Science.gov

Sample records for metabolic responses induced

  1. Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

    PubMed Central

    Lall, R; Ganapathy, S; Yang, M; Xiao, S; Xu, T; Su, H; Shadfan, M; Asara, J M; Ha, C S; Ben-Sahra, I; Manning, B D; Little, J B; Yuan, Z-M

    2014-01-01

    Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1α, which is induced specifically by low-dose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to low-dose radiation has important implications in understanding and assessing the health risks of radiation exposure. PMID:24583639

  2. Role of Metabolism by Intestinal Bacteria in Arbutin-Induced Suppression of Lymphoproliferative Response in vitro.

    PubMed

    Kang, Mi Jeong; Ha, Hyun Woo; Kim, Ghee Hwan; Lee, Sang Kyu; Ahn, Young Tae; Kim, Dong Hyun; Jeong, Hye Gwang; Jeong, Tae Cheon

    2012-03-01

    Role of metabolism by intestinal bacteria in arbutin-induced immunotoxicity was investigated in splenocyte cultures. Following an incubation of arbutin with 5 different intestinal bacteria for 24 hr, its aglycone hydroquinone could be produced and detected in the bacterial culture media with different amounts. Toxic effects of activated arbutin by intestinal bacteria on lymphoproliferative response were tested in splenocyte cultures from normal mice. Lipopolysaccharide and concanavalin A were used as mitogens for B- and T-cells, respectively. When bacteria cultured medium with arbutin was treated into the splenocytes for 3 days, the medium cultured with bacteria producing large amounts of hydroquinone induced suppression of lymphoproliferative responses, indicating that metabolic activation by intestinal bacteria might be required in arbutin-induced toxicity. The results indicated that the present testing system might be applied for determining the possible role of metabolism by intestinal bacteria in certain chemical-induced immunotoxicity in animal cell cultures. PMID:24116295

  3. Metabolic Response of Candida albicans to Phenylethyl Alcohol under Hyphae-Inducing Conditions

    PubMed Central

    Han, Ting-Li; Tumanov, Sergey; Cannon, Richard D.; Villas-Boas, Silas G.

    2013-01-01

    Phenylethyl alcohol was one of the first quorum sensing molecules (QSMs) identified in C. albicans. This extracellular signalling molecule inhibits the hyphal formation of C. albicans at high cell density. Little is known, however, about the underlying mechanisms by which this QSM regulates the morphological switches of C. albicans. Therefore, we have applied metabolomics and isotope labelling experiments to investigate the metabolic changes that occur in C. albicans in response to phenylethyl alcohol under defined hyphae-inducing conditions. Our results showed a global upregulation of central carbon metabolism when hyphal development was suppressed by phenylethyl alcohol. By comparing the metabolic changes in response to phenylethyl alcohol to our previous metabolomic studies, we were able to short-list 7 metabolic pathways from central carbon metabolism that appear to be associated with C. albicans morphogenesis. Furthermore, isotope-labelling data showed that phenylethyl alcohol is indeed taken up and catabolised by yeast cells. Isotope-labelled carbon atoms were found in the majority of amino acids as well as in lactate and glyoxylate. However, isotope-labelled carbon atoms from phenylethyl alcohol accumulated mainly in the pyridine ring of NAD+/NADH and NADP−/NADPH molecules, showing that these nucleotides were the main products of phenylethyl alcohol catabolism. Interestingly, two metabolic pathways where these nucleotides play an important role, nitrogen metabolism and nicotinate/nicotinamide metabolism, were also short-listed through our previous metabolomics works as metabolic pathways likely to be closely associated with C. albicans morphogenesis. PMID:23951145

  4. Aluminum induced metabolic responses in two tea cultivars.

    PubMed

    Xu, Qingshan; Wang, Yu; Ding, Zhaotang; Song, Lubin; Li, Yusheng; Ma, Dexin; Wang, Yi; Shen, Jiazhi; Jia, Sisi; Sun, Haiwei; Zhang, Hong

    2016-04-01

    Tea [Camellia sinensis (L.)], is an aluminum (Al(3+)) hyperaccumulator plant and grows well in acid soils. In the present study, roots of two tea cultivars, JHC and YS were treated with different concentrations of Al(3+). After treatments, the root length, dry matter, root activity and chlorophyll content (SPAD value) of JHC had greater increase than that of YS. We also detected metabolic changes of two varieties using GC-MS method. Comparison between two cultivars indicated that shikimic pathway was more enhanced in YS roots by Al(3+) with higher levels of catechine, quinic acid and shikimic acid. While, more active amino acid synthesis was found in JHC roots and JHC leaves remained the higher level contents of metabolites related to cysteine synthesis. The comparison also showed that a large amount of sugar alcohols were accumulated in roots of two varieties, whereas most of them were reduced in YS leaves. Other well-known ligands, such as phosphoric acid and malic acid were observed in two cultivars that showed significantly altered abundances under Al(3+) treatments. The results indicated that Al(3+) adaptation of two cultivars may be correlated with their differential metabolism of amino acids, sugars and shikimic acids. PMID:26895429

  5. The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress

    PubMed Central

    van der Harg, J M; Nölle, A; Zwart, R; Boerema, A S; van Haastert, E S; Strijkstra, A M; Hoozemans, J JM; Scheper, W

    2014-01-01

    The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases. PMID:25165879

  6. Sexually dimorphic myeloid inflammatory and metabolic responses to diet-induced obesity.

    PubMed

    Griffin, C; Lanzetta, N; Eter, L; Singer, K

    2016-08-01

    It is well known in clinical and animal studies that women and men have different disease risk as well as different disease physiology. Women of reproductive age are protected from metabolic and cardiovascular disease compared with postmenopausal women and men. Most murine studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of similar protection in female mice. We have investigated dietary obesity in a mouse model and have directly compared inflammatory responses in males and females. In this review we will summarize what is known about sex differences in diet-induced inflammation and will summarize our data on this topic. It is clear that sex differences in high-fat diet-induced inflammatory activation are due to cell intrinsic differences in hematopoietic responses to obesogenic cues, but further research is needed to understand what leads to sexually dimorphic responses. PMID:27252473

  7. Botanical and biological pesticides elicit a similar Induced Systemic Response in tomato (Solanum lycopersicum) secondary metabolism.

    PubMed

    Pretali, Luca; Bernardo, Letizia; Butterfield, Timothy S; Trevisan, Marco; Lucini, Luigi

    2016-10-01

    Natural pesticides have attracted substantial interest due to the increase in organic agriculture and enhanced attention to environmental pollution. Plant Growth Promoting Bacteria (PGPB) are applied for both disease control and growth enhancement; PGPBs are known to elicit Induced Systemic Response (ISR) in plants. However, less is known about the effect of botanical pesticides, such as the azadirachtin-containing neem extracts, on plant metabolism. This study aimed to investigate the effects of foliar application of the above-mentioned natural pesticides on the metabolic profiling of tomato. Leaf application of Bacillus subtilis fostered Induced Systemic Resistance (ISR) in treated plants via the Jasmonic acid pathway, and enhanced production of secondary metabolites such as flavonoids, phytoalexins and auxins. Changes in sterols and terpenes, as well as an increase in glucosinolates were also observed. Interestingly, azadirachtin-treated tomatoes also showed an increase in ISR and our results revealed that most of the enriched metabolites are shared with a B. subtilis treatment, suggesting conserved biochemical responses. These (un)expected findings indicate that plants are not insensitive to application of natural pesticide and while Azadirachtin is applied as a direct pesticide, it also stimulates a defense response in tomatoes very similar to B. subtilis induced ISR. PMID:27251587

  8. Zinc oxide induces the stringent response and major reorientations in the central metabolism of Bacillus subtilis.

    PubMed

    Luche, Sylvie; Eymard-Vernain, Elise; Diemer, Hélène; Van Dorsselaer, Alain; Rabilloud, Thierry; Lelong, Cécile

    2016-03-01

    Microorganisms, such as bacteria, are one of the first targets of nanoparticles in the environment. In this study, we tested the effect of two nanoparticles, ZnO and TiO2, with the salt ZnSO4 as the control, on the Gram-positive bacterium Bacillus subtilis by 2D gel electrophoresis-based proteomics. Despite a significant effect on viability (LD50), TiO2 NPs had no detectable effect on the proteomic pattern, while ZnO NPs and ZnSO4 significantly modified B. subtilis metabolism. These results allowed us to conclude that the effects of ZnO observed in this work were mainly attributable to Zn dissolution in the culture media. Proteomic analysis highlighted twelve modulated proteins related to central metabolism: MetE and MccB (cysteine metabolism), OdhA, AspB, IolD, AnsB, PdhB and YtsJ (Krebs cycle) and XylA, YqjI, Drm and Tal (pentose phosphate pathway). Biochemical assays, such as free sulfhydryl, CoA-SH and malate dehydrogenase assays corroborated the observed central metabolism reorientation and showed that Zn stress induced oxidative stress, probably as a consequence of thiol chelation stress by Zn ions. The other patterns affected by ZnO and ZnSO4 were the stringent response and the general stress response. Nine proteins involved in or controlled by the stringent response showed a modified expression profile in the presence of ZnO NPs or ZnSO4: YwaC, SigH, YtxH, YtzB, TufA, RplJ, RpsB, PdhB and Mbl. An increase in the ppGpp concentration confirmed the involvement of the stringent response during a Zn stress. All these metabolic reorientations in response to Zn stress were probably the result of complex regulatory mechanisms including at least the stringent response via YwaC. PMID:26211718

  9. Metabolic flux ratio analysis and multi-objective optimization revealed a globally conserved and coordinated metabolic response of E. coli to paraquat-induced oxidative stress.

    PubMed

    Shen, Tie; Rui, Bin; Zhou, Hong; Zhang, Ximing; Yi, Yin; Wen, Han; Zheng, Haoran; Wu, Jihui; Shi, Yunyu

    2013-01-27

    The ability of a microorganism to adapt to changes in the environment, such as in nutrient or oxygen availability, is essential for its competitive fitness and survival. The cellular objective and the strategy of the metabolic response to an extreme environment are therefore of tremendous interest and, thus, have been increasingly explored. However, the cellular objective of the complex regulatory structure of the metabolic changes has not yet been fully elucidated and more details regarding the quantitative behaviour of the metabolic flux redistribution are required to understand the systems-wide biological significance of this response. In this study, the intracellular metabolic flux ratios involved in the central carbon metabolism were determined by fractional (13)C-labeling and metabolic flux ratio analysis (MetaFoR) of the wild-type E. coli strain JM101 at an oxidative environment in a chemostat. We observed a significant increase in the flux through phosphoenolpyruvate carboxykinase (PEPCK), phosphoenolpyruvate carboxylase (PEPC), malic enzyme (MEZ) and serine hydroxymethyltransferase (SHMT). We applied an ε-constraint based multi-objective optimization to investigate the trade-off relationships between the biomass yield and the generation of reductive power using the in silico iJR904 genome-scale model of E. coli K-12. The theoretical metabolic redistribution supports that the trans-hydrogenase pathway should not play a direct role in the defence mounted by E. coli against oxidative stress. The agreement between the measured ratio and the theoretical redistribution established the significance of NADPH synthesis as the goal of the metabolic reprogramming that occurs in response to oxidative stress. Our work presents a framework that combines metabolic flux ratio analysis and multi-objective optimization to investigate the metabolic trade-offs that occur under varied environmental conditions. Our results led to the proposal that the metabolic response of E

  10. A computational model of skeletal muscle metabolism linking cellular adaptations induced by altered loading states to metabolic responses during exercise

    PubMed Central

    Dash, Ranjan K; DiBella, John A; Cabrera, Marco E

    2007-01-01

    Background The alterations in skeletal muscle structure and function after prolonged periods of unloading are initiated by the chronic lack of mechanical stimulus of sufficient intensity, which is the result of a series of biochemical and metabolic interactions spanning from cellular to tissue/organ level. Reduced activation of skeletal muscle alters the gene expression of myosin heavy chain isoforms to meet the functional demands of reduced mechanical load, which results in muscle atrophy and reduced capacity to process fatty acids. In contrast, chronic loading results in the opposite pattern of adaptations. Methods To quantify interactions among cellular and skeletal muscle metabolic adaptations, and to predict metabolic responses to exercise after periods of altered loading states, we develop a computational model of skeletal muscle metabolism. The governing model equations – with parameters characterizing chronic loading/unloading states- were solved numerically to simulate metabolic responses to moderate intensity exercise (WR ≤ 40% VO2 max). Results Model simulations showed that carbohydrate oxidation was 8.5% greater in chronically unloaded muscle compared with the loaded muscle (0.69 vs. 0.63 mmol/min), while fat oxidation was 7% higher in chronically loaded muscle (0.14 vs. 0.13 mmol/min), during exercise. Muscle oxygen uptake (VO2) and blood flow (Q) response times were 29% and 44% shorter in chronically loaded muscle (0.4 vs. 0.56 min for VO2 and 0.25 vs. 0.45 min for Q). Conclusion The present model can be applied to test complex hypotheses during exercise involving the integration and control of metabolic processes at various organizational levels (cellular to tissue) in individuals who have undergone periods of chronic loading or unloading. PMID:17448235

  11. Extreme Hypoxic Conditions Induce Selective Molecular Responses and Metabolic Reset in Detached Apple Fruit.

    PubMed

    Cukrov, Dubravka; Zermiani, Monica; Brizzolara, Stefano; Cestaro, Alessandro; Licausi, Francesco; Luchinat, Claudio; Santucci, Claudio; Tenori, Leonardo; Van Veen, Hans; Zuccolo, Andrea; Ruperti, Benedetto; Tonutti, Pietro

    2016-01-01

    The ripening physiology of detached fruit is altered by low oxygen conditions with profound effects on quality parameters. To study hypoxia-related processes and regulatory mechanisms, apple (Malus domestica, cv Granny Smith) fruit, harvested at commercial ripening, were kept at 1°C under normoxic (control) and hypoxic (0.4 and 0.8 kPa oxygen) conditions for up to 60 days. NMR analyses of cortex tissue identified eight metabolites showing significantly different accumulations between samples, with ethanol and alanine displaying the most pronounced difference between hypoxic and normoxic treatments. A rapid up-regulation of alcohol dehydrogenase and pyruvate-related metabolism (lactate dehydrogenase, pyruvate decarboxylase, alanine aminotransferase) gene expression was detected under both hypoxic conditions with a more pronounced effect induced by the lowest (0.4 kPa) oxygen concentration. Both hypoxic conditions negatively affected ACC synthase and ACC oxidase transcript accumulation. Analysis of RNA-seq data of samples collected after 24 days of hypoxic treatment identified more than 1000 genes differentially expressed when comparing 0.4 vs. 0.8 kPa oxygen concentration samples. Genes involved in cell-wall, minor and major CHO, amino acid and secondary metabolisms, fermentation and glycolysis as well as genes involved in transport, defense responses, and oxidation-reduction appeared to be selectively affected by treatments. The lowest oxygen concentration induced a higher expression of transcription factors belonging to AUX/IAA, WRKY, HB, Zinc-finger families, while MADS box family genes were more expressed when apples were kept under 0.8 kPa oxygen. Out of the eight group VII ERF members present in apple genome, two genes showed a rapid up-regulation under hypoxia, and western blot analysis showed that apple MdRAP2.12 proteins were differentially accumulated in normoxic and hypoxic samples, with the highest level reached under 0.4 kPa oxygen. These data suggest

  12. Extreme Hypoxic Conditions Induce Selective Molecular Responses and Metabolic Reset in Detached Apple Fruit

    PubMed Central

    Cukrov, Dubravka; Zermiani, Monica; Brizzolara, Stefano; Cestaro, Alessandro; Licausi, Francesco; Luchinat, Claudio; Santucci, Claudio; Tenori, Leonardo; Van Veen, Hans; Zuccolo, Andrea; Ruperti, Benedetto; Tonutti, Pietro

    2016-01-01

    The ripening physiology of detached fruit is altered by low oxygen conditions with profound effects on quality parameters. To study hypoxia-related processes and regulatory mechanisms, apple (Malus domestica, cv Granny Smith) fruit, harvested at commercial ripening, were kept at 1°C under normoxic (control) and hypoxic (0.4 and 0.8 kPa oxygen) conditions for up to 60 days. NMR analyses of cortex tissue identified eight metabolites showing significantly different accumulations between samples, with ethanol and alanine displaying the most pronounced difference between hypoxic and normoxic treatments. A rapid up-regulation of alcohol dehydrogenase and pyruvate-related metabolism (lactate dehydrogenase, pyruvate decarboxylase, alanine aminotransferase) gene expression was detected under both hypoxic conditions with a more pronounced effect induced by the lowest (0.4 kPa) oxygen concentration. Both hypoxic conditions negatively affected ACC synthase and ACC oxidase transcript accumulation. Analysis of RNA-seq data of samples collected after 24 days of hypoxic treatment identified more than 1000 genes differentially expressed when comparing 0.4 vs. 0.8 kPa oxygen concentration samples. Genes involved in cell-wall, minor and major CHO, amino acid and secondary metabolisms, fermentation and glycolysis as well as genes involved in transport, defense responses, and oxidation-reduction appeared to be selectively affected by treatments. The lowest oxygen concentration induced a higher expression of transcription factors belonging to AUX/IAA, WRKY, HB, Zinc-finger families, while MADS box family genes were more expressed when apples were kept under 0.8 kPa oxygen. Out of the eight group VII ERF members present in apple genome, two genes showed a rapid up-regulation under hypoxia, and western blot analysis showed that apple MdRAP2.12 proteins were differentially accumulated in normoxic and hypoxic samples, with the highest level reached under 0.4 kPa oxygen. These data suggest

  13. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways.

