradiol (E2) and [14C]progesterone (P4) were determined. Within 2 days, 97.0 +/- 0.6% and 96.7 +/- 0.5% of recovered E2 and P4 radioactivity, respectively, was found in feces. E2 was excreted as unconjugated estradiol and estrone (40%) and as a non-enzyme-hydrolyzable conjugate (60%). P4 was excreted primarily as non-enzyme-hydrolyzable, conjugated metabolites (78%) and as unconjugated pregnenolone epimers. A simple method for extracting fecal steroid metabolites optimized extraction efficiencies of the E2 and P4 excretion products (90.1 +/- 0.8% and 87.2 +/- 1.4%, respectively). Analysis of HPLC fractions of extracted fecal samples from the radiolabel-injected domestic cats revealed that E2 immunoreactivity coincided primarily with the unconjugated metabolized [14C]E2 peak, whereas progestogen immunoreactivity coincided with a single conjugated epimer and multiple unconjugated pregnenolone epimers. After HPLC separation, similar immunoreactive E2 and P4 metabolite profiles were observed in the leopard cat (F. bengalensis), cheetah (Acinonyx jubatus), clouded leopard (Neofelis nebulosa), and snow leopard (Panthera uncia). Longitudinal analyses demonstrated that changes in fecal E2 and P4 metabolite concentrations reflected natural or artificially induced ovarian activity. For example, severalfold increases in E2 excretion were associated with overt estrus or exogenous gonadotropin treatment, and elevated fecal P4 metabolite concentrations occurred during pregnant and nonpregnant (pseudopregnant) luteal phases. Although overall concentrations were similar, the duration of elevated fecal P4 metabolites during pseudopregnancy was approximately half that observed during pregnancy. In summary, steroid metabolism mechanisms appear to be conserved among these physically

  6. Effects of pre- and postnatal polychlorinated biphenyl exposure on metabolic rate and thyroid hormones of white-footed mice

    USGS Publications Warehouse

    French, J.B.; Voltura, M.B.; Tomasi, T.E.

    2001-01-01

    Energy budgets have proven to be a valuable tool for predicting life history from physiological data in terrestrial vertebrates, yet these concepts have not been applied to the physiological effects of contaminants. Contaminants might affect energy budgets by imposing an additional metabolic cost or by reducing the overall amount of energy taken in; either process will reduce the energy available for production (i.e., growth or reproduction). This study examined whole animal energetic effects of polychlorinated biphenyl (PCB) exposure in white-footed mice (Peromyscus leucopus). Exposure to PCBs is known to reduce concentrations of plasma thyroid hormones, and thyroid hormones exert strong control over the rate of energy metabolism in mammals. Peromyscus leucopus that were proven breeders were fed PCBs in their food at 0, 10, and 25 ppm. Through lactation, offspring were exposed to PCB from conception and were maintained on the maternal diet to adulthood. No effects were seen on energy metabolism (O-2 consumption, measured in adulthood) or on growth, but there were large dose-dependent decreases in thyroid hormone concentrations, particularly T-4. The apparent disparity in our data between unchanged metabolic rates and 50% reductions in T-4 concentrations can be rationalized by noting that free T-3 (the fraction not bound to plasma protein) in treated mice was not significantly different from controls and that metabolism is most strongly influenced by free T-3. Overall, this study did not demonstrate any energetic consequences of PCB exposure in P. leucopus at dietary concentrations up to 25 ppm.

  7. The influence of trilostane on steroid hormone metabolism in canine adrenal glands and corpora lutea-an in vitro study.

    PubMed

    Ouschan, C; Lepschy, M; Zeugswetter, F; Möstl, E

    2012-03-01

    Trilostane is widely used to treat hyperadrenocorticism in dogs. Trilostane competitively inhibits the enzyme 3-beta hydroxysteroid dehydrogenase (3β-HSD), which converts pregnenolone (P5) to progesterone (P4) and dehydroepiandrosterone (DHEA) to androstendione (A4). Although trilostane is frequently used in dogs, the molecular mechanism underlying its effect on canine steroid hormone biosynthesis is still an enigma. Multiple enzymes of 3β-HSD have been found in humans, rats and mice and their presence might explain the contradictory results of studies on the effectiveness of trilostane. We therefore investigated the influence of trilostane on steroid hormone metabolism in dogs by means of an in vitro model. Canine adrenal glands from freshly euthanized dogs and corpora lutea (CL) were incubated with increasing doses of trilostane. Tritiated P5 or DHEA were used as substrates. The resulting radioactive metabolites were extracted, separated by thin layer chromatography and visualized by autoradiography. A wide variety of radioactive metabolites were formed in the adrenal glands and in the CL, indicating high metabolic activity in both tissues. In the adrenal cortex, trilostane influences the P5 metabolism in a dose- and time-dependent manner, while DHEA metabolism and metabolism of both hormones in the CL were unaffected. The results indicate for the first time that there might be more than one enzyme of 3β-HSD present in dogs and that trilostane selectively inhibits P5 conversion to P4 only in the adrenal gland.

  8. Green pathways: Metabolic network analysis of plant systems.

    PubMed

    Dersch, Lisa Maria; Beckers, Veronique; Wittmann, Christoph

    2016-03-01

    Metabolic engineering of plants with enhanced crop yield and value-added compositional traits is particularly challenging as they probably exhibit the highest metabolic network complexity of all living organisms. Therefore, approaches of plant metabolic network analysis, which can provide systems-level understanding of plant physiology, appear valuable as guidance for plant metabolic engineers. Strongly supported by the sequencing of plant genomes, a number of different experimental and computational methods have emerged in recent years to study plant systems at various levels: from heterotrophic cell cultures to autotrophic entire plants. The present review presents a state-of-the-art toolbox for plant metabolic network analysis. Among the described approaches are different in silico modeling techniques, including flux balance analysis, elementary flux mode analysis and kinetic flux profiling, as well as different variants of experiments with plant systems which use radioactive and stable isotopes to determine in vivo plant metabolic fluxes. The fundamental principles of these techniques, the required data input and the obtained flux information are enriched by technical advices, specific to plants. In addition, pioneering and high-impacting findings of plant metabolic network analysis highlight the potential of the field.

  9. Identification of acyl-CoA synthetases involved in the mammalian sphingosine 1-phosphate metabolic pathway.

    PubMed

    Ohkuni, Aya; Ohno, Yusuke; Kihara, Akio

    2013-12-13

    Sphingosine 1-phosphate (S1P) plays important roles both as a bioactive lipid molecule and an intermediate of the sphingolipid-to-glycerophospholipid metabolic pathway. To identify human acyl-CoA synthetases (ACSs) involved in S1P metabolism, we cloned all 26 human ACS genes and examined their abilities to restore deficient sphingolipid-to-glycerophospholipid metabolism in a yeast mutant lacking two ACS genes, FAA1 and FAA4. Here, in addition to the previously identified ACSL family members (ACSL1, 3, 4, 5, and 6), we found that ACSVL1, ACSVL4, and ACSBG1 also restored metabolism. All 8 ACSs were localized either exclusively or partly to the endoplasmic reticulum (ER), where S1P metabolism takes place. We previously proposed the entire S1P metabolic pathway from results obtained using yeast cells, i.e., S1P is metabolized to glycerophospholipids via trans-2-hexadecenal, trans-2-hexadecenoic acid, trans-2-hexadecenoyl-CoA, and palmitoyl-CoA. However, as S1P is not a naturally occurring long-chain base 1-phosphate in yeast, the validity of this pathway required further verification using mammalian cells. In the present study, we treated HeLa cells with the ACS inhibitor triacsin C and found that inhibition of ACSs resulted in accumulation of trans-2-hexadecenoic acid as in ACS mutant yeast. From these results, we conclude that S1P is metabolized by a common pathway in eukaryotes.

  10. "Design Your Own Disease" Assignment: Teaching Students to Apply Metabolic Pathways

    ERIC Educational Resources Information Center

    Flynn, Nick

    2010-01-01

    One of the major focuses of biochemistry courses is metabolic pathways. Although certain aspects of this content may require a rote approach, more applied techniques make these subject areas more interesting. This article describes the use of an assignment, "Design Your Own Disease" to teach students metabolic regulation and biosignaling…

  11. [The use of growth hormone to treat endocrine-metabolic disturbances in acquired immunodeficiency syndrome (AIDS) patients].

    PubMed

    Spinola-Castro, Angela Maria; Siviero-Miachon, Adriana A; da Silva, Marcos Tadeu Nolasco; Guerra-Junior, Gil

    2008-07-01

    Acquired Immunodeficiency Syndrome (Aids) was initially related to HIV-associated wasting syndrome, and its metabolic disturbances to altered body composition. After Highly Active Antiretroviral Therapy (HAART) was started, malnutrition has declined and HIV-associated lipodystrophy syndrome has emerged as an important metabolic disorder. Aids is also characterized by hormonal disturbances, principally in growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. The use of recombinant human GH (hrGH) was formerly indicated to treat wasting syndrome, in order to increase lean body mass. Even though the use of hrGH in lipodystrophy syndrome has been considered, the decrease in insulin sensitivity is a limitation for its use, which has not been officially approved yet. Diversity in therapeutic regimen is another limitation to its use in Aids patients. The present study has reviewed the main HIV-related endocrine-metabolic disorders as well as the use of hrGH in such conditions.

  12. Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas.

    PubMed

    Haas, Susanne; Pierl, Christiane; Harth, Volker; Pesch, Beate; Rabstein, Sylvia; Brüning, Thomas; Ko, Yon; Hamann, Ute; Justenhoven, Christina; Brauch, Hiltrud; Fischer, Hans-Peter

    2006-10-15

    The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p = 0.018) and with reduced lymph node metastasis (GST pi, p = 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p < 0.001). CYP3A4/5 expression was associated with a positive nodal status (p = 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p = 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis.