    PubMed

    Bhasin, Manoj K; Dusek, Jeffery A; Chang, Bei-Hung; Joseph, Marie G; Denninger, John W; Fricchione, Gregory L; Benson, Herbert; Libermann, Towia A

    2013-01-01

    The relaxation response (RR) is the counterpart of the stress response. Millennia-old practices evoking the RR include meditation, yoga and repetitive prayer. Although RR elicitation is an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging, the underlying molecular mechanisms that explain these clinical benefits remain undetermined. To assess rapid time-dependent (temporal) genomic changes during one session of RR practice among healthy practitioners with years of RR practice and also in novices before and after 8 weeks of RR training, we measured the transcriptome in peripheral blood prior to, immediately after, and 15 minutes after listening to an RR-eliciting or a health education CD. Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the latter as compared to novices. RR practice enhanced expression of genes associated with energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stress-related pathways. Interactive network analyses of RR-affected pathways identified mitochondrial ATP synthase and insulin (INS) as top upregulated critical molecules (focus hubs) and NF-κB pathway genes as top downregulated focus hubs. Our results for the first time indicate that RR elicitation, particularly after long-term practice, may evoke its downstream health benefits by improving mitochondrial energy production and utilization and thus promoting mitochondrial resiliency through upregulation of ATPase and insulin function. Mitochondrial resiliency might also be promoted by RR-induced downregulation of NF-κB-associated upstream and downstream targets that mitigates stress. PMID:23650531

  14. Pseudomonas fluorescens induces strain-dependent and strain-independent host plant responses in defense networks, primary metabolism and photosynthesis

    SciTech Connect

    Pelletier, Dale A; Morrell-Falvey, Jennifer L; Karve, Abhijit A; Lu, Tse-Yuan S; Tschaplinski, Timothy J; Tuskan, Gerald A; Chen, Jay; Martin, Madhavi Z; Jawdy, Sara; Weston, David; Doktycz, Mitchel John; Schadt, Christopher Warren

    2012-01-01

    Colonization of plants by nonpathogenic Pseudomonas fluorescens strains can confer enhanced defense capacity against a broad spectrum of pathogens. Few studies, however, have linked defense pathway regulation to primary metabolism and physiology. In this study, physiological data, metabolites, and transcript profiles are integrated to elucidate how molecular networks initiated at the root-microbe interface influence shoot metabolism and whole-plant performance. Experiments with Arabidopsis thaliana were performed using the newly identified P. fluorescens GM30 or P. fluorescens Pf-5 strains. Co-expression networks indicated that Pf-5 and GM30 induced a subnetwork specific to roots enriched for genes participating in RNA regulation, protein degradation, and hormonal metabolism. In contrast, only GM30 induced a subnetwork enriched for calcium signaling, sugar and nutrient signaling, and auxin metabolism, suggesting strain dependence in network architecture. In addition, one subnetwork present in shoots was enriched for genes in secondary metabolism, photosynthetic light reactions, and hormone metabolism. Metabolite analysis indicated that this network initiated changes in carbohydrate and amino acid metabolism. Consistent with this, we observed strain-specific responses in tryptophan and phenylalanine abundance. Both strains reduced host plant carbon gain and fitness, yet provided a clear fitness benefit when plants were challenged with the pathogen P. syringae DC3000.

  15. Nitric oxide is involved in methyl jasmonate-induced defense responses and secondary metabolism activities of Taxus cells.

    PubMed

    Wang, Jian Wen; Wu, Jian Yong

    2005-06-01

    Methyl jasmonate (MeJA), a methyl ester of jasmonic acid (JA), is a well-established signal molecule in plant defense responses and an effective inducer of secondary metabolite accumulation in plant cell cultures such as the valuable anticancer diterpenoid taxol (paclitaxel) in Taxus spp. This work examines the involvement of nitric oxide (NO) in MeJA-induced plant defense responses and secondary metabolism in Taxus chinensis cell cultures. Exogenously supplied MeJA at 100 microM induced rapid production of NO in the Taxus cell cultures, reaching a maximum within 6 h of MeJA supply. Several other responses occurred concomitantly, including the production of hydrogen peroxide (H2O2), and the increases in intracellular malondialdehyde (MDA) content, lipoxygenase (LOX) and phenylalanine ammonium-lyase (PAL) activities. The MeJA-induced H2O2 production was suppressed by an NO donor, sodium nitroprusside (SNP), but enhanced by NO inhibitors, N (omega)-nitro-L-arginine (L-NNA) and 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (PTIO). In contrast, the MeJA-induced MDA, LOX and PAL were all enhanced by the NO donor but suppressed by the NO inhibitors. The NO inhibitors also suppressed MeJA-induced taxol accumulation. These results are suggestive of a role for NO as a signal element for activating the MeJA-induced defense responses and secondary metabolism activities of plant cells. PMID:15829512

  16. PEG-induced osmotic stress in Mentha x piperita L.: Structural features and metabolic responses.

    PubMed

    Búfalo, Jennifer; Rodrigues, Tatiane Maria; de Almeida, Luiz Fernando Rolim; Tozin, Luiz Ricardo Dos Santos; Marques, Marcia Ortiz Mayo; Boaro, Carmen Silvia Fernandes

    2016-08-01

    The present study investigated whether osmotic stress induced by the exposure of peppermint (Mentha x piperita L.) to moderate and severe stress for short periods of time changes the plant's physiological parameters, leaf anatomy and ultrastructure and essential oil. Plants were exposed to two levels of polyethyleneglycol (50 g L(-1) and 100 g L(-1) of PEG) in a hydroponic experiment. The plants exposed to 50 g L(-1) maintained metabolic functions similar to those of the control group (0 g L(-1)) without changes in gas exchange or structural characteristics. The increase in antioxidant enzyme activity reduced the presence of free radicals and protected membranes, including chloroplasts and mitochondria. In contrast, the osmotic stress caused by 100 g L(-1) of PEG inhibited leaf gas exchange, reduced the essential oil content and changed the oil composition, including a decrease in menthone and an increase in menthofuran. These plants also showed an increase in peroxidase activity, but this increase was not sufficient to decrease the lipid peroxidation level responsible for damaging the membranes of organelles. Morphological changes were correlated with the evaluated physiological features: plants exposed to 100 g L(-1) of PEG showed areas with collapsed cells, increases in mesophyll thickness and the area of the intercellular space, cuticle shrinkage, morphological changes in plastids, and lysis of mitochondria. In summary, our results revealed that PEG-induced osmotic stress in M. x piperita depends on the intensity level of the osmotic stress applied; severe osmotic stress changed the structural characteristics, caused damage at the cellular level, and reduced the essential oil content and quality. PMID:27107175

  17. Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism

    PubMed Central

    Naidoo, Nirinjini; Davis, James G; Zhu, Jingxu; Yabumoto, Maya; Singletary, Kristan; Brown, Marishka; Galante, Raymond; Agarwal, Beamon; Baur, Joseph A

    2014-01-01

    Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals, we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase in a pro-apoptotic transcription factor, CHOP, that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, as plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells and that these effects may be exacerbated by normal aging. PMID:24102714

  18. Black and white with some shades of grey: the diverse responses of inducible metabolic pathways in Escherichia coli.

    PubMed

    Rao, Christopher V; Koirala, Santosh

    2014-09-01

    The metabolic pathways for many sugars are inducible. This process has been extensively studied in the case of Escherichia coli lactose metabolism. It has long been known that gratuitous induction of the lac operon with non-metabolizable lactose analogues generates an all-or-nothing response, where some cells express the lac genes at a maximal rate and others not at all. However, the response to lactose itself is graded, where all cells express the lac genes in proportion to lactose concentrations. The mechanisms generating these distinct behaviours in lactose metabolism have been a topic of many studies. Despite this large body of work, little is known about how other pathways respond to their cognate sugars. An article of Molecular Microbiology investigated the response of eight metabolic pathways in E. coli to their cognate sugars at single-cell resolution. The authors demonstrate that these pathways exhibit diverse responses, ranging from graded to all-or-nothing responses and combinations thereof. Remarkably, they were able to interpret these responses using a simple mathematical model and identify the mechanisms likely giving rise to each. PMID:25069377

  19. CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma.

    PubMed

    Dixit, Deobrat; Ahmad, Fahim; Ghildiyal, Ruchi; Joshi, Shanker Datt; Sen, Ellora

    2016-05-15

    Understanding mechanisms that link aberrant metabolic adaptation and pro-survival responses in glioma cells is crucial towards the development of new anti-glioma therapies. As we have previously reported that CK2 is associated with glioma cell survival, we evaluated its involvement in the regulation of glucose metabolism. Inhibition of CK2 increased the expression of metabolic regulators, PDK4 and AMPK along with the key cellular energy sensor CREB. This increase was concomitant with altered metabolic profile as characterized by decreased glucose uptake in a PDK4 and AMPK dependent manner. Increased PDK4 expression was CREB dependent, as exogenous inhibition of CREB functions abrogated CK2 inhibitor mediated increase in PDK4 expression. Interestingly, PDK4 regulated AMPK phosphorylation which in turn affected cell viability in CK2 inhibitor treated glioma cells. CK2 inhibitor 4,5,6,7-Tetrabromobenzotriazole (TBB) significantly retarded the growth of glioma xenografts in athymic nude mouse model. Coherent with the in vitro findings, elevated senescence, pAMPK and PDK4 levels were also observed in TBB-treated xenograft tissue. Taken together, CK2 inhibition in glioma cells drives the PDK4-AMPK axis to affect metabolic profile that has a strong bearing on their survival. PMID:27001465

  20. Halofuginone reduces the inflammatory responses of DSS-induced colitis through metabolic reprogramming.

    PubMed

    Liu, Jing; Xiao, Hai-Tao; Wang, Hong-Sheng; Mu, Huai-Xue; Zhao, Ling; Du, Jun; Yang, Depo; Wang, Dongmei; Bian, Zhao-Xiang; Lin, Shu-Hai

    2016-06-21

    Hypoxia and inflammation have been identified as the hallmarks of colitis, intertwined with metabolism. Here, we report that halofuginone (HF), an antiparasitic drug, attenuates dextran sulfate sodium (DSS)-induced colitis in mice, as represented by attenuating the disease activity index, inhibiting colonic shortening, ameliorating colonic lesions and histological signs of damage, reducing colonic myeloperoxidase activity, and suppressing the production of pro-inflammatory cytokines in colon tissue. Intriguingly, the hypoxia-inducible factor 1alpha (HIF-1α) and tumor necrosis factor alpha were also suppressed by HF treatment in colon tissues, exhibiting a tissue-specific effect. To further reveal the metabolic signatures upon HF treatment, mass spectrometry-based metabolomic analysis of the small molecular metabolites in liver, spleen and colon tissues was performed. As a result, we found that HF treatment counteracted the levels of acylcarnitines, including palmitoyl-l-carnitine, isobutyrylcarnitine, vaccenylcarnitine, and myristoylcarnitine, in colon tissues with DSS induction, but no significant change in the levels of acylcarnitines was observed in liver or spleen tissues. The metabolic signatures may indicate that incomplete fatty acid oxidation (FAO) in the colon could be restored upon HF treatment as the tissue-specific metabolic characterization. Taken together, our findings uncovered that the HF potentiated anti-inflammatory effect in DSS-induced colitis in mice and its underlying mechanisms could be associated with the inhibition of HIF-1α and reduced levels of acylcarnitines, suggesting that both the inhibition of HIF-1α and the counteraction of incomplete FAO might be useful in the prevention and treatment of inflammatory bowel disease. PMID:27197570

  1. Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation

    PubMed Central

    Kienesberger, Petra C.; Pulinilkunnil, Thomas; Nagendran, Jeevan; Young, Martin E.; Bogner-Strauss, Juliane G.; Hackl, Hubert; Khadour, Rammy; Heydari, Emma; Haemmerle, Guenter; Zechner, Rudolf; Kershaw, Erin E.; Dyck, Jason R. B.

    2013-01-01

    Aims While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in part through reducing peroxisome proliferator-activated receptor α (PPARα) activity and subsequent fatty acid oxidation (FAO). However, whether ATGL deficiency specifically in adult cardiomyocytes contributes to impaired PPARα activity, cardiac function, and metabolism is not known. Methods and results To study the effects of acquired cardiac ATGL deficiency on cardiac PPARα activity, function, and metabolism, we generated adult mice with tamoxifen-inducible cardiomyocyte-specific ATGL deficiency (icAtglKO). Within 4–6 weeks following ATGL ablation, icAtglKO mice had markedly increased myocardial TAG accumulation, fibrotic remodelling, and pathological hypertrophy. Echocardiographic analysis of hearts in vivo revealed that contractile function was moderately reduced in icAtglKO mice. Analysis of energy metabolism in ex vivo perfused working hearts showed diminished FAO rates which was not paralleled by markedly impaired PPARα target gene expression. Conclusions This study shows that acquired cardiomyocyte-specific ATGL deficiency in adult mice is sufficient to promote fibrotic and hypertrophic cardiomyopathy and impair myocardial FAO in the absence of markedly reduced PPARα signalling. PMID:23708736

  2. Stress-induced behavioral and metabolic adaptations lead to an obesity-prone phenotype in ewes with elevated cortisol responses.

    PubMed

    Lee, T Kevin; Lee, Caroline; Bischof, Robert; Lambert, Gavin W; Clarke, Iain J; Henry, Belinda A

    2014-09-01

    The underlying cause of predisposition to obesity is complex but one marker is cortisol responsiveness. Selection of sheep for high (HR) or low (LR) cortisol responses to adrenocorticotropin shows that HR are more likely to become obese. Increased propensity to obesity is associated with reduced skeletal muscle thermogenesis. We sought to determine whether metabolic or behavioral responses to stress also contribute to altered propensity to obesity in LR and HR. Animals (n=5-10/group) were exposed to 3 stressors and we measured food intake and thermogenesis (recorded with dataloggers implanted into muscle). Stressors were hypoglycaemia (0.125 units/kg insulin, IV), a barking dog and immune challenge (200 ng/kg lipopolysaccharide--LPS, IV). LR animals showed a greater catabolic state in response to both immune and psychosocial stressors. LPS reduced (P<0.01) food intake in both groups but LR showed a greater (P<0.05) reduction in food intake and a more substantial (P<0.05) rise in muscle temperature. Introduction of the barking dog reduced (P<0.05) food intake in LR only. These metabolic differences coincided with differences in cortisol responsiveness, where HR animals had increased (P<0.05) cortisol in response to both immune and psychosocial stressors. We also assessed behavior in the following paradigms: 1, isolation in the open field test; 2, response to a human intruder; and 3, food competition. LR had greater (P<0.05) activity, reduced fearfulness and displayed a proactive coping style of behavior. Thus we demonstrate that high cortisol responsiveness identifies animals with stress-induced metabolic and behavioral traits that may contribute to susceptibility to obesity. PMID:25001966

  3. Evaluation of the ethanol antagonist' Ro15-4513 on cardiovascular and metabolic responses induced by ethanol

    SciTech Connect

    Lerner, M.R.; Gauvin, D.V.; Holloway, F.A.; Wilson, M.F.; Brackett, D.J. Veterans Affairs Medical Center, Oklahoma City, OK )

    1992-02-26

    The putative ethanol antagonist Ro15-4513 has been reported to attenuate many behavioral responses induced by ethanol, including motor coordination, narcosis, ethanol self administration and intake, and anticonvulsant actions. This study was designed to study the effect of Ro15-4513 on cardiovascular and metabolic responses elicited by intragastric ethanol in conscious rats. Four groups of rats were catheterized under enflurane anesthesia and allowed to regain consciousness. Each group was given either 3.2, 10.0, or 32.0 mg/kg Ro15-4513 or equivalent Tween (i.p.) following ethanol. Ro15-4513 had no effect at any concentration on the decreases in mean arterial pressure, cardiac output, central venous pressure, respiration rate, and cardiac stroke volume and the increases in systemic vascular resistance, heart rate, and glucose evoked by the ethanol challenge. Blood alcohol concentrations measured throughout the study were not affected by any concentration of Ro15-4513. These data suggest that even though Ro15-4513 has significant effects on behavioral responses induced by ethanol it has no effect on the cardiovascular and metabolic responses elicited during ethanol intoxication.