  13. A toolbox model of evolution of metabolic pathways on networks of arbitrary topology.

    PubMed

    Pang, Tin Yau; Maslov, Sergei

    2011-05-01

    In prokaryotic genomes the number of transcriptional regulators is known to be proportional to the square of the total number of protein-coding genes. A toolbox model of evolution was recently proposed to explain this empirical scaling for metabolic enzymes and their regulators. According to its rules, the metabolic network of an organism evolves by horizontal transfer of pathways from other species. These pathways are part of a larger "universal" network formed by the union of all species-specific networks. It remained to be understood, however, how the topological properties of this universal network influence the scaling law of functional content of genomes in the toolbox model. Here we answer this question by first analyzing the scaling properties of the toolbox model on arbitrary tree-like universal networks. We prove that critical branching topology, in which the average number of upstream neighbors of a node is equal to one, is both necessary and sufficient for quadratic scaling. We further generalize the rules of the model to incorporate reactions with multiple substrates/products as well as branched and cyclic metabolic pathways. To achieve its metabolic tasks, the new model employs evolutionary optimized pathways with minimal number of reactions. Numerical simulations of this realistic model on the universal network of all reactions in the KEGG database produced approximately quadratic scaling between the number of regulated pathways and the size of the metabolic network. To quantify the geometrical structure of individual pathways, we investigated the relationship between their number of reactions, byproducts, intermediate, and feedback metabolites. Our results validate and explain the ubiquitous appearance of the quadratic scaling for a broad spectrum of topologies of underlying universal metabolic networks. They also demonstrate why, in spite of "small-world" topology, real-life metabolic networks are characterized by a broad distribution of pathway

  14. Integrating whole-genome expression results into metabolic networks with Pathway Processor.

    PubMed

    Cavalieri, Duccio; Grosu, Paul

    2004-05-01

    Genes never act alone in a biological system, but participate in a cascade of networks. As a result, analyzing microarray data from a pathway perspective leads to a new level of understanding the system. The authors' group has recently developed Pathway Processor (http://cgr.harvard.edu/cavalieri/pp.html), an automatic statistical method to determine which pathways are most affected by transcriptional changes and to map expression data from multiple whole-genome expression experiments on metabolic pathways. This unit presents applications of the Pathway Processor software.

  15. Metabolism of testosterone by human granulosa cells in culture: influence of follicle-stimulating hormone and luteinizing hormone

    SciTech Connect

    Moon, Y.S.; Duleba, A.; Leung, P.C.; Gomel, V.

    1982-03-15

    Human granulosa cells were isolated from follicles (8 to 15 mm) and cultivated for 24 hours in the presence or absence of follicle-stimulating hormone (NIH-FSH-HS-1, 1 microgram/ml) and luteinizing hormone (NIAMDD-hLH-1, 1 microgram/ml). Testosterone -4-14C was added subsequently to all cultures for 4-, 6-, and 24-hour periods. Of the seven metabolites of testosterone studied, 17 beta-estradiol (E2) and estrone (E1) were the major products. In all patients, levels of E2 were three to ten times higher than those of E1. Production of E2, but not E1, was stimulated by either follicle-stimulating hormone (FSH) or luteinizing hormone (LH). The cells of the largest follicle (15 mm) showed greater response to LH than to FSH. Production of the other C19 and C18 metabolites was very low or negligible. These results further suggest that FSH regulates the aromatization of testosterone in human granulosa cells, and that LH may have the same effect on the matured follicle during the preovulatory period.

  16. An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk

    DTIC Science & Technology

    2008-10-01

    1.02-1.9] for carriers of A allele); CYP1B1 (rs1056827: OR = 1.7 ]95% CI:1.2-2.5] for T homozygotes); SRD5A1 (rs248793: OR=1.2 [95% CI: 1.02-1.5... CYP1B1 *2 and GSTP1), breast cancer risk was 1.6 (95% CI: 1.03-2.4) times higher for carriers of 1 high risk genotype and 2.8 (95% CI: 1.5-5.3) times...is modified by variation in genes within hormonal pathways. 15. SUBJECT TERMS Genetic polymorphisms , epidemiology, exogenous risk factors, gene

  17. Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes

    PubMed Central

    Ye, Hanfeng; Ha, Mei; Yang, Min; Yue, Ping; Xie, Zhengyuan; Liu, Changjiang

    2017-01-01

    Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema. Triiodothyronine (T3), thyroxine (T4) and thyrotropin releasing hormone (TRH) were reduced. DEHP caused ROS production, oxidative stress and k-Ras upregulation, thereby activating the ERK and Akt pathways in vivo and in vitro. Moreover, TRH receptor (TRHr) level was elevated after the activation of the Akt pathway and was downregulated after the inhibition of the Akt pathway. However, TRHr was not modulated by the ERK pathway. Additionally, hepatic enzymes, including Ugt1a1, CYP2b1, Sult1e1, and Sult2b1, were significantly induced after DEHP exposure. Taken together, DEHP can perturb TH homeostasis and reduce TH levels. The activated Ras/Akt/TRHr pathway and induced hepatic enzymes play vital roles in thyroid-disrupting effects of DEHP. PMID:28065941

  18. Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes.

    PubMed

    Ye, Hanfeng; Ha, Mei; Yang, Min; Yue, Ping; Xie, Zhengyuan; Liu, Changjiang

    2017-01-09

    Di(2-ethylhexyl) phthalate (DEHP), as a widespread environmental pollutant and an endocrine disruptor, can disturb the homeostasis of thyroid hormones (THs). In order to elucidate roles of the MAPK and PI3K/Akt pathways and hepatic enzymes in thyroid-disrupting effects of DEHP, Sprague-Dawley rats were dosed with DEHP by gavage for 30 consecutive days; Nthy-ori 3-1 cells were treated with DEHP with NAC, k-Ras siRNA or inhibitors (U0126 and wortmannin). Results showed that DEHP led to histopathologic changes in rat thyroid and liver, such as the decrease in thyroid follicular cavity diameter, hepatocyte edema. Triiodothyronine (T3), thyroxine (T4) and thyrotropin releasing hormone (TRH) were reduced. DEHP caused ROS production, oxidative stress and k-Ras upregulation, thereby activating the ERK and Akt pathways in vivo and in vitro. Moreover, TRH receptor (TRHr) level was elevated after the activation of the Akt pathway and was downregulated after the inhibition of the Akt pathway. However, TRHr was not modulated by the ERK pathway. Additionally, hepatic enzymes, including Ugt1a1, CYP2b1, Sult1e1, and Sult2b1, were significantly induced after DEHP exposure. Taken together, DEHP can perturb TH homeostasis and reduce TH levels. The activated Ras/Akt/TRHr pathway and induced hepatic enzymes play vital roles in thyroid-disrupting effects of DEHP.

  19. On the levels of enzymatic substrate specificity: Implications for the early evolution of metabolic pathways

    NASA Technical Reports Server (NTRS)

    Lazcano, A.; Diaz-Villagomez, E.; Mills, T.; Oro, J.

    1995-01-01

    The most frequently invoked explanation for the origin of metabolic pathways is the retrograde evolution hypothesis. In contrast, according to the so-called 'patchwork' theory, metabolism evolved by the recruitment of relatively inefficient small enzymes of broad specificity that could react with a wide range of chemically related substrates. In this paper it is argued that both sequence comparisons and experimental results on enzyme substrate specificity support the patchwork assembly theory. The available evidence supports previous suggestions that gene duplication events followed by a gradual neoDarwinian accumulation of mutations and other minute genetic changes lead to the narrowing and modification of enzyme function in at least some primordial metabolic pathways.

  20. Neuromuscular, metabolic and hormonal profiles of young tennis players and untrained boys.

    PubMed

    Mero, A; Jaakkola, L; Komi, P V

    1989-01-01

    This study compared the neuromuscular, metabolic and hormonal profiles of trained prepubescent tennis players and an untrained group. The boys in the experimental group (n = 9; mean age +/- S.D. = 11.4 +/- 0.5 years) had participated in tennis training for 2.3 +/- 1.0 years and the boys in the control group (n = 9; mean age +/- S.D. = 10.9 +/- 0.4 years) were normal active volunteers. The tennis players were found to be physically more active than the controls when the comparison was made for either 1 year (4.9 +/- 1.8 vs 2.6 +/- 2.5 times per week; P less than 0.05) or for 1 week (3.4 +/- 1.2 vs 0.4 +/- 0.5 times; P less than 0.001) preceding the tests. Choice reaction time was significantly (P less than 0.01) shorter in the experimental group (258 +/- 16 ms) than in the control group (344 +/- 81 ms). Dropping height in the best drop jump was significantly (P less than 0.05) higher in the tennis players (0.46 +/- 0.19 m) than in the control boys (0.27 +/- 0.10 m). The tennis players had significantly lower oxygen consumption at the 'anaerobic threshold' than the controls (P less than 0.05). There were no significant differences between the groups in serum hormone levels. The small differences that existed may have been caused by active participation in sport by the tennis players.

  1. Role of hormonal factors in plasma K alterations in acute respiratory and metabolic alkalosis in dogs.

    PubMed

    Suzuki, H; Hishida, A; Ohishi, K; Kimura, M; Honda, N

    1990-02-01

    Studies were performed on previously nephrectomized dogs to examine roles of hormonal factors in plasma potassium alterations in acute alkalosis. Respiratory and metabolic alkalosis were induced by hyperventilation and intravenous NaHCO3 or tris(hydroxymethyl)aminomethane (Tris) infusion, respectively. Respiratory and NaHCO3-induced alkalosis provoked decreases in plasma potassium from the control value of 5.12 +/- 0.68 (SE) to 4.21 +/- 0.55 meq/l (P less than 0.01) and from 4.65 +/- 0.26 to 3.91 +/- 0.16 meq/l (P less than 0.01) within 180 min, respectively. In contrast, Tris-induced alkalosis elicited an increase in plasma potassium from the control value of 4.56 +/- 0.30 to 5.31 +/- 0.30 meq/l (P less than 0.01). Hypokalemia in respiratory alkalosis was associated with a decrease in the plasma norepinephrine concentration from the control level of 377 +/- 104 to 155 +/- 41 pg/ml (P less than 0.05) but not with changes in plasma levels of epinephrine, insulin, glucagon, cortisol, and aldosterone. However, this hypokalemia was not affected by phentolamine. Also, somatostatin did not modify the hypokalemic response. NaHCO3-induced hypokalemia was associated with a decline in the plasma aldosterone and norepinephrine concentrations. The decline in plasma norepinephrine in NaHCO3-induced alkalosis followed the decrease in plasma potassium. In Tris-induced alkalosis, plasma insulin increased but norepinephrine decreased. The findings do not suggest fundamental roles of the hormonal factors in the plasma potassium alterations in bilaterally nephrectomized dogs with acute alkalosis.

  2. Hormones, metabolism and body composition as major determinants of blood rheology: potential pathophysiological meaning.