  4. Hepatic injury induces contrasting response in liver and kidney to chemicals that are metabolically activated: Role of male sex hormone

    SciTech Connect

    Kim, Young C. Yim, Hye K.; Jung, Young S.; Park, Jae H.; Kim, Sung Y.

    2007-08-15

    Injury to liver, resulting in loss of its normal physiological/biochemical functions, may adversely affect a secondary organ. We examined the response of the liver and kidney to chemical substances that require metabolic activation for their toxicities in mice with a preceding liver injury. Carbon tetrachloride treatment 24 h prior to a challenging dose of carbon tetrachloride or acetaminophen decreased the resulting hepatotoxicity both in male and female mice as determined by histopathological examination and increases in serum enzyme activities. In contrast, the renal toxicity of the challenging toxicants was elevated markedly in male, but not in female mice. Partial hepatectomy also induced similar changes in the hepatotoxicity and nephrotoxicity of a challenging toxicant, suggesting that the contrasting response of male liver and kidney was associated with the reduction of the hepatic metabolizing capacity. Carbon tetrachloride pretreatment or partial hepatectomy decreased the hepatic xenobiotic-metabolizing enzyme activities in both sexes but elevated the renal p-nitrophenol hydroxylase, p-nitroanisole O-demethylase and aminopyrine N-demethylase activities significantly only in male mice. Increases in Cyp2e1 and Cyp2b expression were also evident in male kidney. Castration of males or testosterone administration to females diminished the sex-related differences in the renal response to an acute liver injury. The results indicate that reduction of the hepatic metabolizing capacity induced by liver injury may render secondary target organs susceptible to chemical substances activated in these organs. This effect may be sex-specific. It is also suggested that an integrated approach should be taken for proper assessment of chemical hazards.

  5. Detecting plant metabolic responses induced by ground shock using hyperspectral remote sensing and physiological contact measurements

    SciTech Connect

    Pickles, W.L.; Cater, G.A.

    1996-12-03

    A series of field experiments were done to determine if ground shock could have induced physiological responses in plants and if the level of the response could be observed. The observation techniques were remote sensing techniques and direct contact physiological measurements developed by Carter for detecting pre-visual plant stress. The remote sensing technique was similar to that used by Pickles to detect what appeared to be ground shock induced plant stress above the 1993 Non Proliferation Experiment`s underground chemical explosion. The experiment was designed to provide direct plant physiological measurements and remote sensing ratio images and from the same plants at the same time. The simultaneous direct and remote sensing measurements were done to establish a ground truth dataset to compare to the results of the hyperspectral remote sensing measurements. In addition, the experiment was designed to include data on what was thought to be the most probable interfering effect, dehydration. The experimental design included investigating the relative magnitude of the shock induced stress effects compared to dehydration effects.

  6. Fasting induces a biphasic adaptive metabolic response in murine small intestine

    PubMed Central

    Sokolović, Milka; Wehkamp, Diederik; Sokolović, Aleksandar; Vermeulen, Jacqueline; Gilhuijs-Pederson, Lisa A; van Haaften, Rachel IM; Nikolsky, Yuri; Evelo, Chris TA; van Kampen, Antoine HC; Hakvoort, Theodorus BM; Lamers, Wouter H

    2007-01-01

    Background The gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting. Results Intestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut's structural components, so that the microarrays' tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine, and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed. Conclusion The changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover. PMID:17925015

  7. Experimental sink removal induces stress responses, including shifts in amino acid and phenylpropanoid metabolism, in soybean leaves

    PubMed Central

    Turner, Glenn W.; Cuthbertson, Daniel J.; Voo, Siau Sie; Settles, Matthew L.; Grimes, Howard D.

    2012-01-01

    The repeated removal of flower, fruit, or vegetative buds is a common treatment to simulate sink limitation. These experiments usually lead to the accumulation of specific proteins, which are degraded during later stages of seed development, and have thus been designated as vegetative storage proteins. We used oligonucleotide microarrays to assess global effects of sink removal on gene expression patterns in soybean leaves and found an induction of the transcript levels of hundreds of genes with putative roles in the responses to biotic and abiotic stresses. In addition, these data sets indicated potential changes in amino acid and phenylpropanoid metabolism. As a response to sink removal we detected an induced accumulation of γ-aminobutyric acid, while proteinogenic amino acid levels decreased. We also observed a shift in phenylpropanoid metabolism with an increase in isoflavone levels, concomitant with a decrease in flavones and flavonols. Taken together, we provide evidence that sink removal leads to an up-regulation of stress responses in distant leaves, which needs to be considered as an unintended consequence of this experimental treatment. PMID:22109846

  8. Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses.

    PubMed

    Aho, Vilma; Ollila, Hanna M; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S A; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

    2016-01-01

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases. PMID:27102866

  9. Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses

    PubMed Central

    Aho, Vilma; Ollila, Hanna M.; Kronholm, Erkki; Bondia-Pons, Isabel; Soininen, Pasi; Kangas, Antti J.; Hilvo, Mika; Seppälä, Ilkka; Kettunen, Johannes; Oikonen, Mervi; Raitoharju, Emma; Hyötyläinen, Tuulia; Kähönen, Mika; Viikari, Jorma S.A.; Härmä, Mikko; Sallinen, Mikael; Olkkonen, Vesa M.; Alenius, Harri; Jauhiainen, Matti; Paunio, Tiina; Lehtimäki, Terho; Salomaa, Veikko; Orešič, Matej; Raitakari, Olli T.; Ala-Korpela, Mika; Porkka-Heiskanen, Tarja

    2016-01-01

    Sleep loss and insufficient sleep are risk factors for cardiometabolic diseases, but data on how insufficient sleep contributes to these diseases are scarce. These questions were addressed using two approaches: an experimental, partial sleep restriction study (14 cases and 7 control subjects) with objective verification of sleep amount, and two independent epidemiological cohorts (altogether 2739 individuals) with questions of sleep insufficiency. In both approaches, blood transcriptome and serum metabolome were analysed. Sleep loss decreased the expression of genes encoding cholesterol transporters and increased expression in pathways involved in inflammatory responses in both paradigms. Metabolomic analyses revealed lower circulating large HDL in the population cohorts among subjects reporting insufficient sleep, while circulating LDL decreased in the experimental sleep restriction study. These findings suggest that prolonged sleep deprivation modifies inflammatory and cholesterol pathways at the level of gene expression and serum lipoproteins, inducing changes toward potentially higher risk for cardiometabolic diseases. PMID:27102866

  10. Candida albicans Induces Metabolic Reprogramming in Human NK Cells and Responds to Perforin with a Zinc Depletion Response

    PubMed Central

    Hellwig, Daniela; Voigt, Jessica; Bouzani, Maria; Löffler, Jürgen; Albrecht-Eckardt, Daniela; Weber, Michael; Brunke, Sascha; Martin, Ronny; Kurzai, Oliver; Hünniger, Kerstin

    2016-01-01

    As part of the innate immune system, natural killer (NK) cells are directly involved in the response to fungal infections. Perforin has been identified as the major effector molecule acting against many fungal pathogens. While several studies have shown that perforin mediated fungicidal effects can contribute to fungal clearance, neither the activation of NK cells by fungal pathogens nor the effects of perforin on fungal cells are well-understood. In a dual approach, we have studied the global gene expression pattern of primary and cytokine activated NK cells after co-incubation with Candida albicans and the transcriptomic adaptation of C. albicans to perforin exposure. NK cells responded to the fungal pathogen with an up-regulation of genes involved in immune signaling and release of cytokines. Furthermore, we observed a pronounced increase of genes involved in glycolysis and glycolysis inhibitor 2-deoxy-D-glucose impaired C. albicans induced NK cell activation. This strongly indicates that metabolic adaptation is a major part of the NK cell response to C. albicans infections. In the fungal pathogen, perforin induced a strong up-regulation of several fungal genes involved in the zinc depletion response, such as PRA1 and ZRT1. These data suggest that fungal zinc homeostasis is linked to the reaction to perforin secreted by NK cells. However, deletion mutants in PRA1 and ZRT1 did not show altered susceptibility to perforin. PMID:27242763

  11. Candida albicans Induces Metabolic Reprogramming in Human NK Cells and Responds to Perforin with a Zinc Depletion Response.

    PubMed

    Hellwig, Daniela; Voigt, Jessica; Bouzani, Maria; Löffler, Jürgen; Albrecht-Eckardt, Daniela; Weber, Michael; Brunke, Sascha; Martin, Ronny; Kurzai, Oliver; Hünniger, Kerstin

    2016-01-01

    As part of the innate immune system, natural killer (NK) cells are directly involved in the response to fungal infections. Perforin has been identified as the major effector molecule acting against many fungal pathogens. While several studies have shown that perforin mediated fungicidal effects can contribute to fungal clearance, neither the activation of NK cells by fungal pathogens nor the effects of perforin on fungal cells are well-understood. In a dual approach, we have studied the global gene expression pattern of primary and cytokine activated NK cells after co-incubation with Candida albicans and the transcriptomic adaptation of C. albicans to perforin exposure. NK cells responded to the fungal pathogen with an up-regulation of genes involved in immune signaling and release of cytokines. Furthermore, we observed a pronounced increase of genes involved in glycolysis and glycolysis inhibitor 2-deoxy-D-glucose impaired C. albicans induced NK cell activation. This strongly indicates that metabolic adaptation is a major part of the NK cell response to C. albicans infections. In the fungal pathogen, perforin induced a strong up-regulation of several fungal genes involved in the zinc depletion response, such as PRA1 and ZRT1. These data suggest that fungal zinc homeostasis is linked to the reaction to perforin secreted by NK cells. However, deletion mutants in PRA1 and ZRT1 did not show altered susceptibility to perforin. PMID:27242763

  12. Effect of acute induced metabolic alkalosis on the acid/base responses to sprint exercise of six racing greyhounds.

    PubMed

    Holloway, S A; Sundstrom, D; Senior, D F

    1996-11-01

    To investigate the effect of acute induced metabolic alkalosis on the haematological, biochemical and metabolic responses to sprint exercise, six greyhound dogs with previously placed carotid arterial catheters were raced four times over a distance of 400 metres. Each dog was raced twice after receiving oral sodium bicarbonate solution (NaHCO3) (400 mg kg-1) or lactated Ringer's solution (LRS). Before, and for intervals of up to one hour after, the exercise arterial blood samples were collected for the measurement of blood gases, packed cell volume, total protein, serum biochemistry and plasma lactate. The time to complete the 400 metre sprint ranged from 32.7 seconds to 36.9 seconds. There was no significant difference in racing times between the dogs treated with NaHCO3 and LRS, and there was no significant difference between the plasma lactate measurements after the treatments with NaHCO3 or LRS. Serum chloride concentrations were significantly lower after NaHCO3 than after LRS, and there was a trend towards a lower serum potassium concentration after NaHCO3 treatment. Plasma lactate concentrations showed a similar increase and time course of disappearance after both LRS and NaHCO3 treatments. There were significant changes in all the parameters measured after the exercise, but there were large variations between individual dogs and between races when the dogs were receiving the same treatment. PMID:8938856

  13. Drug-Induced Metabolic Acidosis

    PubMed Central

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W.

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics. PMID:26918138

  14. Drug-Induced Metabolic Acidosis.

    PubMed

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs' characteristics. PMID:26918138

  15. Evaluation of the systemic innate immune response and metabolic alterations of nonlactating cows with diet-induced subacute ruminal acidosis.

    PubMed

    Rodríguez-Lecompte, J C; Kroeker, A D; Ceballos-Márquez, A; Li, S; Plaizier, J C; Gomez, D E

    2014-12-01

    Subacute ruminal acidosis (SARA) increases lipopolysaccharide endotoxin in the rumen, which might translocate into the systemic circulation, triggering a cascade of clinical and immunological alterations. The objective of this study was to characterize the clinical immune and metabolic responses to ruminal-derived lipopolysaccharide in nonlactating cows induced with SARA using 2 challenges, a grain-based SARA challenge (GBSC) or an alfalfa-pellet SARA challenge (APSC). Six dry, nonlactating Holstein cows were used in a 3 × 3 Latin square arrangement of treatments with 4-wk experimental cycles. All cows received the control diet containing 70% forage and 30% mixed concentrates (dry matter basis) for 3 wk. In wk 4, cows received a control diet, GBSC (38% wheat-barley pellets, 32% other mixed concentrate, and 30% forages), or APSC (45% mixed concentrate, 32% alfalfa pellets, and 23% other forages). Total plasma proteins and immunology-related proteins, acute phase proteins, blood cells, serum chemistry, mRNA gene expression of peripheral blood cell surface markers, and selected proinflammatory cytokines were evaluated. Ruminal pH was lower in both groups with induced SARA compared with a control group. Ruminal endotoxins were higher in GBSC; however, plasma endotoxin was not detected in any study group. No significant differences in feed intake, rectal temperature, white blood cell counts, or differentials were found between control and SARA challenge groups; changes in glucose, urea, Ca, and Mg were observed in SARA groups. Total plasma proteins were lower in both SARA groups, and acute phase proteins were higher in GBSC. The expression of CD14, MD2, and TLR4 mRNA in peripheral blood leukocytes was not affected by SARA induction. The induction of SARA as a result of GBSC or APSC challenge was successful; however, LPS was not detected in plasma. Changes in clinical, metabolic, and inflammatory responses were not observed in the SARA-challenged cows, suggesting that

  16. The influence of EDDS on the metabolic and transcriptional responses induced by copper in hydroponically grown Brassica carinata seedlings.

    PubMed

    Cestone, Benedetta; Cuypers, Ann; Vangronsveld, Jaco; Sgherri, Cristina; Navari-Izzo, Flavia

    2012-06-01

    To improve the knowledge about the use of plants for the removal of toxic metals from contaminated soils, metabolic and transcriptional responses of Brassica carinata to different forms of copper (Cu) were studied. Two-week-old hydroponically grown seedlings were exposed for 24 h to 30 μM CuSO₄ or CuEDDS. CuSO₄ appeared to be more toxic than CuEDDS as roots showed higher levels of thiobarbituric acid reactive substances (TBARS) and increased relative leakage ratios (RLR), although the superoxide dismutase (SOD, EC 1.15.1.1) activity increased following both exposures. In CuSO₄-exposed seedlings the higher toxicity was underlined by increased transcription of lipoxygenases (EC 1.13.11.12) and NADPH oxidases (EC 1.6.99.6) and by the higher Cu accumulation in both tissues compared to CuEDDS exposure. The presence of EDDS increased Cu translocation, which resulted 5-times higher than when exposed to CuSO₄. Decreases in catalase (CAT, EC 1.11.1.6), ascorbate peroxidase (APX, EC 1.11.1.11) and glutathione reductase (GR, EC 1.6.4.2) activities together with increases of reduced glutathione (GSH) and tocopherols and a reduction of lipoic acid (LA) were observed in roots of CuSO₄-exposed seedlings. On the contrary, CuEDDS exposure induced a general increase in enzyme activities and decreases in ascorbate (AsA) and tocopherol levels. In the primary leaves, in both exposures Cu differently affected the oxidative stress responses indicating that the cellular redox balance was anyway maintained. EDDS plays a crucial role in B. carinata tolerance to oxidative stress induced by Cu and might be proposed to improve the efficiency of Cu phytoextraction. PMID:22522579

  17. Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain.

    PubMed

    Imran, Imran; Hillert, Markus H; Klein, Jochen

    2015-12-01

    The lithium-pilocarpine model of status epilepticus is a well-known animal model of temporal lobe epilepsy. We combined this model with in vivo microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). Twenty-four hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase in glucose and a prominent, five-fold increase in lactate during seizures. Lactate release was because of neuronal activation as it was strongly reduced by infusion of tetrodotoxin, administration of atropine or when seizures were terminated by diazepam or ketamine. In ex vivo assays, mitochondrial function as measured by respirometry was not affected by 90 min of seizures. Extracellular levels of choline, however, increased two-fold and glycerol levels 10-fold, which indicate cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold and formation of isoprostanes 20-fold, revealing significant oxidative stress in hippocampal tissue. Increases in lactate, glycerol and isoprostanes were abrogated, and increases in choline were completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases in extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains intact for at least 90 min. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin. Status epilepticus (SE) was induced in rats by

  18. Cardiac responses to induced lactate oxidation: NMR analysis of metabolic equilibria.

    PubMed

    Lewandowski, E D; Damico, L A; White, L T; Yu, X

    1995-07-01

    The role of lactate as a source of pyruvate oxidation in supporting cardiac work, energetics, and formation of oxidative metabolites was examined in normal myocardium. 13C- and 31P-nuclear magnetic resonance (NMR) spectra were acquired from isolated rabbit hearts supplied 2.5 mM [3-13C]lactate or [3-13C]pyruvate with or without stimulation of pyruvate dehydrogenase (PDH) by dichloroacetate (DCA). Similar workloads determined by rate-pressure products were noted with pyruvate (21,700 +/- 2,400; mean +/- SE) and lactate (18,970 +/- 1,510). Oxygen consumption was similar in all four groups with means between 19.0 and 22.2 mumol.min-1.g dry weight-1 (SE = 1.6-2.0) as was the ratio of phosphocreatine to ATP with means between 1.8 and 2.1 (SE = 0.1-0.6). Intracellular pH, determined from 31P-NMR spectra, was essentially the same with pyruvate (7.06 +/- 0.02) and lactate (7.05 +/- 0.04). 13C enrichment of glutamate was higher with lactate (92%) than with pyruvate (70%). Pyruvate plus DCA induced no change in glutamate content at 9-10 mumol/g, but 13C enrichment increased to 83%, while lactate plus DCA maintained enrichment at 90%. Levels of alpha-ketoglutarate were lower with lactate (1.81 mumol/g) than with pyruvate (2.36 mumol/g). Lactate plus DCA elevated glutamate by 60% with a proportional increase in alpha-ketoglutarate. Thus the balance between glutamate and alpha-ketoglutarate was affected by substrate supply only and not by PDH activation. The results suggest that the equilibrium between alpha-ketoglutarate and glutamate is sensitive to cytosolic redox state, an important consideration for 13C-NMR analyses that rely on glutamate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7631845

  19. The acute phase response induced by Escherichia coli lipopolysaccharide modifies the pharmacokinetics and metabolism of florfenicol in rabbits.

    PubMed

    Pérez, R; Palma, C; Burgos, R; Jeldres, J A; Espinoza, A; Peñailillo, A K

    2016-04-01

    The aim of this study was to determine the effect of Escherichia coli lipopolysaccharide (LPS)-induced acute phase response (APR) on the pharmaco-kinetics and biotransformation of florfenicol (FFC) in rabbits. Six rabbits (3.0 ± 0.08 kg body weight (bw)) were distributed through a crossover design with 4 weeks of washout period. Pairs of rabbits similar in bw and sex were assigned to experimental groups: Group 1 (LPS) was treated with three intravenous doses of 1 μg/kg bw of E. coli LPS at intervals of 6 h, and Group 2 (control) was treated with an equivalent volume of saline solution (SS) at the same intervals and frequency of Group 1. At 24 h after the first injection of LPS or SS, an intravenous bolus of 20 mg/kg bw of FFC was administered. Blood samples were collected from the auricular vein before drug administration and at different times between 0.05 and 24.0 h after treatment. FFC and florfenicol-amine (FFC-a) were extracted from the plasma, and their concentrations were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic model was used for data analysis, and data were compared using the paired Student t-test. The mean values of AUC0-∞ in the endotoxaemic rabbits (26.3 ± 2.7 μg·h/mL) were significantly higher (P < 0.05) than values observed in healthy rabbits (17.2 ± 0.97 μg·h/mL). The total mean plasma clearance (CLT ) decreased from 1228 ± 107.5 mL·h/kg in the control group to 806.4 ± 91.4 mL·h/kg in the LPS-treated rabbits. A significant increase (P < 0.05) in the half-life of elimination was observed in the endotoxaemic rabbits (5.59 ± 1.14 h) compared to the values observed in healthy animals (3.44 ± 0.57 h). In conclusion, the administration of repeated doses of 1 μg/kg E. coli LPS induced an APR in rabbits, producing significant modifications in plasma concentrations of FFC leading to increases in the AUC, terminal half-life and mean residence time (MRT), but a

  20. Metabolic response to exercise.

    PubMed

    De Feo, P; Di Loreto, C; Lucidi, P; Murdolo, G; Parlanti, N; De Cicco, A; Piccioni, F; Santeusanio, F

    2003-09-01

    At the beginning, the survival of humans was strictly related to their physical capacity. There was the need to resist predators and to provide food and water for life. Achieving these goals required a prompt and efficient energy system capable of sustaining either high intensity or maintaining prolonged physical activity. Energy for skeletal muscle contraction is supplied by anaerobic and aerobic metabolic pathways. The former can allow short bursts of intense physical activity (60-90 sec) and utilizes as energetic source the phosphocreatine shuttle and anaerobic glycolysis. The aerobic system is the most efficient ATP source for skeletal muscle. The oxidative phosporylation of carbohydrates, fats and, to a minor extent, proteins, can sustain physical activity for many hours. Carbohydrates are the most efficient fuel for working muscle and their contribution to total fuel oxidation is positively related to the intensity of exercise. The first metabolic pathways of carbohydrate metabolism to be involved are skeletal muscle glycogenolysis and glycolysis. Later circulating glucose, formed through activated gluconeogenesis, becomes an important energetic source. Among glucose metabolites, lactate plays a primary role as either direct or indirect (gluconeogenesis) energy source for contracting skeletal muscle. Fat oxidation plays a primary role during either low-moderate intensity exercise or protracted physical activity (over 90-120 min). Severe muscle glycogen depletion results in increased rates of muscle proteolysis and branched chain amino acid oxidation. Endurance training ameliorates physical performance by improving cardiopulmonary efficiency and optimizing skeletal muscle supply and oxidation of substrates. PMID:14964437

  1. Sphingolipid metabolism and obesity-induced inflammation.

    PubMed

    Kang, Se-Chan; Kim, Bo-Rahm; Lee, Su-Yeon; Park, Tae-Sik

    2013-01-01

    Obesity is a metabolic disorder developed by overnutrition and a major cause for insulin resistance and cardiovascular events. Since adipose tissue is one of the major sites for the synthesis and secretion of cytokines, enlarged adipose tissue in obese condition alters inflammatory state leading to pathophysiological conditions such as type 2 diabetes and increased cardiovascular risk. A plausible theory for development of metabolic dysregulation is that obesity increases secretion of inflammatory cytokines from adipose tissue and causes a chronic inflammation in the whole body. Additionally accumulation of lipids in non-adipose tissues elevates the cellular levels of bioactive lipids that inhibit the signaling pathways implicated in metabolic regulation together with activated inflammatory response. Recent findings suggest that obesity-induced inflammatory response leads to modulation of sphingolipid metabolism and these bioactive lipids may function as mediators for increased risk of metabolic dysfunction. Importantly, elucidation of mechanism regarding sphingolipid metabolism and inflammatory disease will provide crucial information to development of new therapeutic strategies for the treatment of obesity-induced pathological inflammation. PMID:23761785

  2. Proteomic responses to lead-induced oxidative stress in Talinum triangulare Jacq. (Willd.) roots: identification of key biomarkers related to glutathione metabolisms.

    PubMed

    Kumar, Abhay; Majeti, Narasimha Vara Prasad

    2014-01-01

    In this study, Talinum triangulare Jacq. (Willd.) treated with different lead (Pb) concentrations for 7 days has been investigated to understand the mechanisms of ascorbate-glutathione metabolisms in response to Pb-induced oxidative stress. Proteomic study was performed for control and 1.25 mM Pb-treated plants to examine the root protein dynamics in the presence of Pb. Results of our analysis showed that Pb treatment caused a decrease in non-protein thiols, reduced glutathione (GSH), total ascorbate, total glutathione, GSH/oxidized glutathione (GSSG) ratio, and activities of glutathione reductase and γ-glutamylcysteine synthetase. Conversely, cysteine and GSSG contents and glutathione-S-transferase activity was increased after Pb treatment. Fourier transform infrared spectroscopy confirmed our metabolic and proteomic studies and showed that amino, phenolic, and carboxylic acids as well as alcoholic, amide, and ester-containing biomolecules had key roles in detoxification of Pb/Pb-induced toxic metabolites. Proteomic analysis revealed an increase in relative abundance of 20 major proteins and 3 new proteins (appeared only in 1.25 mM Pb). Abundant proteins during 1.25 mM Pb stress conditions have given a very clear indication about their involvement in root architecture, energy metabolism, reactive oxygen species (ROS) detoxification, cell signaling, primary and secondary metabolisms, and molecular transport systems. Relative accumulation patterns of both common and newly identified proteins are highly correlated with our other morphological, physiological, and biochemical parameters. PMID:24705950

  3. Metabolic responses of Beauveria bassiana to hydrogen peroxide-induced oxidative stress using an LC-MS-based metabolomics approach.

    PubMed

    Zhang, Chen; Wang, Wei; Lu, Ruili; Jin, Song; Chen, Yihui; Fan, Meizhen; Huang, Bo; Li, Zengzhi; Hu, Fenglin

    2016-06-01

    The entomopathogenic fungus, Beauveria bassiana, is commonly used as a biological agent for pest control. Environmental and biological factors expose the fungus to oxidative stress; as a result, B. bassiana has adopted a number of anti-oxidant mechanisms. In this study, we investigated metabolites of B. bassiana that are formed in response to oxidative stress from hydrogen peroxide (H2O2) by using a liquid chromatography mass spectrometry (LC-MS) approach. Partial least-squares discriminant analysis (PLS-DA) revealed differences between the control and the H2O2-treated groups. Hierarchical cluster analysis (HCA) showed 18 up-regulated metabolites and 25 down-regulated metabolites in the H2O2-treated fungus. Pathway analysis indicated that B. bassiana may be able to alleviate oxidative stress by enhancing lipid catabolism and glycometabolism, thus decreasing membrane polarity and preventing polar H2O2 or ROS from permeating into fungal cells and protecting cells against oxidative injury. Meanwhile, most of the unsaturated fatty acids that are derived from glycerophospholipids hydrolysis can convert into oxylipins through autoxidation, which can prevent the reactive oxygen of H2O2 from attacking important macromolecules of the fungus. Results showed also that H2O2 treatment can enhance mycotoxins production which implies that oxidative stress may be able to increase the virulence of the fungus. In comparison to the control group, citric acid and UDP-N-acetylglucosamine were down-regulated, which suggested that metabolic flux was occurring to the TCA cycle and enhancing carbohydrate metabolism. The findings from this study will contribute to the understanding of how the molecular mechanisms of fungus respond to environmental and biological stress factors as well as how the manipulation of such metabolisms may lead to selection of more effective fungal strains for pest control. PMID:27116916

  4. Exercise training and work task induced metabolic and stress-related mRNA and protein responses in myalgic muscles.

    PubMed

    Sjøgaard, Gisela; Zebis, Mette K; Kiilerich, Kristian; Saltin, Bengt; Pilegaard, Henriette

    2013-01-01

    The aim was to assess mRNA and/or protein levels of heat shock proteins, cytokines, growth regulating, and metabolic proteins in myalgic muscle at rest and in response to work tasks and prolonged exercise training. A randomized controlled trial included 28 females with trapezius myalgia and 16 healthy controls. Those with myalgia performed ~7 hrs repetitive stressful work and were subsequently randomized to 10 weeks of specific strength training, general fitness training, or reference intervention. Muscles biopsies were taken from the trapezius muscle at baseline, after work and after 10 weeks intervention. The main findings are that the capacity of carbohydrate oxidation was reduced in myalgic compared with healthy muscle. Repetitive stressful work increased mRNA content for heat shock proteins and decreased levels of key regulators for growth and oxidative metabolism. In contrast, prolonged general fitness as well as specific strength training decreased mRNA content of heat shock protein while the capacity of carbohydrate oxidation was increased only after specific strength training. PMID:23509827

  5. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver

    PubMed Central

    Fusakio, Michael E.; Willy, Jeffrey A.; Wang, Yongping; Mirek, Emily T.; Al Baghdadi, Rana J. T.; Adams, Christopher M.; Anthony, Tracy G.; Wek, Ronald C.

    2016-01-01

    Disturbances in protein folding and membrane compositions in the endoplasmic reticulum (ER) elicit the unfolded protein response (UPR). Each of three UPR sensory proteins—PERK (PEK/EIF2AK3), IRE1, and ATF6—is activated by ER stress. PERK phosphorylation of eIF2 represses global protein synthesis, lowering influx of nascent polypeptides into the stressed ER, coincident with preferential translation of ATF4 (CREB2). In cultured cells, ATF4 induces transcriptional expression of genes directed by the PERK arm of the UPR, including genes involved in amino acid metabolism, resistance to oxidative stress, and the proapoptotic transcription factor CHOP (GADD153/DDIT3). In this study, we characterize whole-body and tissue-specific ATF4-knockout mice and show in liver exposed to ER stress that ATF4 is not required for CHOP expression, but instead ATF6 is a primary inducer. RNA-Seq analysis indicates that ATF4 is responsible for a small portion of the PERK-dependent UPR genes and reveals a requirement for expression of ATF4 for expression of genes involved in oxidative stress response basally and cholesterol metabolism both basally and under stress. Consistent with this pattern of gene expression, loss of ATF4 resulted in enhanced oxidative damage, and increased free cholesterol in liver under stress accompanied by lowered cholesterol in sera. PMID:26960794

  6. Response to diet-induced obesity produces time-dependent induction and progression of metabolic osteoarthritis in rat knees.

    PubMed

    Collins, Kelsey H; Hart, David A; Reimer, Raylene A; Seerattan, Ruth A; Herzog, Walter

    2016-06-01

    Obesity, and corresponding chronic-low grade inflammation, is associated with the onset and progression of knee OA. The origin of this inflammation is poorly understood. Here, the effect of high fat, high sucrose (HFS) diet induced obesity (DIO) on local (synovial fluid), and systemic (serum) inflammation is evaluated after a 12-week obesity induction and a further 16-week adaptation period. For 12-weeks of obesity induction, n = 40 DIO male Sprague-Dawley rats consumed a HFS diet while the control group (n = 14) remained on chow. DIO rats were allocated to prone (DIO-P, top 33% based on weight change) or resistant (DIO-R, bottom 33%) groups at 12-weeks. Animals were euthanized at 12- and after an additional 16-weeks on diet (28-weeks). At sacrifice, body composition and knee joints were collected and assessed. Synovial fluid and sera were profiled using cytokine array analysis. At 12-weeks, DIO-P animals demonstrated increased Modified Mankin scores compared to DIO-R and chow (p = 0.026), and DIO-R had higher Mankin scores compared to chow (p = 0.049). While numerous systemic and limited synovial fluid inflammatory markers were increased at 12-weeks in DIO animals compared to chow, by 28-weeks there were limited systemic differences but marked increases in local synovial fluid inflammatory marker concentrations. Metabolic OA may manifest from an initial systemic inflammatory disturbance. Twelve weeks of obesity induction leads to a unique inflammatory profile and induction of metabolic OA which is altered after a further 16-weeks of obesity and HFS diet intake, suggesting that obesity is a dynamic, progressive process. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1010-1018, 2016. PMID:26572064

  7. The surgically induced stress response.

    PubMed

    Finnerty, Celeste C; Mabvuure, Nigel Tapiwa; Ali, Arham; Kozar, Rosemary A; Herndon, David N

    2013-09-01

    The stress response to surgery, critical illness, trauma, and burns encompasses derangements of metabolic and physiological processes that induce perturbations in the inflammatory, acute phase, hormonal, and genomic responses. Hypermetabolism and hypercatabolism result, leading to muscle wasting, impaired immune function and wound healing, organ failure, and death. The surgery-induced stress response is largely similar to that triggered by traumatic injuries; the duration of the stress response, however, varies according to the severity of injury (surgical or traumatic). This spectrum of injuries and insults ranges from small lacerations to severe insults such as large poly-traumatic and burn injuries. Burn injuries provide an extreme model of trauma induced stress responses that can be used to study the long-term effects of a prolonged stress response. Although the stress response to acute trauma evolved to confer improved chances of survival following injury, in modern surgical practice the stress response can be detrimental. PMID:24009246

  8. (Uncommon) Mechanisms of Branchial Ammonia Excretion in the Common Carp (Cyprinus carpio) in Response to Environmentally Induced Metabolic Acidosis.