    PubMed

    Brun, J F

    2002-01-01

    The rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status and plasma protein pattern are well known to exert a major influence. The oxidative stress induced by increased free radicals production decreases red cell deformability. Among circulating substances, the divalent cations magnesium and zinc improve red cell deformability probably via calcium antagonistic effects. Some metabolites like lactate or ketone bodies decrease red cell deformability, although the former has apparently the opposite effect in highly trained individuals. Endothelium-derived factors such as nitric oxide (NO) and several arachidonic acid derivatives modulate both RBC and white cell mechanics. Endothelium regulates also blood rheology via the release of PAI-1 which governs plasma fibrinogen levels. However, endothelium is not the only organ involved in the regulation of blood rheology: the kidney (by releasing erythropoietin which is a major "viscoregulatory" factor), the endocrine pancreas (via the action of insulin and glucagon on red cells), the adrenal gland (norepinephrine) and the endocrine heart (atrial natriuretic peptide) are also likely to exert important effects. Recently, increasing evidence is accumulating for a role of two other endocrine tissues in the regulation of blood rheology: the adipose tissue (free fatty acids, PAI-1, IL-6, leptin) and the pituitary gland (growth hormone-somatomedin axis, including the somatomedin carrier protein IGFBP1). These organs provide a link between body composition and hemorheology, since GH and somatomedins are major regulators of the body content in fat and water while the endocrine activity of fat mass is apparently proportional to its size. These mechanisms explain to some extent why many situations, either physiological (diet, exercise) or pathological (diabetes, uremia) are associated with marked

  3. Deciphering the biological effects of acupuncture treatment modulating multiple metabolism pathways.

    PubMed

    Zhang, Aihua; Yan, Guangli; Sun, Hui; Cheng, Weiping; Meng, Xiangcai; Liu, Li; Xie, Ning; Wang, Xijun

    2016-02-16

    Acupuncture is an alternative therapy that is widely used to treat various diseases. However, detailed biological interpretation of the acupuncture stimulations is limited. We here used metabolomics and proteomics technology, thereby identifying the serum small molecular metabolites into the effect and mechanism pathways of standardized acupuncture treatments at 'Zusanli' acupoint which was the most often used acupoint in previous reports. Comprehensive overview of serum metabolic profiles during acupuncture stimulation was investigated. Thirty-four differential metabolites were identified in serum metabolome and associated with ten metabolism pathways. Importantly, we have found that high impact glycerophospholipid metabolism, fatty acid metabolism, ether lipid metabolism were acutely perturbed by acupuncture stimulation. As such, these alterations may be useful to clarify the biological mechanism of acupuncture stimulation. A series of differentially expressed proteins were identified and such effects of acupuncture stimulation were found to play a role in transport, enzymatic activity, signaling pathway or receptor interaction. Pathway analysis further revealed that most of these proteins were found to play a pivotal role in the regulation of multiple metabolism pathways. It demonstrated that the metabolomics coupled with proteomics as a powerful approach for potential applications in understanding the biological effects of acupuncture stimulation.

  4. Simultaneous prediction of enzyme orthologs from chemical transformation patterns for de novo metabolic pathway reconstruction

    PubMed Central

    Tabei, Yasuo; Yamanishi, Yoshihiro; Kotera, Masaaki

    2016-01-01

    Motivation: Metabolic pathways are an important class of molecular networks consisting of compounds, enzymes and their interactions. The understanding of global metabolic pathways is extremely important for various applications in ecology and pharmacology. However, large parts of metabolic pathways remain unknown, and most organism-specific pathways contain many missing enzymes. Results: In this study we propose a novel method to predict the enzyme orthologs that catalyze the putative reactions to facilitate the de novo reconstruction of metabolic pathways from metabolome-scale compound sets. The algorithm detects the chemical transformation patterns of substrate–product pairs using chemical graph alignments, and constructs a set of enzyme-specific classifiers to simultaneously predict all the enzyme orthologs that could catalyze the putative reactions of the substrate–product pairs in the joint learning framework. The originality of the method lies in its ability to make predictions for thousands of enzyme orthologs simultaneously, as well as its extraction of enzyme-specific chemical transformation patterns of substrate–product pairs. We demonstrate the usefulness of the proposed method by applying it to some ten thousands of metabolic compounds, and analyze the extracted chemical transformation patterns that provide insights into the characteristics and specificities of enzymes. The proposed method will open the door to both primary (central) and secondary metabolism in genomics research, increasing research productivity to tackle a wide variety of environmental and public health matters. Availability and Implementation: Contact: maskot@bio.titech.ac.jp PMID:27307627

  5. A review of the physical and metabolic effects of cross-sex hormonal therapy in the treatment of gender dysphoria.

    PubMed

    Seal, Leighton J

    2016-01-01

    This review focuses on the effect that cross-gender sex steroid therapy has on metabolic and hormonal parameters. There is an emphasis on those changes that result in significant clinical effects such as the positive effects of the development of secondary sexual characteristics and negative effects such as haemostatic effects and thromboembolism in transwomen or dyslipidaemia in transmen. There is also a description of the current hormonal regimens used at the largest UK gender identity clinic. The overall safety of these treatments in the context of long-term outcome data is reviewed.

  6. Ghrelin and its interactions with growth hormone, leptin and orexins: implications for the sleep-wake cycle and metabolism.

    PubMed

    García-García, Fabio; Juárez-Aguilar, Enrique; Santiago-García, Juan; Cardinali, Daniel P

    2014-02-01

    Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep-wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern.

  7. Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer.

    PubMed

    Tan, Juan; Yu, Chen-Yang; Wang, Zhen-Hua; Chen, Hao-Yan; Guan, Jian; Chen, Ying-Xuan; Fang, Jing-Yuan

    2015-02-16

    Members of the inositol phosphate metabolism pathway regulate cell proliferation, migration and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and are frequently dysregulated in cancer. Whether germline genetic variants in inositol phosphate metabolism pathway are associated with cancer risk remains to be clarified. We examined the association between inositol phosphate metabolism pathway genes and risk of eight types of cancer using data from genome-wide association studies. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-based associations were tested using the permutation-based adaptive rank-truncated product method. The overall inositol phosphate metabolism pathway was significantly associated with risk of lung cancer (P = 2.00 × 10(-4)), esophageal squamous cell carcinoma (P = 5.70 × 10(-3)), gastric cancer (P = 3.03 × 10(-2)) and renal cell carcinoma (P = 1.26 × 10(-2)), but not with pancreatic cancer (P = 1.40 × 10(-1)), breast cancer (P = 3.03 × 10(-1)), prostate cancer (P = 4.51 × 10(-1)), and bladder cancer (P = 6.30 × 10(-1)). Our results provide a link between inherited variation in the overall inositol phosphate metabolism pathway and several individual genes and cancer. Further studies will be needed to validate these positive findings, and to explore its mechanisms.

  8. Improving fatty acids production by engineering dynamic pathway regulation and metabolic control

    PubMed Central

    Xu, Peng; Li, Lingyun; Zhang, Fuming; Stephanopoulos, Gregory; Koffas, Mattheos

    2014-01-01

    Global energy demand and environmental concerns have stimulated increasing efforts to produce carbon-neutral fuels directly from renewable resources. Microbially derived aliphatic hydrocarbons, the petroleum-replica fuels, have emerged as promising alternatives to meet this goal. However, engineering metabolic pathways with high productivity and yield requires dynamic redistribution of cellular resources and optimal control of pathway expression. Here we report a genetically encoded metabolic switch that enables dynamic regulation of fatty acids (FA) biosynthesis in Escherichia coli. The engineered strains were able to dynamically compensate the critical enzymes involved in the supply and consumption of malonyl-CoA and efficiently redirect carbon flux toward FA biosynthesis. Implementation of this metabolic control resulted in an oscillatory malonyl-CoA pattern and a balanced metabolism between cell growth and product formation, yielding 15.7- and 2.1-fold improvement in FA titer compared with the wild-type strain and the strain carrying the uncontrolled metabolic pathway. This study provides a new paradigm in metabolic engineering to control and optimize metabolic pathways facilitating the high-yield production of other malonyl-CoA–derived compounds. PMID:25049420

  9. Engineering specialized metabolic pathways--is there a room for enzyme improvements?

    PubMed

    Bar-Even, Arren; Salah Tawfik, Dan

    2013-04-01

    Recent advances in enzyme engineering enable dramatic improvements in catalytic efficiency and/or selectivity, as well as de novo engineering of enzymes to catalyze reactions where natural enzymes are not available. Can these capabilities be utilized to transform biosynthesis pathways? Metabolic engineering is traditionally based on combining existing enzymes to give new, or modified, pathways, within a new context and/or organism. How efficient, however, are the individual enzyme components? Is there room to improve pathway performance by enzyme engineering? We discuss the differences between enzymes in central versus specialized, or secondary metabolism and highlight unique features of specialized metabolism enzymes participating in the synthesis of natural products. We argue that, for the purpose of metabolic engineering, the catalytic efficiency and selectivity of many enzymes can be improved with the aim of achieving higher rates, yields and product purities. We also note the relative abundance of spontaneous reactions in specialized metabolism, and the potential advantage of engineering enzymes that will catalyze these steps. Specialized metabolism therefore offers new opportunities to integrate enzyme and pathway engineering, thereby achieving higher metabolic efficiencies, enhanced production rates and improved product purities.

  10. Absorption and metabolization of sex hormones and their transformation into contraceptive technologies: the paths taken by medical thought in Brazil.

    PubMed

    Bonan, Claudia; Teixeira, Luiz Antonio; Nakano, Andreza Rodrigues

    2017-01-01

    The article analyses knowledge assimilation and the development of clinical and research practices relating to sex hormones among Brazilian gynaecologists. It discusses the paths taken by medical thought from the reception of the hormones to their transformation into contraceptives. Our objective is to comprehend styles of introducing and disseminating medical technologies in the area of reproductive health in Brazil. It uses methods of historical analysis and takes as its source the Anais Brasileiros de Ginecologia, a journal published between 1936 and 1970. From the outset, the accompaniment of scientific breakthroughs in relation to sex hormones and their use to treat diverse female illnesses played a key role in the rapid medical acceptance of hormonal contraception. Scientific and technical questions (side effects, dosages) and the demographic issue formed part of the majority of the debates. Objections from the Catholic Church were considered but did not set the agenda of medical thought on contraceptives. The quest to consolidate gynaecology as a scientific, modern and cosmopolitan area of expertise, along with sanitary and demographic motives that allowed contraceptives to be classed as ethical drugs, are identified as processes underlying the assimilation and metabolization of sex hormones as hormonal contraceptives.