    PubMed

    Wright, Patricia A; Wood, Chris M; Hiroi, Junya; Wilson, Jonathan M

    2016-01-01

    Freshwater fishes generally increase ammonia excretion in acidic waters. The new model of ammonia transport in freshwater fish involves an association between the Rhesus (Rh) protein Rhcg-b, the Na(+)/H(+) exchanger (NHE), and a suite of other membrane transporters. We tested the hypothesis that Rhcg-b and NHE3 together play a critical role in branchial ammonia excretion in common carp (Cyprinus carpio) chronically exposed to a low-pH environment. Carp were exposed to three sequential environmental treatments-control pH 7.6 water (24 h), pH 4.0 water (72 h), and recovery pH 7.6 water (24 h)-or in a separate series were simply exposed to either control (72 h) or pH 4.0 (72 h) water. Branchial ammonia excretion was increased by ∼2.5-fold in the acid compared with the control period, despite the absence of an increase in the plasma-to-water partial pressure NH3 gradient. Alanine aminotransferase activity was higher in the gills of fish exposed to pH 4 versus control water, suggesting that ammonia may be generated in gill tissue. Gill Rhcg-b and NHE3b messenger RNA levels were significantly elevated in acid-treated relative to control fish, but at the protein level Rhcg-b decreased (30%) and NHE3b increased (2-fold) in response to water of pH 4.0. Using immunofluorescence microscopy, NHE3b and Rhcg-b were found to be colocalized to ionocytes along the interlamellar space of the filament of control fish. After 72 h of acid exposure, Rhcg-b staining almost disappeared from this region, and NHE3b was more prominent along the lamellae. We propose that ammoniagenesis within the gill tissue itself is responsible for the higher rates of branchial ammonia excretion during chronic metabolic acidosis. Unexpectedly, gill Rhcg-b does not appear to be important in gill ammonia transport in low-pH water, but the strong induction of NHE3b suggests that some NH4(+) may be eliminated directly in exchange for Na(+). These findings contrast with previous studies in larval zebrafish

  9. Stress memory induced transcriptional and metabolic changes of perennial ryegrass (Lolium perenne) in response to salt stress.

    PubMed

    Hu, Tao; Jin, Yupei; Li, Huiying; Amombo, Erick; Fu, Jinmin

    2016-01-01

    Preexposure to a stress could induce stable signals and reactions on plant physiology and gene expression during future encounters as a 'stress memory'. In this study, we found that two trainable genes, BPSP encoding putative brown plant hopper susceptibility protein and sucs encoding sucrose synthase displayed transcriptional memory for their considerably higher transcript levels during two or more subsequent stresses (S3, S4) relative to the initial stress (S0), and their expression returning to basal transcript levels (non-stressed) during the recovery states (R1, R2 and R3). Removing the repetitive stress/recovery exercise, activated transcriptional memory from two trainable genes persisted for at least 4 days in perennial ryegrass. The pretrainable genes with stress memory effort had higher response to the subsequent elevated NaCl concentration treatment than the non-trainable plants, which was confirmed by lower electrolyte leakage and minimum H2 O2 and O2 (-) accumulation. Salt stress elevated the content of 41 metabolites in perennial ryegrass leaves, and sugars and sugar alcohol accounted for more than 74.1% of the total metabolite content. The salt stress memory was associated with higher contents of 11 sugars and 1 sugar alcohol in the pretrainable grass leaves. Similarly, six sugars showed greater content in the pretrainable grass roots. These novel phenomena associated with transcriptional memory and metabolite profiles could lead to new insights into improving plant salinity acclimation process. PMID:25913889

  10. Effects in cats of atipamezole, flumazenil and 4-aminopyridine on stress-related neurohormonal and metabolic responses induced by medetomidine, midazolam and ketamine.

    PubMed

    Ueoka, Naotami; Hikasa, Yoshiaki

    2015-08-01

    This study aimed to investigate the antagonistic effects of a fixed dose of atipamezole (ATI), flumazenil (FLU) and 4-aminopyridine (4AP), both alone and in various combinations, on key stress-related neurohormonal and metabolic changes induced by medetomidine (MED), midazolam (MID) and ketamine (KET) in healthy cats. Seven cats were used consistently in eight investigation groups. Cats were administered a mixture of 0.05 mg/kg MED and 0.5 mg/kg MID followed 10 mins later by 10 mg/kg KET intramuscularly. Twenty minutes after KET injection, the cats were intravenously injected with either a physiological saline solution at 0.1 ml/kg (control) or one of the seven variations of experimental drugs, alone or in combination: ATI, FLU, 4AP, ATI + FLU, FLU + 4AP, ATI + 4AP and ATI + FLU + 4AP. Blood samples were collected 10 times during the 24 h test period. Plasma glucose, insulin, cortisol, epinephrine, norepinephrine and non-esterified fatty acid levels were measured. The administration of MED + MID + KET resulted in hyperglycaemia and decreases in epinephrine, norepinephrine, cortisol and non-esterified fatty acid levels. FLU or 4AP alone or FLU + 4AP did not effectively antagonise the effects induced by MED + MID + KET but enhanced the hyperglycaemia. ATI alone was effective in antagonising these effects. Compared with non-ATI regimens, combinations with ATI were more effective in antagonising the effects induced by MED + MID + KET; however, ATI + FLU + 4AP caused large increases in cortisol, epinephrine and norepinephrine concentrations. ATI, both alone and in combination, is effective in antagonising the neurohormonal and metabolic effects of MED + MID + KET in cats. However, ATI + FLU + 4AP is not suitable because of large stress-related hormonal responses. PMID:25366173

  11. The Surgically Induced Stress Response

    PubMed Central

    Finnerty, Celeste C.; Mabvuure, Nigel Tapiwa; Ali, Arham; Kozar, Rosemary A.; Herndon, David N.

    2013-01-01

    The stress response to surgery, critical illness, trauma, and burns encompasses derangements of metabolic and physiological processes which induce perturbations in the inflammatory, acute phase, hormonal, and genomic responses. Hypermetabolism and hypercatabolism result, leading to muscle wasting, impaired immune function and wound healing, organ failure, and death. The surgery-induced stress response is largely similar to that triggered by traumatic injuries; the duration of the stress response, however, varies according to the severity of injury (surgical or traumatic). This spectrum of injuries and insults ranges from small lacerations to severe insults such as large poly-traumatic and burn injuries. Although the stress response to acute trauma evolved to improve chances of survival following injury, in modern surgical practice the stress response can be detrimental. PMID:24009246

  12. Diet-Induced Metabolic Disturbances As Modulators of Brain Homeostasis

    PubMed Central

    Zhang, Le; Bruce-Keller, Annadora J.; Dasuri, Kalavathi; Nguyen, AnhThao; Liu, Dr Ying; Keller, Jeffrey N.

    2009-01-01

    A number of metabolic disturbances occur in response to the consumption of a high fat Western diet. Such metabolic disturbances can include the progressive development of hyperglycemia, hyperinsulemia, obesity, metabolic syndrome, and diabetes. Cumulatively, diet-induced disturbance in metabolism are known to promote increased morbidity and negatively impact life expectancy through a variety of mechanisms. While the impact of metabolic disturbances on the hepatic, endocrine, and cardiovascular systems are well established there remains a noticeable void in understanding the basis by which the central nervous system (CNS) becomes altered in response to diet-induced metabolic dysfunction. In particular, it remains to be fully elucidated which established features of diet-induced pathogenesis (observed in non-CNS tissues) are recapitulated in the brain, and identification as to whether the observed changes in the brain are a direct or indirect effect of peripheral metabolic disturbances. This review will focus on each of these key issues and identify some critical experimental questions which remain to be elucidated experimentally, as well as provide an outline of our current understanding for how diet-induced alterations in metabolism may impact the brain during aging and age-related diseases of the nervous system. PMID:18926905

  13. Selected Metabolic Responses to Skateboarding

    ERIC Educational Resources Information Center

    Hetzler, Ronald K.; Hunt, Ian; Stickley, Christopher D.; Kimura, Iris F.

    2011-01-01

    Despite the popularity of skateboarding worldwide, the authors believe that no previous studies have investigated the metabolic demands associated with recreational participation in the sport. Although metabolic equivalents (METs) for skateboarding were published in textbooks, the source of these values is unclear. Therefore, the rise in…

  14. Metabolic disorders and adipose tissue insulin responsiveness in neonatally STZ-induced diabetic rats are improved by long-term melatonin treatment.

    PubMed

    de Oliveira, Ariclécio C; Andreotti, Sandra; Farias, Talita da S M; Torres-Leal, Francisco L; de Proença, André R G; Campaña, Amanda B; de Souza, Arnaldo H; Sertié, Rogério A L; Carpinelli, Angelo R; Cipolla-Neto, José; Lima, Fábio B

    2012-05-01

    Diabetes mellitus is a product of low insulin sensibility and pancreatic β-cell insufficiency. Rats with streptozotocin-induced diabetes during the neonatal period by the fifth day of age develop the classic diabetic picture of hyperglycemia, hypoinsulinemia, polyuria, and polydipsia aggravated by insulin resistance in adulthood. In this study, we investigated whether the effect of long-term treatment with melatonin can improve insulin resistance and other metabolic disorders in these animals. At the fourth week of age, diabetic animals started an 8-wk treatment with melatonin (1 mg/kg body weight) in the drinking water at night. Animals were then killing, and the sc, epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed, and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Blood samples were collected for biochemical assays. Melatonin treatment reduced hyperglycemia, polydipsia, and polyphagia as well as improved insulin resistance as demonstrated by constant glucose disappearance rate and homeostasis model of assessment-insulin resistance. However, melatonin treatment was unable to recover body weight deficiency, fat mass, and adipocyte size of diabetic animals. Adiponectin and fructosamine levels were completely recovered by melatonin, whereas neither plasma insulin level nor insulin secretion capacity was improved in diabetic animals. Furthermore, melatonin caused a marked delay in the sexual development, leaving genital structures smaller than those of nontreated diabetic animals. Melatonin treatment improved the responsiveness of adipocytes to insulin in diabetic animals measured by tests of glucose uptake (sc, EP, and RP), glucose oxidation, and incorporation of glucose into lipids (EP and RP), an effect that seems partially related to an increased expression of insulin receptor substrate 1, acetyl-coenzyme A carboxylase and fatty acid

  15. Metabolic alterations accompanying oncogene-induced senescence

    PubMed Central

    Aird, Katherine M; Zhang, Rugang

    2014-01-01

    Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs in normal primary human cells after activation of an oncogene in the absence of other cooperating oncogenic stimuli. OIS is therefore considered a bona fide tumor suppression mechanism in vivo. Indeed, overcoming OIS-associated stable cell growth arrest can lead to tumorigenesis. Although cells that have undergone OIS do not replicate their DNA, they remain metabolically active. A number of recent studies report significant changes in cellular metabolism during OIS, including alterations in nucleotide, glucose, and mitochondrial metabolism and autophagy. These alterations may be necessary for stable senescence-associated cell growth arrest, and overcoming these shifts in metabolism may lead to tumorigenesis. This review highlights what is currently known about alterations in cellular metabolism during OIS and the implication of OIS-associated metabolic changes in cellular transformation and the development of cancer therapeutic strategies. PMID:27308349

  16. Mitochondrial metabolic remodeling in response to genetic and environmental perturbations.

    PubMed

    Hollinshead, Kate E R; Tennant, Daniel A

    2016-07-01

    Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia-induced changes in the proteome mediated by the activity of transcription factors such as hypoxia-inducible factor 1. Hypoxia is a well-described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer-associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272-285. doi: 10.1002/wsbm.1334 For further resources related to this article, please visit the WIREs website. PMID:27196610

  17. Mitochondrial metabolic remodeling in response to genetic and environmental perturbations

    PubMed Central

    Hollinshead, Kate E.R.

    2016-01-01

    Mitochondria are metabolic hubs within mammalian cells and demonstrate significant metabolic plasticity. In oxygenated environments with ample carbohydrate, amino acid, and lipid sources, they are able to use the tricarboxylic acid cycle for the production of anabolic metabolites and ATP. However, in conditions where oxygen becomes limiting for oxidative phosphorylation, they can rapidly signal to increase cytosolic glycolytic ATP production, while awaiting hypoxia‐induced changes in the proteome mediated by the activity of transcription factors such as hypoxia‐inducible factor 1. Hypoxia is a well‐described phenotype of most cancers, driving many aspects of malignancy. Improving our understanding of how mitochondria change their metabolism in response to this stimulus may therefore elicit the design of new selective therapies. Many of the recent advances in our understanding of mitochondrial metabolic plasticity have been acquired through investigations of cancer‐associated mutations in metabolic enzymes, including succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. This review will describe how metabolic perturbations induced by hypoxia and mutations in these enzymes have informed our knowledge in the control of mitochondrial metabolism, and will examine what this may mean for the biology of the cancers in which these mutations are observed. WIREs Syst Biol Med 2016, 8:272–285. doi: 10.1002/wsbm.1334 For further resources related to this article, please visit the WIREs website. PMID:27196610

  18. Glycation does not modify bovine serum albumin (BSA)-induced reduction of rat aortic relaxation: The response to glycated and nonglycated BSA is lost in metabolic syndrome

    PubMed Central

    Rubio-Ruiz, Maria Esther; Díaz-Díaz, Eulises; Cárdenas-León, Mario; Argüelles-Medina, Rabindranath; Sánchez-Canales, Patricia; Larrea-Gallo, Fernando; Soria-Castro, Elizabeth; Guarner-Lans, Verónica

    2008-01-01

    The effects of nonglycated bovine serum albumin (BSA) and advanced glycosylation end products of BSA (AGE-BSA) on vascular responses of control and metabolic syndrome (MS) rats characterized by hypertriglyceridemia, hypertension, hyperinsulinemia, and insulin resistance were studied. Albumin and in vitro prepared AGE-BSA have vascular effects; however, recent studies indicate that some effects of in vitro prepared AGEs are due to the conditions in which they were generated. We produced AGEs by incubating glucose with BSA for 60 days under sterile conditions in darkness and at 37°C. To develop MS rats, male Wistar animals were given 30% sucrose in drinking water since weanling. Six month old animals were used. Blood pressure, insulin, triglycerides, and serum albumin were increased in MS rats. Contraction of aortic rings elicited with norepinephrine was stronger. There were no effects of nonglycated BSA or AGE-BSA on contractions in control or MS rats; however, both groups responded to L-NAME, an inhibitor of nitric oxide synthesis. Arterial relaxation induced using acetylcholine was smaller in MS rats. Nonglycated BSA and AGE-BSA significantly diminished relaxation in a 35% in the control group but the decrease was similar when using nonglycated BSA and AGE-BSA. This decrease was not present in the MS rats and was not due to increased RAGEs or altered biochemical characteristics of BSA. In conclusion, both BSA and AGE-BSA inhibit vascular relaxation in control artic rings. In MS rats the effect is lost possibly due to alterations in endothelial cells that are a consequence of the illness. PMID:18458031

  19. MNK1-induced eIF-4E phosphorylation in myeloma cells: a pathway mediating IL-6-induced expansion and expression of genes involved in metabolic and proteotoxic responses.

    PubMed

    Shi, Yijiang; Frost, Patrick; Hoang, Bao; Yang, Yonghui; Bardeleben, Carolyne; Gera, Joseph; Lichtenstein, Alan

    2014-01-01

    Because multiple myeloma (MM) cells are at risk for endoplasmic reticulum (ER) stress, they require a carefully regulated mechanism to promote protein translation of selected transcripts when proliferation is stimulated. MAPK-interacting kinases (MNKs) may provide this mechanism by enhancing cap-dependent translation of a small number of critical transcripts. We, thus, tested whether MNKs played a role in MM responses to the myeloma growth factor interleukin-6 (IL-6). IL-6 activated MNK1 phosphorylation and induced phosphorylation of its substrate, eIF-4E, in MM lines and primary specimens. MNK paralysis, achieved pharmacologically or by shRNA, prevented MM expansion stimulated by IL-6. A phosphodefective eIF-4E mutant also prevented the IL-6 response, supporting the notion that MNK's role was via phosphorylation of eIF-4E. Both pharmacological MNK inhibition and expression of the phosphodefective eIF-4E mutant inhibited MM growth in mice. Although critical for IL-6-induced expansion, eIF-4E phosphorylation had no significant effect on global translation or Ig expression. Deep sequencing of ribosome-protected mRNAs revealed a repertoire of genes involved in metabolic processes and ER stress modulation whose translation was regulated by eIF-4E phosphorylation. These data indicate MM cells exploit the MNK/eIF-4E pathway for selective mRNA translation without enhancing global translation and risking ER stress. PMID:24714040

  20. Early Life Stress Induced by Limited Nesting Material Produces Metabolic Resilience in Response to a High-Fat and High-Sugar Diet in Male Rats

    PubMed Central

    Maniam, Jayanthi; Antoniadis, Christopher P.; Wang, Kristy W.; Morris, Margaret J.