  11. FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4-dependent and independent pathways.

    PubMed

    Wu, Ai-Luen; Coulter, Sally; Liddle, Christopher; Wong, Anne; Eastham-Anderson, Jeffrey; French, Dorothy M; Peterson, Andrew S; Sonoda, Junichiro

    2011-03-18

    Fibroblast growth factor 19 (FGF19) is a hormone-like protein that regulates carbohydrate, lipid and bile acid metabolism. At supra-physiological doses, FGF19 also increases hepatocyte proliferation and induces hepatocellular carcinogenesis in mice. Much of FGF19 activity is attributed to the activation of the liver enriched FGF Receptor 4 (FGFR4), although FGF19 can activate other FGFRs in vitro in the presence of the coreceptor βKlotho (KLB). In this report, we investigate the role of FGFR4 in mediating FGF19 activity by using Fgfr4 deficient mice as well as a variant of FGF19 protein (FGF19v) which is specifically impaired in activating FGFR4. Our results demonstrate that FGFR4 activation mediates the induction of hepatocyte proliferation and the suppression of bile acid biosynthesis by FGF19, but is not essential for FGF19 to improve glucose and lipid metabolism in high fat diet fed mice as well as in leptin-deficient ob/ob mice. Thus, FGF19 acts through multiple receptor pathways to elicit pleiotropic effects in regulating nutrient metabolism and cell proliferation.

  12. Anaplasma phagocytophilum Infection Subverts Carbohydrate Metabolic Pathways in the Tick Vector, Ixodes scapularis

    PubMed Central

    Cabezas-Cruz, Alejandro; Alberdi, Pilar; Valdés, James J.; Villar, Margarita; de la Fuente, José

    2017-01-01

    The obligate intracellular pathogen, Anaplasma phagocytophilum, is the causative agent of human, equine, and canine granulocytic anaplasmosis and tick-borne fever (TBF) in ruminants. A. phagocytophilum has become an emerging tick-borne pathogen in the United States, Europe, Africa, and Asia, with increasing numbers of infected people and animals every year. It has been recognized that intracellular pathogens manipulate host cell metabolic pathways to increase infection and transmission in both vertebrate and invertebrate hosts. However, our current knowledge on how A. phagocytophilum affect these processes in the tick vector, Ixodes scapularis is limited. In this study, a genome-wide search for components of major carbohydrate metabolic pathways was performed in I. scapularis ticks for which the genome was recently published. The enzymes involved in the seven major carbohydrate metabolic pathways glycolysis, gluconeogenesis, pentose phosphate, tricarboxylic acid cycle (TCA), glyceroneogenesis, and mitochondrial oxidative phosphorylation and β-oxidation were identified. Then, the available transcriptomics and proteomics data was used to characterize the mRNA and protein levels of I. scapularis major carbohydrate metabolic pathway components in response to A. phagocytophilum infection of tick tissues and cultured cells. The results showed that major carbohydrate metabolic pathways are conserved in ticks. A. phagocytophilum infection inhibits gluconeogenesis and mitochondrial metabolism, but increases the expression of glycolytic genes. A model was proposed to explain how A. phagocytophilum could simultaneously control tick cell glucose metabolism and cytoskeleton organization, which may be achieved in part by up-regulating and stabilizing hypoxia inducible factor 1 alpha in a hypoxia-independent manner. The present work provides a more comprehensive view of the major carbohydrate metabolic pathways involved in the response to A. phagocytophilum infection in ticks

  13. Drought Tolerance Conferred to Sugarcane by Association with Gluconacetobacter diazotrophicus: A Transcriptomic View of Hormone Pathways

    PubMed Central

    Vargas, Lívia; Santa Brígida, Ailton B.; Mota Filho, José P.; de Carvalho, Thais G.; Rojas, Cristian A.; Vaneechoutte, Dries; Van Bel, Michiel; Farrinelli, Laurent; Ferreira, Paulo C. G.; Vandepoele, Klaas; Hemerly, Adriana S.

    2014-01-01

    Sugarcane interacts with particular types of beneficial nitrogen-fixing bacteria that provide fixed-nitrogen and plant growth hormones to host plants, promoting an increase in plant biomass. Other benefits, as enhanced tolerance to abiotic stresses have been reported to some diazotrophs. Here we aim to study the effects of the association between the diazotroph Gluconacetobacter diazotrophicus PAL5 and sugarcane cv. SP70-1143 during water depletion by characterizing differential transcriptome profiles of sugarcane. RNA-seq libraries were generated from roots and shoots of sugarcane plants free of endophytes that were inoculated with G. diazotrophicus and subjected to water depletion for 3 days. A sugarcane reference transcriptome was constructed and used for the identification of differentially expressed transcripts. The differential profile of non-inoculated SP70-1143 suggests that it responds to water deficit stress by the activation of drought-responsive markers and hormone pathways, as ABA and Ethylene. qRT-PCR revealed that root samples had higher levels of G. diazotrophicus 3 days after water deficit, compared to roots of inoculated plants watered normally. With prolonged drought only inoculated plants survived, indicating that SP70-1143 plants colonized with G. diazotrophicus become more tolerant to drought stress than non-inoculated plants. Strengthening this hypothesis, several gene expression responses to drought were inactivated or regulated in an opposite manner, especially in roots, when plants were colonized by the bacteria. The data suggests that colonized roots would not be suffering from stress in the same way as non-inoculated plants. On the other hand, shoots specifically activate ABA-dependent signaling genes, which could act as key elements in the drought resistance conferred by G. diazotrophicus to SP70-1143. This work reports for the first time the involvement of G. diazotrophicus in the promotion of drought-tolerance to sugarcane cv. SP70

  14. Drought tolerance conferred to sugarcane by association with Gluconacetobacter diazotrophicus: a transcriptomic view of hormone pathways.

    PubMed

    Vargas, Lívia; Santa Brígida, Ailton B; Mota Filho, José P; de Carvalho, Thais G; Rojas, Cristian A; Vaneechoutte, Dries; Van Bel, Michiel; Farrinelli, Laurent; Ferreira, Paulo C G; Vandepoele, Klaas; Hemerly, Adriana S

    2014-01-01

    Sugarcane interacts with particular types of beneficial nitrogen-fixing bacteria that provide fixed-nitrogen and plant growth hormones to host plants, promoting an increase in plant biomass. Other benefits, as enhanced tolerance to abiotic stresses have been reported to some diazotrophs. Here we aim to study the effects of the association between the diazotroph Gluconacetobacter diazotrophicus PAL5 and sugarcane cv. SP70-1143 during water depletion by characterizing differential transcriptome profiles of sugarcane. RNA-seq libraries were generated from roots and shoots of sugarcane plants free of endophytes that were inoculated with G. diazotrophicus and subjected to water depletion for 3 days. A sugarcane reference transcriptome was constructed and used for the identification of differentially expressed transcripts. The differential profile of non-inoculated SP70-1143 suggests that it responds to water deficit stress by the activation of drought-responsive markers and hormone pathways, as ABA and Ethylene. qRT-PCR revealed that root samples had higher levels of G. diazotrophicus 3 days after water deficit, compared to roots of inoculated plants watered normally. With prolonged drought only inoculated plants survived, indicating that SP70-1143 plants colonized with G. diazotrophicus become more tolerant to drought stress than non-inoculated plants. Strengthening this hypothesis, several gene expression responses to drought were inactivated or regulated in an opposite manner, especially in roots, when plants were colonized by the bacteria. The data suggests that colonized roots would not be suffering from stress in the same way as non-inoculated plants. On the other hand, shoots specifically activate ABA-dependent signaling genes, which could act as key elements in the drought resistance conferred by G. diazotrophicus to SP70-1143. This work reports for the first time the involvement of G. diazotrophicus in the promotion of drought-tolerance to sugarcane cv. SP70

  15. Engineering of Metabolic Pathways by Artificial Enzyme Channels

    PubMed Central

    Pröschel, Marlene; Detsch, Rainer; Boccaccini, Aldo R.; Sonnewald, Uwe

    2015-01-01

    Application of industrial enzymes for production of valuable chemical compounds has greatly benefited from recent developments in Systems and Synthetic Biology. Both, in vivo and in vitro systems have been established, allowing conversion of simple into complex compounds. Metabolic engineering in living cells needs to be balanced which is achieved by controlling gene expression levels, translation, scaffolding, compartmentation, and flux control. In vitro applications are often hampered by limited protein stability/half-life and insufficient rates of substrate conversion. To improve stability and catalytic activity, proteins are post-translationally modified and arranged in artificial metabolic channels. Within the review article, we will first discuss the supramolecular organization of enzymes in living systems and second summarize current and future approaches to design artificial metabolic channels by additive manufacturing for the efficient production of desired products. PMID:26557643

  16. Aging signaling pathways and circadian clock-dependent metabolic derangements

    PubMed Central

    Tevy, Maria Florencia; Giebultowicz, Jadwiga; Pincus, Zachary; Mazzoccoli, Gianluigi; Vinciguerra, Manlio

    2013-01-01

    The circadian clock machinery orchestrates organism metabolism in order to ensure that development, survival and reproduction are attuned to diurnal environmental variations. For unknown reasons, there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissues homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient sensing networks might underlie age-related diseases; overall, greater knowledge of the molecular mediators of and variations in clock networks during lifespan may shed light on the aging process and how it may be delayed. In this review we address the complex links between the circadian clock, metabolic (dys)functions and aging in different model organisms. PMID:23299029

  17. Identification of cisplatin-regulated metabolic pathways in pluripotent stem cells.

    PubMed

    von Stechow, Louise; Ruiz-Aracama, Ainhoa; van de Water, Bob; Peijnenburg, Ad; Danen, Erik; Lommen, Arjen

    2013-01-01

    The chemotherapeutic compound, cisplatin causes various kinds of DNA lesions but also triggers other pertubations, such as ER and oxidative stress. We and others have shown that treatment of pluripotent stem cells with cisplatin causes a plethora of transcriptional and post-translational alterations that, to a major extent, point to DNA damage response (DDR) signaling. The orchestrated DDR signaling network is important to arrest the cell cycle and repair the lesions or, in case of damage beyond repair, eliminate affected cells. Failure to properly balance the various aspects of the DDR in stem cells contributes to ageing and cancer. Here, we performed metabolic profiling by mass spectrometry of embryonic stem (ES) cells treated for different time periods with cisplatin. We then integrated metabolomics with transcriptomics analyses and connected cisplatin-regulated metabolites with regulated metabolic enzymes to identify enriched metabolic pathways. These included nucleotide metabolism, urea cycle and arginine and proline metabolism. Silencing of identified proline metabolic and catabolic enzymes indicated that altered proline metabolism serves as an adaptive, rather than a toxic response. A group of enriched metabolic pathways clustered around the metabolite S-adenosylmethionine, which is a hub for methylation and transsulfuration reactions and polyamine metabolism. Enzymes and metabolites with pro- or anti-oxidant functions were also enriched but enhanced levels of reactive oxygen species were not measured in cisplatin-treated ES cells. Lastly, a number of the differentially regulated metabolic enzymes were identified as target genes of the transcription factor p53, pointing to p53-mediated alterations in metabolism in response to genotoxic stress. Altogether, our findings reveal interconnecting metabolic pathways that are responsive to cisplatin and may serve as signaling modules in the DDR in pluripotent stem cells.

  18. Metabolic Profiling of Retrograde Pathway Transcription Factors Rtg1 and Rtg3 Knockout Yeast

    PubMed Central

    Hashim, Zanariah; Mukai, Yukio; Bamba, Takeshi; Fukusaki, Eiichiro

    2014-01-01

    Rtg1 and Rtg3 are two basic helix-loop-helix (bHLH) transcription factors found in yeast Saccharomyces cerevisiae that are involved in the regulation of the mitochondrial retrograde (RTG) pathway. Under RTG response, anaplerotic synthesis of citrate is activated, consequently maintaining the supply of important precursors necessary for amino acid and nucleotide synthesis. Although the roles of Rtg1 and Rtg3 in TCA and glyoxylate cycles have been extensively reported, the investigation of other metabolic pathways has been lacking. Characteristic dimer formation in bHLH proteins, which allows for combinatorial gene expression, and the link between RTG and other regulatory pathways suggest more complex metabolic signaling involved in Rtg1/Rtg3 regulation. In this study, using a metabolomics approach, we examined metabolic alteration following RTG1 and RTG3 deletion. We found that apart from TCA and glyoxylate cycles, which have been previously reported, polyamine biosynthesis and other amino acid metabolism were significantly altered in RTG-deficient strains. We revealed that metabolic alterations occurred at various metabolic sites and that these changes relate to different growth phases, but the difference can be detected even at the mid-exponential phase, when mitochondrial function is repressed. Moreover, the effect of metabolic rearrangements can be seen through the chronological lifespan (CLS) measurement, where we confirmed the role of the RTG pathway in extending the yeast lifespan. Through a comprehensive metabolic profiling, we were able to explore metabolic phenotypes previously unidentified by other means and illustrate the possible correlations of Rtg1 and Rtg3 in different pathways. PMID:25007314

  19. iTRAQ-based quantitative proteomic analysis of Thermobifida fusca reveals metabolic pathways of cellulose utilization.

    PubMed

    Adav, Sunil S; Ng, Chee Sheng; Sze, Siu Kwan

    2011-09-06

    Thermobifida fusca is an aerobic, thermophilic, cellulose degrading bacterium identified in heated organic materials. This study applied iTRAQ quantitative proteomic analysis to the cellular and membrane proteomes of T. fusca grown in presence and absence of cellulose to elucidate the cellular processes induced by cellulose nutrient. Using an iTRAQ-based quantitative proteomic approach, 783 cytosolic and 181 membrane proteins expressed during cellulose hydrolysis were quantified with ≤1% false discovery rate. The comparative iTRAQ quantification revealed considerable induction in the expression levels and up-regulation of specific proteins in cellulosic medium than non-cellulosic medium. The regulated proteins in cellulosic medium were grouped under central carbohydrate metabolism such as glycolysis/gluconeogenesis, pentose phosphate pathways, citric acid cycle, starch, sugars, pyruvate, propanoate and butanoate metabolism; energy metabolism that includes oxidative phosphorylation, nitrogen, methane and sulfur metabolism; fatty acid metabolism, amino acid metabolic pathways, purine and pyrimidine metabolism, and main cellular genetic information processing functions like replication, transcription, translation, and cell wall synthesis; and environmental information processing (membrane transport and signal transduction). The results demonstrated cellulose induced several metabolic pathways during cellulose utilization.

  20. Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways.

    PubMed Central

    Robson, R A; Miners, J O; Wing, L M; Birkett, D J

    1984-01-01

    The effect of rifampicin pre-treatment (600 mg daily for 6 days) on theophylline disposition at steady state was investigated in six healthy males. Following rifampicin treatment total plasma clearance of theophylline increased by 82%. Theophylline clearance through each metabolic pathway was increased, 1-demethylation by (116 +/- 34%) (mean +/- s.e. mean), 3-demethylation by (91 +/- 16%) and 8-oxidation by (81 +/- 17%). Renal clearance of unchanged drug was not altered. Previous studies have suggested that two forms of cytochrome P-450 are involved in theophylline metabolism, one mediating the N-demethylations and the other 8-oxidation. Thus, unlike the selective inductive effect of rifampicin on antipyrine metabolic pathways, rifampicin does not differentially affect those forms of cytochrome P-450 involved in theophylline metabolism. The extent to which theophylline metabolism is induced by rifampicin is likely to have important clinical consequences. PMID:6487483

  1. Metabolic Pathways of the Camptothecin Analog AR-67

    PubMed Central

    Horn, Jamie; Milewska, Marta; Arnold, Susanne M.

    2011-01-01

    7-tert-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67; also known as DB-67) is a novel lipophilic camptothecin analog in early-phase anticancer clinical trials. In support of these studies, we evaluated the metabolism of AR-67 in vitro and identified potential metabolites in patient samples. The lactone form of AR-67 was found to be preferentially metabolized over AR-67 carboxylate in human microsomes. Subsequently, the lactone form was tested as a substrate in a panel of CYP450 and UDP-glucuronosyltransferase (UGT) enzymes known to metabolize the majority of clinically approved molecules. AR-67 was metabolized by CYP3A5, CYP3A4, CYP1A1, and CYP1A2, in order of activity. Extrahepatic UGT1A8 and UGT1A7 possessed at least 6-fold higher metabolizing activity than UGT1A1 and other UGT enzymes tested. CYP1A1 and UGT1A7 displayed Michaelis-Menten kinetics, whereas CYP3A4, CYP3A5, and UGT1A8 displayed kinetics consistent with substrate inhibition. Chromatographic analysis of representative patient plasma and urine samples demonstrated the presence of AR-67 glucuronides and oxidized products in the urine but only in very minimal amounts. We conclude that limited in vivo metabolism of AR-67 by UGT1A1 may partly explain the absence of AR-67 glucuronides in plasma and hypothesize that UGT1A8- and CYP3A-mediated biotransformation within the gastrointestinal epithelium may provide protective mechanisms against AR-67 gastrointestinal toxicity. PMID:21189330

  2. IN VITRO METABOLISM OF THYROID HORMONES BY RECOMBINANT HUMAN UDP-GLUCORONOSYLTRANSFERASES AND SULFOTRANSFERASES

    EPA Science Inventory

    Endocrine disruptors can decrease thyroid hormone levels via the induction of hepatic uridinediphosphate-glucoronosyltransferases (UGTs) and sulfotransferases (SULTs). Due to their ability to catalyze glucuronidation and sulfation of hormones and xenobiotics, UGTs and SULTs play ...

  3. Investigation of the central carbon metabolism of Sorangium cellulosum: metabolic network reconstruction and quantification of pathway fluxes.

    PubMed

    Bolten, Christoph J; Heinzle, Elmar; Müller, Rolf; Wittmann, Christoph

    2009-01-01

    In the present work, the metabolic network of primary metabolism of the slow-growing myxobacterium Sorangium cellulosum was reconstructed from the annotated genome sequence of the type strain So ce56. During growth on glucose as the carbon source and asparagine as the nitrogen source, So ce56 showed a very low growth rate of 0.23 d-(1), equivalent to a doubling time of 3 days. Based on a complete stoichiometric and isotopomer model of the central metabolism, 13C metabolic flux analysis was carried out for growth with glucose as carbon and asparagine as nitrogen sources. Normalized to the uptake flux for glucose (100%), cells recruited glycolysis (51%) and the pentose phosphate pathway (48%) as major catabolic pathways. The Entner-Doudoroff pathway and glyoxylate shunt were not active. A high flux through the TCA cycle (118%) enabled a strong formation of ATP, but cells revealed a rather low yield for biomass. Inspection of fluxes linked to energy metabolism revealed that S. cellulosum utilized only 10% of the ATP formed for growth, whereas 90% is required for maintenance. This explains the apparent discrepancy between the relatively low biomass yield and the high flux through the energy-delivering TCA cycle. The total flux of NADPH supply (216%) was higher than the demand for anabolism (156%), indicating additional reactions for balancing of NADPH. The cells further exhibited a highly active metabolic cycle, interconverting C3 and C4 metabolites of glycolysis and the TCA cycle. The present work provides the first insight into fluxes of the primary metabolism of myxobacteria, especially for future investigation on the supply of cofactors, building blocks, and energy in myxobacteria, producing natural compounds of biotechnological interest.

  4. Initial water deficit effects on Lupinus albus photosynthetic performance, carbon metabolism, and hormonal balance: metabolic reorganization prior to early stress responses.

    PubMed

    Pinheiro, Carla; António, Carla; Ortuño, Maria Fernanda; Dobrev, Petre I; Hartung, Wolfram; Thomas-Oates, Jane; Ricardo, Cândido Pinto; Vanková, Radomira; Chaves, M Manuela; Wilson, Julie C

    2011-10-01

    The early (2-4 d) effects of slowly imposed soil water deficit on Lupinus albus photosynthetic performance, carbon metabolism, and hormonal balance in different organs (leaf blade, stem stele, stem cortex, and root) were evaluated on 23-d-old plants (growth chamber assay). Our work shows that several metabolic adjustments occurred prior to alteration of the plant water status, implying that water deficit is perceived before the change in plant water status. The slow, progressive decline in soil water content started to be visible 3 d after withholding water (3 DAW). The earliest plant changes were associated with organ-specific metabolic responses (particularly in the leaves) and with leaf conductance and only later with plant water status and photosynthetic rate (4 DAW) or photosynthetic capacity (according to the Farquhar model; 6 DAW). Principal component analysis (PCA) of the physiological parameters, the carbohydrate and the hormone levels and their relative values, as well as leaf water-soluble metabolites full scan data (LC-MS/MS), showed separation of the different sampling dates. At 6 DAW classically described stress responses are observed, with plant water status, ABA level, and root hormonal balance contributing to the separation of these samples. Discrimination of earlier stress stages (3 and 4 DAW) is only achieved when the relative levels of indole-3-acetic acid (IAA), cytokinins (Cks), and carbon metabolism (glucose, sucrose, raffinose, and starch levels) are taken into account. Our working hypothesis is that, in addition to single responses (e.g. ABA increase), the combined alterations in hormone and carbohydrate levels play an important role in the stress response mechanism. Response to more advanced stress appears to be associated with a combination of cumulative changes, occurring in several plant organs. The carbohydrate and hormonal balance in the leaf (IAA to bioactive-Cks; soluble sugars to IAA and starch to IAA; relative abundances of the