    2015-01-01

    Environmental conditions experienced in early life can profoundly influence long-term metabolic health, but the additive impact of poor nutrition is poorly understood. Here, we tested the hypothesis that early life stress (ELS) induced by limited nesting material (LN) combined with high-fat and high-sugar diet (HFHS) post-weaning would worsen diet-related metabolic risk. Sprague-Dawley male rats were exposed to LN, postnatal days 2–9, and at weaning (3 weeks), siblings were given unlimited access to chow or HFHS resulting in (Con-Chow, Con-HFHS, LN-Chow, and LN-HFHS, n = 11–15/group). Glucose and insulin tolerance were tested and rats were killed at 13 weeks. LN rats weighed less at weaning but were not different to control at 13 weeks; HFHS diet led to similar increases in body weight. LN-chow rats had improved glucose and insulin tolerance relative to Con-Chow, whereas LN-HFHS improved insulin sensitivity versus Con-HFHS, associated with increased peroxisome proliferator-activated receptor gamma co-activator-1-alpha (Pgc-1α) mRNA in muscle. No effect of LN on plasma or liver triglycerides was observed, and hepatic gluconeogenic regulatory genes were unaltered. In summary, this study demonstrates that ELS induced by LN conferred some metabolic protection against insulin and/or glucose intolerance in a diet-dependent manner during adulthood. PMID:26441828

  1. [Metabolic response to trauma and stress].

    PubMed

    Omerbegović, Meldijana; Durić, Amira; Muratović, Nusreta; Mulalić, Lejla; Hamzanija, Emina

    2003-01-01

    Trauma, surgery, burns and infection are accompanied with catabolic response which is characterized by enhanced protelysis, enhanced excretion of nitrogen, neoglucogenesis and resistance of peripheral tissues to insulin. This catabolic response is mediated through neural pathways and neuroendocrine axis. The purpose of this response is restoration of adequate perfusion and oxygenation and releasing of energy and substrates for the tissues, organs and systems which functions are essential for the survival. Metabolic response to injury and severe infection leads to decomposition of skeletal muscle proteins to amino acids, intensive liver gluconcogenesis from lactate, glycerol and alanin with enhanced oxidation of aminoacids. These substrates are necessary for synthesis of various mediators of protein or lipid nature, which are important for the defense and tissue regeneration. The changes result in negative balance of nitrogen, loss of body weight, and lower plasma concentration of all aminoacids. Patients who were unable to develop this hypercatabolic response have poor prognosis, and the patients with hypercatabolic response rapidly lose their body cell mass and without metabolic and nutritive support have more complications and higher mortality. Although neoglucogenesis, proteolysis and lipolysis are resistant to exogenous nutrients, metabolic support in critical illness improves the chances for survival until the healing of the disease. Casual therapy in such conditions is elimination of "stressors" which maintain abnormal endocrine and metabolic response. Adequate oxygenation, hemostasis, infection control and control of extracellular compartment expansion and low flows, are essential for the efficacy of nutritive support and that is the only way to convalescence and wound healing. PMID:15017867

  2. Glucose metabolism and hexosamine pathway regulate oncogene-induced senescence.

    PubMed

    Gitenay, D; Wiel, C; Lallet-Daher, H; Vindrieux, D; Aubert, S; Payen, L; Simonnet, H; Bernard, D

    2014-01-01

    Oncogenic stress-induced senescence (OIS) prevents the ability of oncogenic signals to induce tumorigenesis. It is now largely admitted that the mitogenic effect of oncogenes requires metabolic adaptations to respond to new energetic and bio constituent needs. Yet, whether glucose metabolism affects OIS response is largely unknown. This is largely because of the fact that most of the OIS cellular models are cultivated in glucose excess. In this study, we used human epithelial cells, cultivated without glucose excess, to study alteration and functional role of glucose metabolism during OIS. We report a slowdown of glucose uptake and metabolism during OIS. Increasing glucose metabolism by expressing hexokinase2 (HK2), which converts glucose to glucose-6-phosphate (G6P), favors escape from OIS. Inversely, expressing a glucose-6-phosphatase, [corrected] pharmacological inhibition of HK2, or adding nonmetabolizable glucose induced a premature senescence. Manipulations of various metabolites covering G6P downstream pathways (hexosamine, glycolysis, and pentose phosphate pathways) suggest an unexpected role of the hexosamine pathway in controlling OIS. Altogether, our results show that decreased glucose metabolism occurs during and participates to OIS. PMID:24577087

  3. Metabolic Profiling of the Response to an Oral Glucose Tolerance Test Detects Subtle Metabolic Changes

    PubMed Central

    Wopereis, Suzan; Rubingh, Carina M.; van Erk, Marjan J.; Verheij, Elwin R.; van Vliet, Trinette; Cnubben, Nicole H. P.; Smilde, Age K.; van der Greef, Jan; van Ommen, Ben; Hendriks, Henk F. J.

    2009-01-01

    Background The prevalence of overweight is increasing globally and has become a serious health problem. Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. Novel tools to understand these processes are needed. Metabolic profiling is one such tool that can provide novel insights into the impact of treatments on metabolism. Methodology To study the metabolic changes induced by a mild anti-inflammatory drug intervention, plasma metabolic profiling was applied in overweight human volunteers with elevated levels of the inflammatory plasma marker C-reactive protein. Liquid and gas chromatography mass spectrometric methods were used to detect high and low abundant plasma metabolites both in fasted conditions and during an oral glucose tolerance test. This is based on the concept that the resilience of the system can be assessed after perturbing a homeostatic situation. Conclusions Metabolic changes were subtle and were only detected using metabolic profiling in combination with an oral glucose tolerance test. The repeated measurements during the oral glucose tolerance test increased statistical power, but the metabolic perturbation also revealed metabolites that respond differentially to the oral glucose tolerance test. Specifically, multiple metabolic intermediates of the glutathione synthesis pathway showed time-dependent suppression in response to the glucose challenge test. The fact that this is an insulin sensitive pathway suggests that inflammatory modulation may alter insulin signaling in overweight men. PMID:19242536

  4. Biofilm shows spatially stratified metabolic responses to contaminant exposure

    PubMed Central

    Cao, Bin; Majors, Paul D.; Ahmed, Bulbul; Renslow, Ryan S.; Silvia, Crystal P.; Shi, Liang; Kjelleberg, Staffan; Fredrickson, Jim K.; Beyenal, Haluk

    2012-01-01

    Summary Biofilms are core to a range of biological processes, including the bioremediation of environmental contaminants. Within a biofilm population, cells with diverse genotypes and phenotypes coexist, suggesting that distinct metabolic pathways may be expressed based on the local environmental conditions in a biofilm. However, metabolic responses to local environmental conditions in a metabolically active biofilm interacting with environmental contaminants have never been quantitatively elucidated. In this study, we monitored the spatiotemporal metabolic responses of metabolically active Shewanella oneidensis MR-1 biofilms to U(VI) (uranyl, UO22+) and Cr(VI) (chromate, CrO42−) using noninvasive nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) approaches to obtain insights into adaptation in biofilms during biofilm-contaminant interactions. While overall biomass distribution was not significantly altered upon exposure to U(VI) or Cr(VI), MRI and spatial mapping of the diffusion revealed localized changes in the water diffusion coefficients in the biofilms, suggesting significant contaminant-induced changes in structural or hydrodynamic properties during bioremediation. Finally, we quantitatively demonstrated that the metabolic responses of biofilms to contaminant exposure are spatially stratified, implying that adaptation in biofilms is custom-developed based on local microenvironments. PMID:22925136

  5. Metabolic consequences of exercise-induced muscle damage.

    PubMed

    Tee, Jason C; Bosch, Andrew N; Lambert, Mike I

    2007-01-01

    Exercise-induced muscle damage (EIMD) is commonly experienced following either a bout of unaccustomed physical activity or following physical activity of greater than normal duration or intensity. The mechanistic factor responsible for the initiation of EIMD is not known; however, it is hypothesised to be either mechanical or metabolic in nature. The mechanical stress hypothesis states that EIMD is the result of physical stress upon the muscle fibre. In contrast, the metabolic stress model predicts that EIMD is the result of metabolic deficiencies, possibly through the decreased action of Ca(2+)-adenosine triphosphatase. Irrespective of the cause of the damage, EIMD has a number of profound metabolic effects. The most notable metabolic effects of EIMD are decreased insulin sensitivity, prolonged glycogen depletion and an increase in metabolic rate both at rest and during exercise. Based on current knowledge regarding the effects that various types of damaging exercise have on muscle metabolism, a new model for the initiation of EIMD is proposed. This model states that damage initiation may be either metabolic or mechanical, or a combination of both, depending on the mode, intensity and duration of exercise and the training status of the individual. PMID:17887809

  6. Induced polarization response of microbial induced sulfideprecipitation

    SciTech Connect

    Ntarlagiannis, Dimitrios; Williams, Kenneth Hurst; Slater, Lee; Hubbard, Susan

    2004-06-04

    A laboratory scale experiment was conducted to examine the use of induced polarization and electrical conductivity to monitor microbial induced sulfide precipitation under anaerobic conditions in sand filled columns. Three columns were fabricated; one for electrical measurements, one for geochemical sampling and a third non-inoculated column was used as a control. A continual upward flow of nutrients and metals in solution was established in each column. Desulfovibrio vulgaris microbes were injected into the middle of the geochemical and electrical columns. Iron and zinc sulfides precipitated along a microbial action front as a result of sulfate reduction due by Desulfovibrio vulgaris. The precipitation front initially developed near the microbial injection location, and subsequently migrated towards the nutrient inlet, as a result of chemotaxis by Desulfovibrio vulgaris. Sampling during and subsequent to the experiment revealed spatiotemporal changes in the biogeochemical measurements associated with microbial sulfate reduction. Conductivity measurements were insensitive to all biogeochemical changes occurred within the column. Changes in the IP response (of up to 14 mrad)were observed to coincide in place and in time with the active microbe respiration/sulfide precipitation front as determined from geochemical sampling. The IP response is correlated with the lactate concentration gradient, an indirect measurement of microbial metabolism, suggesting the potential of IP as a method for monitoring microbial respiration/activity. Post experimental destructive sample analysis and SEM imaging verified the geochemical results and supported our hypothesis that microbe induced sulfide precipitation is directly detectable using electrical methods. Although the processes not fully understood, the IP response appears to be sensitive to this anaerobic microbial precipitation, suggesting a possible novel application for the IP method.

  7. ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate.

    PubMed

    Shin, Sejeong; Buel, Gwen R; Wolgamott, Laura; Plas, David R; Asara, John M; Blenis, John; Yoon, Sang-Oh

    2015-08-01

    Insufficient nutrients disrupt physiological homeostasis, resulting in diseases and even death. Considering the physiological and pathological consequences of this metabolic stress, the adaptive responses that cells utilize under this condition are of great interest. We show that under low-glucose conditions, cells initiate adaptation followed by apoptosis responses using PERK/Akt and MEK1/ERK2 signaling, respectively. For adaptation, cells engage the ER stress-induced unfolded protein response, which results in PERK/Akt activation and cell survival. Sustained and extreme energetic stress promotes a switch to isoform-specific MEK1/ERK2 signaling, induction of GCN2/eIF2α phosphorylation, and ATF4 expression, which overrides PERK/Akt-mediated adaptation and induces apoptosis through ATF4-dependent expression of pro-apoptotic factors including Bid and Trb3. ERK2 activation during metabolic stress contributes to changes in TCA cycle and amino acid metabolism, and cell death, which is suppressed by glutamate and α-ketoglutarate supplementation. Taken together, our results reveal promising targets to protect cells or tissues from metabolic stress. PMID:26190261

  8. Disparate metabolic response to fructose feeding between different mouse strains

    PubMed Central

    Montgomery, M. K.; Fiveash, C. E.; Braude, J. P.; Osborne, B.; Brown, S. H. J.; Mitchell, T. W.; Turner, N.

    2015-01-01

    Diets enriched in fructose (FR) increase lipogenesis in the liver, leading to hepatic lipid accumulation and the development of insulin resistance. Previously, we have shown that in contrast to other mouse strains, BALB/c mice are resistant to high fat diet-induced metabolic deterioration, potentially due to a lack of ectopic lipid accumulation in the liver. In this study we have compared the metabolic response of BALB/c and C57BL/6 (BL6) mice to a fructose-enriched diet. Both strains of mice increased adiposity in response to FR-feeding, while only BL6 mice displayed elevated hepatic triglyceride (TAG) accumulation and glucose intolerance. The lack of hepatic TAG accumulation in BALB/c mice appeared to be linked to an altered balance between lipogenic and lipolytic pathways, while the protection from fructose-induced glucose intolerance in this strain was likely related to low levels of ER stress, a slight elevation in insulin levels and an altered profile of diacylglycerol species in the liver. Collectively these findings highlight the multifactorial nature of metabolic defects that develop in response to changes in the intake of specific nutrients and the divergent response of different mouse strains to dietary challenges. PMID:26690387

  9. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia

    PubMed Central

    2014-01-01

    Background Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy. Results We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia. Conclusions Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss. PMID:25228990

  10. Enhanced regional brain metabolic responses to benzodiazepines in cocaine abusers

    SciTech Connect

    Volkow, N.D.; Wang, G.J.; Fowler, J.S.

    1997-05-01

    While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in cocaine addiction is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors (which arc predominantly located on GABA cells) in cocaine abusers. This finding coupled to GABA`s role as an effector for DA led us to investigate if there were GABAergic abnormalities in cocaine abusers. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission). Methods: The experimental subjects consisted of 12 active cocaine abusers and 32 age matched controls. Each subject underwent two PET FDG scans obtained within 1 week of each other. The first FDG scan was obtained after administration of placebo (3 cc of saline solution) given 40-50 minutes prior to FDG; and the second after administration of lorazepam (30 {mu}g/kg) given 40-50 minutes prior to FDG. The subjects were blind to the drugs received. Results: Lorazepam-induced sleepiness was significantly greater in abusers than in controls (p<0.001). Lorazepam-induced decreases in brain glucose metabolism were significantly larger in cocaine abusers than in controls. Whereas in controls whole brain metabolism decreased 13{+-}7 %, in cocaine abusers it decreased 21{+-}13 % (p < 0.05). Lorazepam-induced decrements in regional metabolism were significantly larger in striatum (p < 0.0 1), thalamus (p < 0.01) and cerebellum (p < 0.005) of cocaine abusers than of controls (ANOVA diagnosis by condition (placebo versus lorazepam) interaction effect). The only brain region for which the absolute metabolic changes-induced by lorazepam in cocaine abusers were equivalent to those in controls was the orbitofrontal cortex. These results document an accentuated sensitivity to benzodiazepines in cocaine abusers which is compatible with disrupted GABAergic function in these patients.

  11. Pancreatic Islet Responses to Metabolic Trauma.

    PubMed

    Burke, Susan J; Karlstad, Michael D; Collier, J Jason

    2016-09-01

    Carbohydrate, lipid, and protein metabolism are largely controlled by the interplay of various hormones, which includes those secreted by the pancreatic islets of Langerhans. While typically representing only 1% to 2% of the total pancreatic mass, the islets have a remarkable ability to adapt to disparate situations demanding a change in hormone release, such as peripheral insulin resistance. There are many different routes to the onset of insulin resistance, including obesity, lipodystrophy, glucocorticoid excess, and the chronic usage of atypical antipsychotic drugs. All of these situations are coupled to an increase in pancreatic islet size, often with a corresponding increase in insulin production. These adaptive responses within the islets are ultimately intended to maintain glycemic control and to promote macronutrient homeostasis during times of stress. Herein, we review the consequences of specific metabolic trauma that lead to insulin resistance and the corresponding adaptive alterations within the pancreatic islets. PMID:26974425

  12. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements.