  5. The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.

    PubMed

    Roques, Béatrice B; Leghait, Julien; Lacroix, Marlène Z; Lasserre, Frédéric; Pineau, Thierry; Viguié, Catherine; Martin, Pascal G P

    2013-10-01

    Fipronil is described as a thyroid disruptor in rat. Based on the hypothesis that this results from a perturbation of hepatic thyroid hormone metabolism, our goal was to investigate the pathways involved in fipronil-induced liver gene expression regulations. First, we performed a microarray screening in the liver of rats treated with fipronil or vehicle. Fipronil treatment led to the upregulation of several genes involved in the metabolism of xenobiotics, including the cytochrome P450 Cyp2b1, Cyp2b2 and Cyp3a1, the carboxylesterases Ces2 and Ces6, the phase II enzymes Ugt1a1, Sult1b1 and Gsta2, and the membrane transporters Abcc2, Abcc3, Abcg5, Abcg8, Slco1a1 and Slco1a4. Based on a large overlap with the target genes of constitutive androstane receptor (CAR) and pregnane X receptor (PXR), we postulated that these two nuclear receptors are involved in mediating the effects of fipronil on liver gene expression in rodents. We controlled that liver gene expression changes induced by fipronil were generally reproduced in mice, and then studied the effects of fipronil in wild-type, CAR- and PXR-deficient mice. For most of the genes studied, the gene expression modulations were abolished in the liver of PXR-deficient mice and were reduced in the liver of CAR-deficient mice. However, CAR and PXR activation in mouse liver was not associated with a marked increase of thyroid hormone clearance, as observed in rat. Nevertheless, our data clearly indicate that PXR and CAR are key modulators of the hepatic gene expression profile following fipronil treatment which, in rats, may contribute to increase thyroid hormone clearance.

  6. Serum Adiponectin Level and Clinical, Metabolic, and Hormonal Markers in Patients with Polycystic Ovary Syndrome

    PubMed Central

    Yildiz, Yunus; Ozaksit, Gülnur; Serdar Unlu, Bekir; Ozgu, Emre; Energin, Hasan; Kaba, Metin; Ugur, Mustafa

    2014-01-01

    Background: To investigate the relationship between adiponectin, metabolic and hor- monal parameters, and insulin resistance in patients with non-treated polycystic ovary syndrome. Materials and Methods: In this cross-sectional observational study, 81 patients admitted to out-patient clinic with complaints of menstrual irregularity, hirsutism and obesity were enrolled. Serum adiponectin, biochemical and hormonal parameters, and 75 gram oral glu- cose tolerance test (OGTT) were measured. Spearman’s correlation coefficient was used for statistical analysis. Results: We observed inverse correlations between serum adiponectin level and body mass index, homeostasis model assessment insulin-resistance score, insulin level, fast- ing glucose level, and prolactin level (p=0.001, p=0.02, p=0.04, p=0.02, and p=0.005, respectively). No significant correlations were found between serum adiponectin level and age, height, weight, Ferriman-Gallwey score, 2 hours OGTT test value and free tes- tosterone level (p=0.3, p=0.6, p=0.2, p=0.8, p=0.9, and p=0.01, respectively). Conclusion: The present study demonstrated that in polycystic ovary syndrome patients, when serum adiponectin level decreased, degree of insulin resistance increased. Our find- ings indicate that serum adiponectin level is likely to be an adequate marker for deter- mination of the degree of insulin resistance, and may be a predictor of diseases, such as type 2 diabetes mellitus (T2DM) and metabolic syndrome, which develop on the basis of insulin resistance. PMID:24520503

  7. Neonicotinoid metabolism: compounds, substituents, pathways, enzymes, organisms, and relevance.

    PubMed

    Casida, John E

    2011-04-13

    Neonicotinoids are one of the three principal insecticide chemotypes. The seven major commercial neonicotinoids are readily biodegraded by metabolic attack at their N-heterocyclylmethyl moiety, heterocyclic or acyclic spacer, and N-nitroimine, nitromethylene, or N-cyanoimine tip. Phase I metabolism is largely dependent on microsomal CYP450 isozymes with situ selectivity in hydroxylation, desaturation, dealkylation, sulfoxidation, and nitro reduction. Cytosolic aldehyde oxidase is a nitroreductase for some neonicotinoids. Phase II metabolism involves methylation, acetylation, and formation of glucuronide, glucoside, amino acid, and sulfate- and glutathione-derived conjugates. Some neonicotinoids act as proinsecticides with metabolism to more potent nicotinic agonists. Pest resistance is more commonly due to synergist-reversible CYP450 detoxification than to nAChR mutants or variants. Metabolites in some cases contribute to mammalian hepatotoxicity and carcinogenesis and in others to enhanced plant vigor and stress shields. These relationships explain much of neonicotinoid comparative toxicology and provide the basis for continued and improved safety and effectiveness of this chemotype.

  8. Steady state analysis of metabolic pathways using Petri nets.

    PubMed

    Voss, Klaus; Heiner, Monika; Koch, Ina

    2003-01-01

    Computer assisted analysis and simulation of biochemical pathways can improve the understanding of the structure and the dynamics of cell processes considerably. The construction and quantitative analysis of kinetic models is often impeded by the lack of reliable data. However, as the topological structure of biochemical systems can be regarded to remain constant in time, a qualitative analysis of a pathway model was shown to be quite promising as it can render a lot of useful knowledge, e. g., about its structural invariants. The topic of this paper are pathways whose substances have reached a dynamic concentration equilibrium (steady state). It is argued that appreciated tools from biochemistry and also low-level Petri nets can yield only part of the desired results, whereas executable high-level net models lead to a number of valuable additional insights by combining symbolic analysis and simulation.

  9. Structure to function of an α-glucan metabolic pathway that promotes Listeria monocytogenes pathogenesis.

    PubMed

    Light, Samuel H; Cahoon, Laty A; Halavaty, Andrei S; Freitag, Nancy E; Anderson, Wayne F

    2016-11-07

    Here we employ a 'systems structural biology' approach to functionally characterize an unconventional α-glucan metabolic pathway from the food-borne pathogen Listeria monocytogenes (Lm). Crystal structure determination coupled with basic biochemical and biophysical assays allowed for the identification of anabolic, transport, catabolic and regulatory portions of the cycloalternan pathway. These findings provide numerous insights into cycloalternan pathway function and reveal the mechanism of repressor, open reading frame, kinase (ROK) transcription regulators. Moreover, by developing a structural overview we were able to anticipate the cycloalternan pathway's role in the metabolism of partially hydrolysed starch derivatives and demonstrate its involvement in Lm pathogenesis. These findings suggest that the cycloalternan pathway plays a role in interspecies resource competition-potentially within the host gastrointestinal tract-and establish the methodological framework for characterizing bacterial systems of unknown function.

  10. Differential involvement of signaling pathways in the regulation of growth hormone release by somatostatin and growth hormone-releasing hormone in orange-spotted grouper (Epinephelus coioides).

    PubMed

    Wang, Bin; Qin, Chaobin; Zhang, Cong; Jia, Jirong; Sun, Caiyun; Li, Wensheng

    2014-02-15

    Somatostatin is the most effective inhibitor of GH release, and GHRH was recently identified as one of the primary GH-releasing factors in teleosts. In this study, we analyzed the possible intracellular transduction pathways that are involved in the mechanisms induced by SRIF and GHRH to regulate GH release. Using a pharmacological approach, the blockade of the PLC/IP/PKC pathway reversed the SRIF-induced inhibition of GH release but did not affect the GHRH-induced stimulation of GH release. Furthermore, SRIF reduced the GH release induced by two PKC activators. Inhibitors of the AC/cAMP/PKA pathway reversed both the SRIF- and GHRH-induced effects on GH release. Moreover, the GH release evoked by forskolin and 8-Br-cAMP were completely abolished by SRIF. The blockade of the NOS/NO pathway attenuated the GHRH-induced GH release but had minimal effects on the inhibitory actions of SRIF. In addition, inhibitors of the sGC/cGMP pathway did not modify the SRIF- or GHRH-induced regulation of GH release. Taken together, these findings indicate that the SRIF-induced inhibition of GH release is mediated by both the PLC/IP/PKC and the AC/cAMP/PKA pathways and not by the NOS/NO/sGC/cGMP pathway. In contrast, the GHRH-induced stimulation of GH secretion is mediated by both the AC/cAMP/PKA and the NOS/NO pathways and is independent of the sGC/cGMP pathway and the PLC/IP/PKC system.

  11. Effects of Hormone Therapy on Oxidative Stress in Postmenopausal Women with Metabolic Syndrome

    PubMed Central

    Sánchez-Rodríguez, Martha A.; Zacarías-Flores, Mariano; Castrejón-Delgado, Lizett; Ruiz-Rodríguez, Ana Karen; Mendoza-Núñez, Víctor Manuel

    2016-01-01

    The aim of this study was to determine the effect of oral hormone therapy (HT) on oxidative stress (OS) in postmenopausal women with metabolic syndrome (MetS). A randomized, double blind, placebo-controlled trial was carried out. We formed four groups of 25 women each; healthy (HW) and MetS women (MSW) were assigned to HT (1 mg/day of estradiol valerate plus 5 mg/10 day of medroxiprogesterone) or placebo. We measured plasma lipoperoxides, erythrocyte superoxide dismutase and glutathione peroxidase, total plasma antioxidant status and uric acid, as OS markers. Alternative cut-off values of each parameter were defined and a stress score (SS) ranging from 0 to 7 was used as total OS. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria. Participants were seen at baseline, 3 and 6 months. After 6 months, MetS decreased in MSW-HT (48%), their triglycerides and high-density lipoprotein cholesterol (HDL-c) improved; in the other groups no difference was found. SS in MSW-HT decreased (3.8 ± 0.3 to 1.7 ± 0.3, p < 0.05) and OS was also reduced (44%), this effect was evident since 3 mo. HW-HT with high OS also decreased (40%). In placebo groups there was no change. Our findings suggest that HT improve lipids and OS associated to MetS in postmenopausal women. PMID:27563883

  12. Metabolic profiling of cholesterol and sex steroid hormones to monitor urological diseases

    PubMed Central

    Moon, Ju-Yeon

    2016-01-01

    Cholesterol and sex steroid hormones including androgens and estrogens play a critical role in the development and progression of urological diseases such as prostate cancer. This disease remains the most commonly diagnosed malignant tumor in men and is the leading cause of death from different cancers. Attempts to understand the role of cholesterol and steroid metabolism in urological diseases have been ongoing for many years, but despite this, our mechanistic and translational understanding remains elusive. In order to further evaluate the problem, we have taken an interest in metabolomics; a discipline dedicated to the systematic study of biologically active metabolites in cells, tissues, hair and biofluids. Recently, we provided evidence that a quantitative measurement of cholesterol and sex steroid metabolites can be successfully achieved using hair of human and mouse models. The overall goal of this short review article is to introduce current metabolomic technologies for the quantitative biomarker assay development and also to provide new insight into understanding the underlying mechanisms that trigger the pathological condition. Furthermore, this review will place a particular emphasis on how to prepare biospecimens (e.g., hair fiber), quantify molecular profiles and assess their clinical significance in various urological diseases. PMID:27580660

  13. Reconstructing metabolic flux vectors from extreme pathways: defining the alpha-spectrum.

    PubMed

    Wiback, Sharon J; Mahadevan, Radhakrishnan; Palsson, Bernhard Ø

    2003-10-07

    The move towards genome-scale analysis of cellular functions has necessitated the development of analytical (in silico) methods to understand such large and complex biochemical reaction networks. One such method is extreme pathway analysis that uses stoichiometry and thermodynamic irreversibly to define mathematically unique, systemic metabolic pathways. These extreme pathways form the edges of a high-dimensional convex cone in the flux space that contains all the attainable steady state solutions, or flux distributions, for the metabolic network. By definition, any steady state flux distribution can be described as a nonnegative linear combination of the extreme pathways. To date, much effort has been focused on calculating, defining, and understanding these extreme pathways. However, little work has been performed to determine how these extreme pathways contribute to a given steady state flux distribution. This study represents an initial effort aimed at defining how physiological steady state solutions can be reconstructed from a network's extreme pathways. In general, there is not a unique set of nonnegative weightings on the extreme pathways that produce a given steady state flux distribution but rather a range of possible values. This range can be determined using linear optimization to maximize and minimize the weightings of a particular extreme pathway in the reconstruction, resulting in what we have termed the alpha-spectrum. The alpha-spectrum defines which extreme pathways can and cannot be included in the reconstruction of a given steady state flux distribution and to what extent they individually contribute to the reconstruction. It is shown that accounting for transcriptional regulatory constraints can considerably shrink the alpha-spectrum. The alpha-spectrum is computed and interpreted for two cases; first, optimal states of a skeleton representation of core metabolism that include transcriptional regulation, and second for human red blood cell

  14. Predicting the types of metabolic pathway of compounds using molecular fragments and sequential minimal optimization.

    PubMed

    Chen, Lei; Chu, Chen; Feng, Kaiyan

    2016-01-01

    A metabolic pathway is a series of biological processes providing necessary molecules and energies for an organism, which could be essential to the lives of the living organisms. Most metabolic pathways require the involvement of compounds and given a compound it is helpful to know what types of metabolic pathways the compound participates in. In this study, compounds are first represented by molecular fragments which are then delivered to a prediction engine called Sequential Minimal Optimization (SMO) for predictions. Maximum relevance and minimum redundancy (mRMR) and incremental feature selection are adopted to extract key features based on which an optimal prediction engine is established. The proposed method is effective comparing to the random forest, Dagging and a popular method that integrating chemical-chemical interactions and chemical-chemical similarities. We also make predictions using some compounds with unknown metabolic pathways and choose 17 compounds for analysis. The results indicate that the method proposed may become a useful tool in predicting and analyzing metabolic pathways.

  15. Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model.

    PubMed

    O'Neil, Derek; Mendez-Figueroa, Hector; Mistretta, Toni-Ann; Su, Chunliu; Lane, Robert H; Aagaard, Kjersti M

    2013-11-01

    In our primate model of maternal high fat diet exposure, we have described that fetal epigenomic modifications to the peripheral circadian Npas2 are associated with persistent alterations in fetal hepatic metabolism and non-alcoholic fatty liver. As the interaction of circadian response with metabolism is not well understood, we employed a murine knockout model to characterize the molecular mechanisms with which Npas2 reprograms the fetal hepatic metabolic response. cDNA was generated from Npas2-/- and +/+ (wild type) livers at day 2 (newborn) and at 25 weeks (adult) of life. Newborn samples were analyzed by exon array (n = 3/cohort). Independent pathway analysis software determined that the primary dysregulated pathway(s) in the Npas2-/- animals uniformly converged on lipid metabolism. Of particular interest, Ppargc1a, which integrates circadian and metabolism pathways, was significantly (p < .01) over expressed in newborn (1.7 fold) and adult (1.8 fold) Npas2-/- animals. These findings are consistent with an essential role for Npas2 in programming the peripheral circadian response and hepatic metabolism, which has not been previously described.

  16. 3,3'-Diindolylmethane downregulates pro-survival pathway in hormone independent prostate cancer

    SciTech Connect

    Garikapaty, Venkata P.S.; Ashok, Badithe T.; Tadi, Kiranmayi; Mittelman, Abraham; Tiwari, Raj K. . E-mail: raj_tiwari@nymc.edu

    2006-02-10

    Epidemiological evidences suggest that the progression and promotion of prostate cancer (CaP) can be modulated by diet. Since all men die with prostate cancer rather than of the disease, it is of particular interest to prevent or delay the progression of the disease by chemopreventive strategies. We have been studying the anticancer properties of compounds present in cruciferous vegetables such as indole-3-carbinol (I3C). Diindolylmethane (DIM) is a dimer of I3C that is formed under acidic conditions and unlike I3C is more stable with higher anti-cancer effects. In the present report, we demonstrate that DIM is a potent anti-proliferative agent compared to I3C in the hormone independent DU 145 CaP cells. The anti-prostate cancer effect is mediated by the inhibition of the Akt signal transduction pathway as DIM, in sharp contrast to I3C, induces the downregulation of Akt, p-Akt, and PI3 kinase. DIM also induced a G1 arrest in DU 145 cells by flow cytometry and downstream concurrent inhibition of cell cycle parameters such as cyclin D1, cdk4, and cdk6. Our data suggest a need for further development of DIM, as a chemopreventive agent for CaP, which justifies epidemiological evidences and molecular targets that are determinants for CaP dissemination/progression. The ingestion of DIM may benefit CaP patients and reduce disease recurrence by eliminating micro-metastases that may be present in patients who undergo radical prostatectomy.

  17. The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases

    PubMed Central

    Caspi, Ron; Altman, Tomer; Dale, Joseph M.; Dreher, Kate; Fulcher, Carol A.; Gilham, Fred; Kaipa, Pallavi; Karthikeyan, Athikkattuvalasu S.; Kothari, Anamika; Krummenacker, Markus; Latendresse, Mario; Mueller, Lukas A.; Paley, Suzanne; Popescu, Liviu; Pujar, Anuradha; Shearer, Alexander G.; Zhang, Peifen; Karp, Peter D.

    2010-01-01

    The MetaCyc database (MetaCyc.org) is a comprehensive and freely accessible resource for metabolic pathways and enzymes from all domains of life. The pathways in MetaCyc are experimentally determined, small-molecule metabolic pathways and are curated from the primary scientific literature. With more than 1400 pathways, MetaCyc is the largest collection of metabolic pathways currently available. Pathways reactions are linked to one or more well-characterized enzymes, and both pathways and enzymes are annotated with reviews, evidence codes, and literature citations. BioCyc (BioCyc.org) is a collection of more than 500 organism-specific Pathway/Genome Databases (PGDBs). Each BioCyc PGDB contains the full genome and predicted metabolic network of one organism. The network, which is predicted by the Pathway Tools software using MetaCyc as a reference, consists of metabolites, enzymes, reactions and metabolic pathways. BioCyc PGDBs also contain additional features, such as predicted operons, transport systems, and pathway hole-fillers. The BioCyc Web site offers several tools for the analysis of the PGDBs, including Omics Viewers that enable visualization of omics datasets on two different genome-scale diagrams and tools for comparative analysis. The BioCyc PGDBs generated by SRI are offered for adoption by any party interested in curation of metabolic, regulatory, and genome-related information about an organism. PMID:19850718

  18. Sex hormone imbalances and adipose tissue dysfunction impacting on metabolic syndrome; a paradigm for the discovery of novel adipokines.

    PubMed

    Zhang, Hui; Sairam, M Ram

    2014-02-01

    Sex hormone imbalance is causally related with visceral adipose tissue (AT) dysfunction and visceral obesity - an etiological component of metabolic syndrome (MetS), associated with high risk of both cardiovascular disease (CVD) and type 2 diabetes. In general, premenopausal women appear to be protected from CVD and the dramatic decline in sex steroid hormone occurring during menopausal transitions or other sex-related disorders influence the regional distribution, function, and metabolism of AT and increase the risk of CVD. Visceral AT dysfunction, manifesting as abnormality of fatty acid metabolism, increased oxidative stress, endothelial dysfunction, and excessive production of adipokines have been proposed in the pathogenesis of MetS. However, direct evidence of molecular mechanisms of depot-specific AT alterations, and dysfunction causally related to MetS is limited in studies on postmenopausal women due to difficulty in collecting discrete AT specimens at different ages and repeated sampling from different fat depots. This can be overcome using animal models that can mimic the cluster of pathology leading to MetS and help establish the molecular basis of links between loss of gonadal function on various AT depots and their contribution to MetS. Our group used sex hormone imbalance FSH receptor knock out (FORKO) female mice to recapitulate different aspects of the MetS and addressed the mechanism of visceral obesity related to MetS and discover two novel sex steroid hormone-regulated deep mesenteric estrogen-dependent adipose (MEDAs) genes. Taken together, such recent studies raise hopes for pharmacologic intervention strategies targeting sex steroid hormone signaling in AT to provide protection against AT dysfunction.

  19. Metabolic Pathways in Methanococcus jannaschii and Other Methanogenic Bacteria.

    PubMed

    Sprott, G D; Ekiel, I; Patel, G B

    1993-04-01

    Eleven strains of methanogenic bacteria were divided into two groups on the basis of the directionality (oxidative or reductive) of their citric acid pathways. These pathways were readily identified for most methanogens from the patterns of carbon atom labeling in glutamate, following growth in the presence of [2-C]acetate. All used noncyclic pathways, but members of the family Methanosarcinaceae were the only methanogens found to use the oxidative direction. Methanococcus jannaschii failed to incorporate carbon from acetate despite transmembrane equilibration comparable to other weak acids. This organism was devoid of detectable activities of the acetate-incorporating enzymes acetyl coenzyme A synthetase, acetate kinase, and phosphotransacetylase. However, incorporation of [1-C]-, [2-C]-, or [3-C]pyruvate during the growth of M. jannaschii was possible and resulted in labeling patterns indicative of a noncyclic citric acid pathway operating in the reductive direction to synthesize amino acids. Carbohydrates were labeled consistent with glucogenesis from pyruvate. Leucine, isoleucine, phenylalanine, lysine, formate, glycerol, and mevalonate were incorporated when supplied to the growth medium. Lysine was preferentially incorporated into the lipid fraction, suggesting a role as a phytanyl chain precursor.