    PubMed

    Swithers, Susan E

    2013-09-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements. PMID:23850261

  13. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements

    PubMed Central

    Swithers, Susan E.

    2013-01-01

    The negative impact of consuming sugar-sweetened beverages on weight and other health outcomes has been increasingly recognized; therefore, many people have turned to high-intensity sweeteners like aspartame, sucralose, and saccharin as a way to reduce the risk of these consequences. However, accumulating evidence suggests that frequent consumers of these sugar substitutes may also be at increased risk of excessive weight gain, metabolic syndrome, type 2 diabetes, and cardiovascular disease. This paper discusses these findings and considers the hypothesis that consuming sweet-tasting but noncaloric or reduced-calorie food and beverages interferes with learned responses that normally contribute to glucose and energy homeostasis. Because of this interference, frequent consumption of high-intensity sweeteners may have the counterintuitive effect of inducing metabolic derangements. PMID:23850261

  14. The Metabolic Responses to Aerial Diffusion of Essential Oils

    PubMed Central

    Xie, Guoxiang; Zhao, Aihua; Pan, Xiaolan; Chen, Tianlu; Hu, Yixue; Liu, Yumin; Cheng, Yu; Chi, Yi; Yao, Lei; Jia, Wei

    2012-01-01

    Anxiety disorders are the most prevalent psychiatric disorders and affect a great number of people worldwide. Essential oils, take effects through inhalation or topical application, are believed to enhance physical, emotional, and spiritual well-being. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of essential oils in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive gas chromatography time-of-flight mass spectrometry (GC-TOFMS) based metabonomics study that reveals the aromas-induced metabolic changes and the anxiolytic effect of aromas in elevated plus maze (EPM) induced anxiety model rats. The significant alteration of metabolites in the EPM group was attenuated by aromas treatment, concurrent with the behavioral improvement with significantly increased open arms time and open arms entries. Brain tissue and urinary metabonomic analysis identified a number of altered metabolites in response to aromas intervention. These metabolic changes included the increased carbohydrates and lowered levels of neurotransmitters (tryptophan, serine, glycine, aspartate, tyrosine, cysteine, phenylalanine, hypotaurine, histidine, and asparagine), amino acids, and fatty acids in the brain. Elevated aspartate, carbohydrates (sucrose, maltose, fructose, and glucose), nucleosides and organic acids such as lactate and pyruvate were also observed in the urine. The EPM induced metabolic differences observed in urine or brain tissue was significantly reduced after 10 days of aroma inhalation, as noted with the loss of statistical significance on many of the metabolites in the aroma-EPM group. This study demonstrates, for the first time, that the metabonomics approach can capture the subtle metabolic changes resulting from exposure to essential oils and provide the

  15. Local auxin metabolism regulates environment-induced hypocotyl elongation.

    PubMed

    Zheng, Zuyu; Guo, Yongxia; Novák, Ondřej; Chen, William; Ljung, Karin; Noel, Joseph P; Chory, Joanne

    2016-01-01

    A hallmark of plants is their adaptability of size and form in response to widely fluctuating environments. The metabolism and redistribution of the phytohormone auxin play pivotal roles in establishing active auxin gradients and resulting cellular differentiation. In Arabidopsis thaliana, cotyledons and leaves synthesize indole-3-acetic acid (IAA) from tryptophan through indole-3-pyruvic acid (3-IPA) in response to vegetational shade. This newly synthesized auxin moves to the hypocotyl where it induces elongation of hypocotyl cells. Here we show that loss of function of VAS2 (IAA-amido synthetase Gretchen Hagen 3 (GH3).17) leads to increases in free IAA at the expense of IAA-Glu (IAA-glutamate) in the hypocotyl epidermis. This active IAA elicits shade- and high temperature-induced hypocotyl elongation largely independently of 3-IPA-mediated IAA biosynthesis in cotyledons. Our results reveal an unexpected capacity of local auxin metabolism to modulate the homeostasis and spatial distribution of free auxin in specialized organs such as hypocotyls in response to shade and high temperature. PMID:27249562

  16. Metabolic Responses of Bacterial Cells to Immobilization.

    PubMed

    Żur, Joanna; Wojcieszyńska, Danuta; Guzik, Urszula

    2016-01-01

    In recent years immobilized cells have commonly been used for various biotechnological applications, e.g., antibiotic production, soil bioremediation, biodegradation and biotransformation of xenobiotics in wastewater treatment plants. Although the literature data on the physiological changes and behaviour of cells in the immobilized state remain fragmentary, it is well documented that in natural settings microorganisms are mainly found in association with surfaces, which results in biofilm formation. Biofilms are characterized by genetic and physiological heterogeneity and the occurrence of altered microenvironments within the matrix. Microbial cells in communities display a variety of metabolic differences as compared to their free-living counterparts. Immobilization of bacteria can occur either as a natural phenomenon or as an artificial process. The majority of changes observed in immobilized cells result from protection provided by the supports. Knowledge about the main physiological responses occurring in immobilized cells may contribute to improving the efficiency of immobilization techniques. This paper reviews the main metabolic changes exhibited by immobilized bacterial cells, including growth rate, biodegradation capabilities, biocatalytic efficiency and plasmid stability. PMID:27455220

  17. Stress memory induced rearrangements of HSP transcription, photosystem II photochemistry and metabolism of tall fescue (Festuca arundinacea Schreb.) in response to high-temperature stress

    PubMed Central

    Hu, Tao; Liu, Shu-Qian; Amombo, Erick; Fu, Jin-Min

    2015-01-01

    When plants are pre-exposed to stress, they can produce some stable signals and physiological reactions that may be carried forward as “stress memory”. However, there is insufficient information about plants' stress memory responses mechanisms. Here, two tall fescue genotypes, heat-tolerant PI 574522 and heat-sensitive PI 512315, were subjected to recurring high-temperature pre-acclimation treatment. Two heat shock protein (HSP) genes, LMW-HSP and HMW-HSP, exhibited transcriptional memory for their higher transcript abundance during one or more subsequent stresses (S2, S3, S4) relative to the first stress (S1), and basal transcript levels during the recovery states (R1, R2, and R3). Activated transcriptional memory from two trainable genes could persist up to 4 days, and induce higher thermotolerance in tall fescue. This was confirmed by greater turf quality and lower electrolyte leakage. Pre-acclimation treatment inhibited the decline at steps of O-J-I-P and energy transport fluxes in active Photosystem II reaction center (PSII RC) for both tall fescue genotypes. The heat stress memory was associated with major shifts in leaf metabolite profiles. Furthermore, there was an exclusive increase in leaf organic acids (citric acid, malic acid, tris phosphoric acid, threonic acid), sugars (sucrose, glucose, idose, allose, talose, glucoheptose, tagatose, psicose), amino acids (serine, proline, pyroglutamic acid, glycine, alanine), and one fatty acid (butanoic acid) in pre-acclimated plants. These observations involved in transcriptional memory, PSII RC energy transport and metabolite profiles could provide new insights into the plant high–temperature response process. PMID:26136755

  18. Challenges in diagnosing a metabolic disorder: error of pyruvate metabolism or drug induced?

    PubMed

    Mampilly, George Tomy; Mampilly, Tomy Kochuvareed; Christopher, Rita; Chandramohan, Neeradha; Janaki, Vijayalakshmy

    2014-06-01

    Certain drugs are known to cause metabolic changes resulting in altered metabolic profiles. We report here a case where a combination of antiepileptic drugs resulted in a profile that mimicked a metabolic disorder. A 16month-old female child on antiepileptic drugs (valproate and topiramate) was suspected to have the inherited metabolic disorder, dihydrolipoamide dehydrogenase deficiency, based on clinical symptoms and metabolic profile showing hyperalaninemia, elevated branched-chain amino acids, and lactate-pyruvate ratio. Suspecting that the observed metabolic changes could have also arised from medication, current medication was weaned off and replaced with levetiracetam, clonazepam, and levocarnitine (supportive therapy). Metabolic profiling conducted after 47 days showed normal alanine, branched-chain amino acids, ornithine, and lactate-pyruvate ratio, suggesting that the earlier abnormalities could have been medication induced. We stress that metabolic changes resulting from chronic medication should be considered while interpreting a positive result when investigating an inherited metabolic disorder. PMID:23439713

  19. Can valproic acid be an inducer of clozapine metabolism?

    PubMed Central

    Diaz, Francisco J.; Eap, Chin B.; Ansermot, Nicolas; Crettol, Severine; Spina, Edoardo; de Leon, Jose

    2014-01-01

    Introduction Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that 1) VPA is a net inducer of clozapine metabolism, and 2) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. Methods After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. Results VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14% to 39%) after controlling for confounding variables including smoking (35% lower, 28% to 56%). Discussion Prospective studies are needed to definitively establish that VPA may 1) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and 2) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID:24764199

  20. Precision Metabolic Engineering: the Design of Responsive, Selective, and Controllable Metabolic Systems

    PubMed Central

    McNerney, Monica P.; Watstein, Daniel M.; Styczynski, Mark P.

    2015-01-01

    Metabolic engineering is generally focused on static optimization of cells to maximize production of a desired product, though recently dynamic metabolic engineering has explored how metabolic programs can be varied over time to improve titer. However, these are not the only types of applications where metabolic engineering could make a significant impact. Here, we discuss a new conceptual framework, termed “precision metabolic engineering,” involving the design and engineering of systems that make different products in response to different signals. Rather than focusing on maximizing titer, these types of applications typically have three hallmarks: sensing signals that determine the desired metabolic target, completely directing metabolic flux in response to those signals, and producing sharp responses at specific signal thresholds. In this review, we will first discuss and provide examples of precision metabolic engineering. We will then discuss each of these hallmarks and identify which existing metabolic engineering methods can be applied to accomplish those tasks, as well as some of their shortcomings. Ultimately, precise control of metabolic systems has the potential to enable a host of new metabolic engineering and synthetic biology applications for any problem where flexibility of response to an external signal could be useful. PMID:26189665

  1. Metabolic product response profiles of Cherax quadricarinatus towards white spot syndrome virus infection.

    PubMed

    Fan, Weiwei; Ye, Yangfang; Chen, Zhen; Shao, Yina; Xie, Xiaolu; Zhang, Weiwei; Liu, Hai-Peng; Li, Chenghua

    2016-08-01

    White spot syndrome virus (WSSV) is one of the most devastating viral pathogens in both shrimp and crayfish farms, which often causes disease outbreak and leads to massive moralities with significant economic losses of aquaculture. However, limited research has been carried out on the intrinsic mechanisms toward WSSV challenge at the metabolic level. To gain comprehensive insight into metabolic responses induced by WSSV, we applied an NMR approach to investigate metabolic changes of crayfish gill and hepatopancreas infected by WSSV for 1, 6 and 12 h. In gill, an enhanced energy metabolism was observed in WSSV-challenged crayfish samples at 1 h, as marked by increased glucose, alanine, methionine, glutamate and uracil. Afterwards, energy metabolism, lipid metabolism as well as osmoregulation were markedly increased at 6 hpi, as shown by elevated glucose, alanine, methionine, fumarate, tyrosine, tryptophan, histidine, phosphorylcholine, betaine and uracil, whereas no obvious metabolites change was detected at 12 hpi. As for hepatopancreas, disturbed lipid metabolism and induced osmotic regulation was found at 6 hpi based on the metabolic biomarkers such as branched chain amino acids, threonine, alanine, methionine, glutamate, glutamine, tyrosine, phenylalanine, lactate and lipid. However, no obvious metabolic change was shown in hepatopancreas at both 1 hpi and 12 hpi. Taken together, our present results provided essential metabolic information about host-pathogen interactions in crayfish, which shed new light on our understanding of WSSV infection at metabolic level. PMID:27068762

  2. Oroxylin A regulates glucose metabolism in response to hypoxic stress with the involvement of Hypoxia-inducible factor-1 in human hepatoma HepG2 cells.

    PubMed

    Dai, Qinsheng; Yin, Qian; Wei, Libin; Zhou, Yuxin; Qiao, Chen; Guo, Yongjian; Wang, Xiaotang; Ma, Shiping; Lu, Na

    2016-08-01

    Metabolic alteration in cancer cells is one of the most conspicuous characteristics that distinguish cancer cells from normal cells. In this study, we investigated the influence and signaling ways of oroxylin A affecting cancer cell energy metabolism under hypoxia. The data showed that oroxylin A remarkably reduced the generation of lactate and glucose uptake under hypoxia in HepG2 cells. Moreover, oroxylin A inhibited HIF-1α expression and its stability. The downstream targets (PDK1, LDHA, and HK II), as well as their mRNA levels were also suppressed by oroxylin A under hypoxia. The silencing or the overexpression of HIF-1α assays suggested that HIF-1α is required for metabolic effect of oroxylin A in HepG2 cells during hypoxia. Furthermore, oroxylin A could reduce the expression of complex III in mitochondrial respiratory chain, and then decrease the accumulation of ROS at moderate concentrations (0-50 µM) under hypoxia, which was benefit for its inhibition on glycolytic activity by decreasing ROS-mediated HIF-1 expression. Besides, oroxylin A didn't cause the loss of MMP under hypoxia and had no obvious effects on the expression of OXPHOS complexes, suggesting that oroxylin A did not affect mitochondrial mass at the moderate stress of oroxylin A. The suppressive effect of oroxylin A on glycolysis led to a significantly repress of ATP generation, for ATP generation mostly depends on glycolysis in HepG2 cells. This study revealed a new aspect of glucose metabolism regulation of oroxylin A under hypoxia, which may contribute to its new anticancer mechanism. © 2015 Wiley Periodicals, Inc. PMID:26259145

  3. Targeting One Carbon Metabolism with an Antimetabolite Disrupts Pyrimidine Homeostasis and Induces Nucleotide Overflow.

    PubMed

    Ser, Zheng; Gao, Xia; Johnson, Christelle; Mehrmohamadi, Mahya; Liu, Xiaojing; Li, Siqi; Locasale, Jason W

    2016-06-14

    Antimetabolites that affect nucleotide metabolism are frontline chemotherapy agents in several cancers and often successfully target one carbon metabolism. However, the precise mechanisms and resulting determinants of their therapeutic value are unknown. We show that 5-fluorouracil (5-FU), a commonly used antimetabolite therapeutic with varying efficacy, induces specific alterations to nucleotide metabolism by disrupting pyrimidine homeostasis. An integrative metabolomics analysis of the cellular response to 5-FU reveals intracellular uracil accumulation, whereas deoxyuridine levels exhibited increased flux into the extracellular space, resulting in an induction of overflow metabolism. Subsequent analysis from mice bearing colorectal tumors treated with 5-FU show specific secretion of metabolites in tumor-bearing mice into serum that results from alterations in nucleotide flux and reduction in overflow metabolism. Together, these findings identify a determinant of an antimetabolite response that may be exploited to more precisely define the tumors that could respond to targeting cancer metabolism. PMID:27264180

  4. Metabolic and hormonal responses to exercise in partially hepatectomised rats.

    PubMed

    Lavoie, J M; Warren, C; Arcelin, K; Latour, M G; Désy, F; Shinoda, M; Ethier, C; Gascon-Barré, M

    1998-06-01

    To characterise how the liver affects metabolic and hormonal exercise responses, hepatectomised (70%; HX) rats were submitted to a 30- or 50-min treadmill exercise (26 m/min, 0% slope) 48 hr or 7 days after surgery (reduced or normal liver mass, respectively). To determine whether metabolic effects of liver mass reduction during exercise were caused by reduced capacity of the liver to produce glucose, metabolic and hormonal responses to the same exercise protocol were measured in 48-hr HX rats. Euglycemia, maintained by exogenous glucose infusion, produced attenuated lactate, insulin, and glucagon values in 48-hr HX rats but did not affect FFA, glycerol, and plasma catecholamine responses. Results indicate that metabolic and hormonal exercise responses are amplified in 48-hr HX rats. Maintaining euglycemia in 48-hr HX rats during exercise does not reduce all responses. Intrahepatic events, similar to those in a short-term (48-hr) HX liver, may influence metabolic and hormonal exercise responses. PMID:9615872

  5. RELATCH: relative optimality in metabolic networks explains robust metabolic and regulatory responses to perturbations

    PubMed Central

    2012-01-01

    Predicting cellular responses to perturbations is an important task in systems biology. We report a new approach, RELATCH, which uses flux and gene expression data from a reference state to predict metabolic responses in a genetically or environmentally perturbed state. Using the concept of relative optimality, which considers relative flux changes from a reference state, we hypothesize a relative metabolic flux pattern is maintained from one state to another, and that cells adapt to perturbations using metabolic and regulatory reprogramming to preserve this relative flux pattern. This constraint-based approach will have broad utility where predictions of metabolic responses are needed. PMID:23013597

  6. Metabolic profiling of the tissue-specific responses in mussel Mytilus galloprovincialis towards Vibrio harveyi challenge.