  20. FragariaCyc: A Metabolic Pathway Database for Woodland Strawberry Fragaria vesca

    PubMed Central

    Naithani, Sushma; Partipilo, Christina M.; Raja, Rajani; Elser, Justin L.; Jaiswal, Pankaj

    2016-01-01

    FragariaCyc is a strawberry-specific cellular metabolic network based on the annotated genome sequence of Fragaria vesca L. ssp. vesca, accession Hawaii 4. It was built on the Pathway-Tools platform using MetaCyc as the reference. The experimental evidences from published literature were used for supporting/editing existing entities and for the addition of new pathways, enzymes, reactions, compounds, and small molecules in the database. To date, FragariaCyc comprises 66 super-pathways, 488 unique pathways, 2348 metabolic reactions, 3507 enzymes, and 2134 compounds. In addition to searching and browsing FragariaCyc, researchers can compare pathways across various plant metabolic networks and analyze their data using Omics Viewer tool. We view FragariaCyc as a resource for the community of researchers working with strawberry and related fruit crops. It can help understanding the regulation of overall metabolism of strawberry plant during development and in response to diseases and abiotic stresses. FragariaCyc is available online at http://pathways.cgrb.oregonstate.edu. PMID:26973684

  1. FragariaCyc: A Metabolic Pathway Database for Woodland Strawberry Fragaria vesca.

    PubMed

    Naithani, Sushma; Partipilo, Christina M; Raja, Rajani; Elser, Justin L; Jaiswal, Pankaj

    2016-01-01

    FragariaCyc is a strawberry-specific cellular metabolic network based on the annotated genome sequence of Fragaria vesca L. ssp. vesca, accession Hawaii 4. It was built on the Pathway-Tools platform using MetaCyc as the reference. The experimental evidences from published literature were used for supporting/editing existing entities and for the addition of new pathways, enzymes, reactions, compounds, and small molecules in the database. To date, FragariaCyc comprises 66 super-pathways, 488 unique pathways, 2348 metabolic reactions, 3507 enzymes, and 2134 compounds. In addition to searching and browsing FragariaCyc, researchers can compare pathways across various plant metabolic networks and analyze their data using Omics Viewer tool. We view FragariaCyc as a resource for the community of researchers working with strawberry and related fruit crops. It can help understanding the regulation of overall metabolism of strawberry plant during development and in response to diseases and abiotic stresses. FragariaCyc is available online at http://pathways.cgrb.oregonstate.edu.

  2. Common and divergent physiological, hormonal and metabolic responses of Arabidopsis thaliana and Thellungiella halophila to water and salt stress.

    PubMed

    Arbona, Vicent; Argamasilla, Rosa; Gómez-Cadenas, Aurelio

    2010-11-01

    To explain the higher tolerance of Thellungiella to abiotic stress in comparison to Arabidopsis, several studies have focused on differences in ion absorption and gene expression. However, little is known about hormone regulation and metabolic responses. In this work, plants of both species were subjected to desiccation and salt stress to compare common and divergent responses. In control conditions, the number of significantly upregulated mass features as well as proline levels was higher in Tellungiella than in Arabidopsis. When subjected to desiccation, both species exhibited similar rates of water loss but proline over accumulation only occurred in Thellungiella; both species accumulated ABA and JA with a similar trend although Arabidopsis showed higher concentrations of both hormones which indicated a stronger impact of desiccation on Arabidopsis. However, Arabidopsis showed a higher number of significantly altered mass features than Thellungiella. Under salt stress, Thellungiella plants accumulated lower amounts of Cl(-) ions than Arabidopsis but exhibited a similar proline response. Under these conditions, ABA and JA levels increased in Arabidopsis whereas minimal changes in both hormone concentrations were recorded in Thellungiella. Contrastingly, the impact of salt stress on metabolite profiles was higher in Thellungiella than in Arabidopsis. Overall, data indicated that physiological responses in Arabidopsis are induced after stress imposition through hormonal regulation whereas Thellungiella has a basal metabolic configuration, better prepared to endure environmental cues.

  3. Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

    PubMed Central

    Esser, Dominik; Rauch, Bernadette

    2014-01-01

    SUMMARY The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many “classical” pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of “new,” unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented. PMID:24600042

  4. Incomplete Wood-Ljungdahl pathway facilitates one-carbon metabolism in organohalide-respiring Dehalococcoides mccartyi.

    PubMed

    Zhuang, Wei-Qin; Yi, Shan; Bill, Markus; Brisson, Vanessa L; Feng, Xueyang; Men, Yujie; Conrad, Mark E; Tang, Yinjie J; Alvarez-Cohen, Lisa

    2014-04-29

    The acetyl-CoA "Wood-Ljungdahl" pathway couples the folate-mediated one-carbon (C1) metabolism to either CO2 reduction or acetate oxidation via acetyl-CoA. This pathway is distributed in diverse anaerobes and is used for both energy conservation and assimilation of C1 compounds. Genome annotations for all sequenced strains of Dehalococcoides mccartyi, an important bacterium involved in the bioremediation of chlorinated solvents, reveal homologous genes encoding an incomplete Wood-Ljungdahl pathway. Because this pathway lacks key enzymes for both C1 metabolism and CO2 reduction, its cellular functions remain elusive. Here we used D. mccartyi strain 195 as a model organism to investigate the metabolic function of this pathway and its impacts on the growth of strain 195. Surprisingly, this pathway cleaves acetyl-CoA to donate a methyl group for production of methyl-tetrahydrofolate (CH3-THF) for methionine biosynthesis, representing an unconventional strategy for generating CH3-THF in organisms without methylene-tetrahydrofolate reductase. Carbon monoxide (CO) was found to accumulate as an obligate by-product from the acetyl-CoA cleavage because of the lack of a CO dehydrogenase in strain 195. CO accumulation inhibits the sustainable growth and dechlorination of strain 195 maintained in pure cultures, but can be prevented by CO-metabolizing anaerobes that coexist with D. mccartyi, resulting in an unusual syntrophic association. We also found that this pathway incorporates exogenous formate to support serine biosynthesis. This study of the incomplete Wood-Ljungdahl pathway in D. mccartyi indicates a unique bacterial C1 metabolism that is critical for D. mccartyi growth and interactions in dechlorinating communities and may play a role in other anaerobic communities.

  5. Metabolic flexibility of a butyrate pathway mutant of Clostridium acetobutylicum.

    PubMed

    Yoo, Minyeong; Croux, Christian; Meynial-Salles, Isabelle; Soucaille, Philippe

    2017-01-31

    Clostridium acetobutylicum possesses two homologous buk genes, buk (or buk1) and buk2, which encode butyrate kinases involved in the last step of butyrate formation. To investigate the contribution of buk in detail, an in-frame deletion mutant was constructed. However, in all the Δbuk mutants obtained, partial deletions of the upstream ptb gene were observed, and low phosphotransbutyrylase and butyrate kinase activities were measured. This demonstrates that i) buk (CA_C3075) is the key butyrate kinase-encoding gene and that buk2 (CA_C1660) that is poorly transcribed only plays a minor role; and ii) strongly suggests that a Δbuk mutant is not viable if the ptb gene is not also inactivated, probably due to the accumulation of butyryl-phosphate, which might be toxic for the cell. One of the ΔbukΔptb mutants was subjected to quantitative transcriptomic (mRNA molecules/cell) and fluxomic analyses in acidogenic, solventogenic and alcohologenic chemostat cultures. In addition to the low butyrate production, drastic changes in metabolic fluxes were also observed for the mutant: i) under acidogenic conditions, the primary metabolite was butanol and a new metabolite, 2-hydroxy-valerate, was produced ii) under solventogenesis, 58% increased butanol production was obtained compared to the control strain under the same conditions, and a very high yield of butanol formation (0.3gg(-1)) was reached; and iii) under alcohologenesis, the major product was lactate. Furthermore, at the transcriptional level, adhE2, which encodes an aldehyde/alcohol dehydrogenase and is known to be a gene specifically expressed in alcohologenesis, was surprisingly highly expressed in all metabolic states in the mutant. The results presented here not only support the key roles of buk and ptb in butyrate formation but also highlight the metabolic flexibility of C. acetobutylicum in response to genetic alteration of its primary metabolism.

  6. Design of pathway-level bioprocess monitoring and control strategies supported by metabolic networks.

    PubMed

    Isidro, Inês A; Ferreira, Ana R; Clemente, João J; Cunha, António E; Dias, João M L; Oliveira, Rui

    2013-01-01

    In this chapter we explore the basic tools for the design of bioprocess monitoring, optimization, and control algorithms that incorporate a priori knowledge of metabolic networks. The main advantage is that this ultimately enables the targeting of intracellular control variables such as metabolic reactions or metabolic pathways directly linked with productivity and product quality. We analyze in particular design methods that target elementary modes of metabolic networks. The topics covered include the analysis of the structure of metabolic networks, computation and reduction of elementary modes, measurement methods for the envirome, envirome-guided metabolic reconstruction, and macroscopic dynamic modeling and control. These topics are illustrated with applications to a cultivation process of a recombinant Pichia pastoris X33 strain expressing a single-chain antibody fragment (scFv).

  7. Analysis and Engineering of Metabolic Pathway Fluxes in Corynebacterium glutamicum

    NASA Astrophysics Data System (ADS)

    Wittmann, Christoph

    The Gram-positive soil bacterium Corynebacterium glutamicum was discovered as a natural overproducer of glutamate about 50 years ago. Linked to the steadily increasing economical importance of this microorganism for production of glutamate and other amino acids, the quest for efficient production strains has been an intense area of research during the past few decades. Efficient production strains were created by applying classical mutagenesis and selection and especially metabolic engineering strategies with the advent of recombinant DNA technology. Hereby experimental and computational approaches have provided fascinating insights into the metabolism of this microorganism and directed strain engineering. Today, C. glutamicum is applied to the industrial production of more than 2 million tons of amino acids per year. The huge achievements in recent years, including the sequencing of the complete ge