    PubMed

    Liu, Xiaoli; Ji, Chenglong; Zhao, Jianmin; Wang, Qing; Li, Fei; Wu, Huifeng

    2014-08-01

    Mussel Mytilus galloprovincialis is a marine aquaculture shellfish distributing widely along the coast in north China. In this work, we studied the differential metabolic responses induced by Vibrio harveyi in digestive gland and gill tissues from M. galloprovincialis using NMR-based metabolomics. The differential metabolic responses in the two tissue types were detected, except the similarly altered taurine and betaine. These metabolic responses suggested that V. harveyi mainly induced osmotic disruption and reduced energy demand via the metabolic pathways of glucose synthesis and ATP/AMP conversion in mussel digestive gland. In mussel gill tissues, V. harveyi basically caused osmotic stress and possible reduced energy demand as shown by the elevated phosphocholine that is involved in one of the metabolic pathways of ATP synthesis from ADP and phosphocholine. The altered mRNA expression levels of related genes (superoxide dismutase with copper and zinc, heat shock protein 90, defensin and lysozyme) suggested that V. harveyi induced clear oxidative and immune stresses in both digestive gland and gill tissues. However, the mRNA expression levels of both lysozyme and defensin in digestive gland were more significantly up-regulated than those in gill from V. harveyi-challenged mussel M. galloprovincialis, meaning that the immune organ, digestive gland, was more sensitive than gill. Overall, our results indicated that V. harveyi could induce tissue-specific metabolic responses in mussel M. galloprovincialis. PMID:24911264

  7. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

    PubMed Central

    Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

    2016-01-01

    Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug’s impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and

  8. Mechanisms of sulfur mustard-induced metabolic injury

    SciTech Connect

    Martens, M.E.; Smith, W.J.

    1993-05-13

    Studies on the mechanism of metabolic injury induced by sulfur mustard (2, 2'- dichlorodiethyl sulfide, HD) have demonstrated that exposure of human epidermal keratinocytes in culture to HD induces time- and dose-dependent NAD+ depletion and inhibition of glucose metabolism (Martens, Biochem. Pharmacol., in press). Both occurred relatively early after alkylation, preceding the loss of membrane integrity that is indicative of metabolic cell death. The inhibition of glycolysis induced by HD was only partially correlated with the depletion of NAD+ and, thus, was not simply of changes in the NAD+ level. Rather, HD appeared to induce complex shifts in the pattern of glucose metabolism that paralleled both the timing and degree of injury. In line with these findings, recent experiments have shown that partial protection against HD-induced NAD+ depletion by 1 mM niacinamide did not protect against the inhibition of glycolysis. In preliminary experiments examining the effect of HD-induced metabolic changes on the cellular energy state, dose-dependent depletion of ATP was seen at 24 hours after exposure, but not at 4 or 8 hours. As seen for glucose metabolism, 1 mM niacinamide did not prevent the loss of high-energy intermediate (ATP). We conclude from these studies that relationships among HD exposure, glucose metabolism, and intracellular NAD and ATP are more complex than originally proposed (Papirmeister et al, Fund. Appl. Toxicol. 5:S134, 1985).

  9. Drought, salt, and temperature stress-induced metabolic rearrangements and regulatory networks.

    PubMed

    Krasensky, Julia; Jonak, Claudia

    2012-02-01

    Plants regularly face adverse growth conditions, such as drought, salinity, chilling, freezing, and high temperatures. These stresses can delay growth and development, reduce productivity, and, in extreme cases, cause plant death. Plant stress responses are dynamic and involve complex cross-talk between different regulatory levels, including adjustment of metabolism and gene expression for physiological and morphological adaptation. In this review, information about metabolic regulation in response to drought, extreme temperature, and salinity stress is summarized and the signalling events involved in mediating stress-induced metabolic changes are presented. PMID:22291134

  10. Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.

    PubMed

    Mignion, Lionel; Danhier, Pierre; Magat, Julie; Porporato, Paolo E; Masquelier, Julien; Gregoire, Vincent; Muccioli, Giulio G; Sonveaux, Pierre; Gallez, Bernard; Jordan, Bénédicte F

    2016-04-15

    The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1)H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1)H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling. PMID:26595604

  11. Metabolic host responses to infection by intracellular bacterial pathogens

    PubMed Central

    Eisenreich, Wolfgang; Heesemann, Jürgen; Rudel, Thomas; Goebel, Werner

    2013-01-01

    The interaction of bacterial pathogens with mammalian hosts leads to a variety of physiological responses of the interacting partners aimed at an adaptation to the new situation. These responses include multiple metabolic changes in the affected host cells which are most obvious when the pathogen replicates within host cells as in case of intracellular bacterial pathogens. While the pathogen tries to deprive nutrients from the host cell, the host cell in return takes various metabolic countermeasures against the nutrient theft. During this conflicting interaction, the pathogen triggers metabolic host cell responses by means of common cell envelope components and specific virulence-associated factors. These host reactions generally promote replication of the pathogen. There is growing evidence that pathogen-specific factors may interfere in different ways with the complex regulatory network that controls the carbon and nitrogen metabolism of mammalian cells. The host cell defense answers include general metabolic reactions, like the generation of oxygen- and/or nitrogen-reactive species, and more specific measures aimed to prevent access to essential nutrients for the respective pathogen. Accurate results on metabolic host cell responses are often hampered by the use of cancer cell lines that already exhibit various de-regulated reactions in the primary carbon metabolism. Hence, there is an urgent need for cellular models that more closely reflect the in vivo infection conditions. The exact knowledge of the metabolic host cell responses may provide new interesting concepts for antibacterial therapies. PMID:23847769

  12. Ozone-Induced Responses in Croton floribundus Spreng. (Euphorbiaceae): Metabolic Cross-Talk between Volatile Organic Compounds and Calcium Oxalate Crystal Formation

    PubMed Central

    Cardoso-Gustavson, Poliana; Bolsoni, Vanessa Palermo; de Oliveira, Debora Pinheiro; Guaratini, Maria Tereza Gromboni; Aidar, Marcos Pereira Marinho; Marabesi, Mauro Alexandre; Alves, Edenise Segala; de Souza, Silvia Ribeiro

    2014-01-01

    Here, we proposed that volatile organic compounds (VOC), specifically methyl salicylate (MeSA), mediate the formation of calcium oxalate crystals (COC) in the defence against ozone (O3) oxidative damage. We performed experiments using Croton floribundus, a pioneer tree species that is tolerant to O3 and widely distributed in the Brazilian forest. This species constitutively produces COC. We exposed plants to a controlled fumigation experiment and assessed biochemical, physiological, and morphological parameters. O3 induced a significant increase in the concentrations of constitutive oxygenated compounds, MeSA and terpenoids as well as in COC number. Our analysis supported the hypothesis that ozone-induced VOC (mainly MeSA) regulate ROS formation in a way that promotes the opening of calcium channels and the subsequent formation of COC in a fast and stable manner to stop the consequences of the reactive oxygen species in the tissue, indeed immobilising the excess calcium (caused by acute exposition to O3) that can be dangerous to the plant. To test this hypothesis, we performed an independent experiment spraying MeSA over C. floribundus plants and observed an increase in the number of COC, indicating that this compound has a potential to directly induce their formation. Thus, the tolerance of C. floribundus to O3 oxidative stress could be a consequence of a higher capacity for the production of VOC and COC rather than the modulation of antioxidant balance. We also present some insights into constitutive morphological features that may be related to the tolerance that this species exhibits to O3. PMID:25165889

  13. Ozone-induced responses in Croton floribundus Spreng. (Euphorbiaceae): metabolic cross-talk between volatile organic compounds and calcium oxalate crystal formation.

    PubMed

    Cardoso-Gustavson, Poliana; Bolsoni, Vanessa Palermo; de Oliveira, Debora Pinheiro; Guaratini, Maria Tereza Gromboni; Aidar, Marcos Pereira Marinho; Marabesi, Mauro Alexandre; Alves, Edenise Segala; de Souza, Silvia Ribeiro

    2014-01-01

    Here, we proposed that volatile organic compounds (VOC), specifically methyl salicylate (MeSA), mediate the formation of calcium oxalate crystals (COC) in the defence against ozone (O3) oxidative damage. We performed experiments using Croton floribundus, a pioneer tree species that is tolerant to O3 and widely distributed in the Brazilian forest. This species constitutively produces COC. We exposed plants to a controlled fumigation experiment and assessed biochemical, physiological, and morphological parameters. O3 induced a significant increase in the concentrations of constitutive oxygenated compounds, MeSA and terpenoids as well as in COC number. Our analysis supported the hypothesis that ozone-induced VOC (mainly MeSA) regulate ROS formation in a way that promotes the opening of calcium channels and the subsequent formation of COC in a fast and stable manner to stop the consequences of the reactive oxygen species in the tissue, indeed immobilising the excess calcium (caused by acute exposition to O3) that can be dangerous to the plant. To test this hypothesis, we performed an independent experiment spraying MeSA over C. floribundus plants and observed an increase in the number of COC, indicating that this compound has a potential to directly induce their formation. Thus, the tolerance of C. floribundus to O3 oxidative stress could be a consequence of a higher capacity for the production of VOC and COC rather than the modulation of antioxidant balance. We also present some insights into constitutive morphological features that may be related to the tolerance that this species exhibits to O3. PMID:25165889

  14. Global Metabolic Responses to Salt Stress in Fifteen Species

    PubMed Central

    Pollak, Georg R.; Kuehne, Andreas; Sauer, Uwe

    2016-01-01

    Cells constantly adapt to unpredictably changing extracellular solute concentrations. A cornerstone of the cellular osmotic stress response is the metabolic supply of energy and building blocks to mount appropriate defenses. Yet, the extent to which osmotic stress impinges on the metabolic network remains largely unknown. Moreover, it is mostly unclear which, if any, of the metabolic responses to osmotic stress are conserved among diverse organisms or confined to particular groups of species. Here we investigate the global metabolic responses of twelve bacteria, two yeasts and two human cell lines exposed to sustained hyperosmotic salt stress by measuring semiquantitative levels of hundreds of cellular metabolites using nontargeted metabolomics. Beyond the accumulation of osmoprotectants, we observed significant changes of numerous metabolites in all species. Global metabolic responses were predominantly species-specific, yet individual metabolites were characteristically affected depending on species’ taxonomy, natural habitat, envelope structure or salt tolerance. Exploiting the breadth of our dataset, the correlation of individual metabolite response magnitudes across all species implicated lower glycolysis, tricarboxylic acid cycle, branched-chain amino acid metabolism and heme biosynthesis to be generally important for salt tolerance. Thus, our findings place the global metabolic salt stress response into a phylogenetic context and provide insights into the cellular phenotype associated with salt tolerance. PMID:26848578

  15. Nitrate Starvation Induced Changes in Root System Architecture, Carbon:Nitrogen Metabolism, and miRNA Expression in Nitrogen-Responsive Wheat Genotypes.

    PubMed

    Sinha, Subodh Kumar; Rani, Manju; Bansal, Niketa; Gayatri; Venkatesh, K; Mandal, P K

    2015-11-01

    Improvement of nutrient use efficiency in cereal crops is highly essential not only to reduce the cost of cultivation but also to save the environmental pollution, reduce energy consumption for production of these chemical fertilizers, improve soil health, and ultimately help in mitigating climate change. In the present investigation, we have studied the morphological (with special emphasis on root system architecture) and biochemical responses (in terms of assay of the key enzymes involved in N assimilation) of two N-responsive wheat genotypes, at the seedling stage, under nitrate-optimum and nitrate-starved conditions grown in hydroponics. Expression profile of a few known wheat micro RNAs (miRNAs) was also studied in the root tissue. Total root size, primary root length, and first- and second-order lateral root numbers responded significantly under nitrate-starved condition. Morphological parameters in terms of root and shoot length and fresh and dry weight of roots and shoots have also been observed to be significant between N-optimum and N-starved condition for each genotypes. Nitrate reductase (NR), glutamine synthatase (GS), and glutamate dehydrogenase (GDH) activity significantly decreased under N-starved condition. Glutamine oxoglutarate amino transferase (GOGAT) and pyruvate kinase (PK) activity was found to be genotype dependent. Most of the selected miRNAs were expressed in root tissues, and some of them showed their differential N-responsive expression. Our studies indicate that one of the N-responsive genotype (NP-890) did not get affected significantly under nitrogen starvation at seedling stage. PMID:26315134

  16. Role of retinal metabolism in methanol-induced retinal toxicity

    SciTech Connect

    Garner, C.D. |; Lee, E.W.; Terzo, T.S.; Louis-Ferdinand, R.T.

    1995-08-01

    Methanol is a toxicant that causes systemic and ocular toxicity after acute exposure. The folate-reduced (FR) rat is an excellent animal model that mimics characteristic human methanol toxic responses. The present study examines the role of the methanol metabolites formaldehyde and formate in the initiation of methanol-induced retinal toxicity. After a single oral dose of 3.0 g/kg methanol, blood methanol concentrations were not significantly different in FR rats compared with folate-sufficient (FS) (control) rats. However, FR rats treated with 3.0 g/kg methanol displayed elevated blood (14.6 mM) and vitreous humor (19.5 mM) formate levels and abnormal electroretinograms (loss of b-wave) 48 h postdose. FR rats pretreated with disulfiram (DSF) prior to 3.0 g/kg methanol treatment failed to display these symptoms. Formaldehyde was not detected in blood or vitreous humor with or without DSF treatment, suggesting that formate is the toxic metabolite in methanol-induced retinal toxicity. Additionally, creating a blood formate profile (14.2 mM at 48 h) similar to that observed in methanol-treated rats by iv infusion of pH-buffered formate does not alter the electroretinogram as is observed with methanol treatment. These data suggest that intraretinal metabolism of methanol is necessary for the formate-mediated initiation of methanol-induced retinal toxicity. 31 refs., 5 figs., 2 tabs.

  17. 13C metabolic flux analysis shows that resistin impairs the metabolic response to insulin in L6E9 myotubes

    PubMed Central

    2014-01-01

    Background It has been suggested that the adipokine resistin links obesity and insulin resistance, although how resistin acts on muscle metabolism is controversial. We aimed to quantitatively analyse the effects of resistin on the glucose metabolic flux profile and on insulin response in L6E9 myotubes at the metabolic level using a tracer-based metabolomic approach and our in-house developed software, Isodyn. Results Resistin significantly increased glucose uptake and glycolysis, altering pyruvate utilisation by the cell. In the presence of resistin, insulin only slightly increased glucose uptake and glycolysis, and did not alter the flux profile around pyruvate induced by resistin. Resistin prevented the increase in gene expression in pyruvate dehydrogenase-E1 and the sharp decrease in gene expression in cytosolic phosphoenolpyruvate carboxykinase-1 induced by insulin. Conclusions These data suggest that resistin impairs the metabolic activation of insulin. This impairment cannot be explained by the activity of a single enzyme, but instead due to reorganisation of the whole metabolic flux distribution. PMID:25217974

  18. Opposite metabolic responses of shoots and roots to drought

    NASA Astrophysics Data System (ADS)

    Gargallo-Garriga, Albert; Sardans, Jordi; Pérez-Trujillo, Míriam; Rivas-Ubach, Albert; Oravec, Michal; Vecerova, Kristyna; Urban, Otmar; Jentsch, Anke; Kreyling, Juergen; Beierkuhnlein, Carl; Parella, Teodor; Peñuelas, Josep

    2014-10-01

    Shoots and roots are autotrophic and heterotrophic organs of plants with different physiological functions. Do they have different metabolomes? Do their metabolisms respond differently to environmental changes such as drought? We used metabolomics and elemental analyses to answer these questions. First, we show that shoots and roots have different metabolomes and nutrient and elemental stoichiometries. Second, we show that the shoot metabolome is much more variable among species and seasons than is the root metabolome. Third, we show that the metabolic response of shoots to drought contrasts with that of roots; shoots decrease their growth metabolism (lower concentrations of sugars, amino acids, nucleosides, N, P, and K), and roots increase it in a mirrored response. Shoots are metabolically deactivated during drought to reduce the consumption of water and nutrients, whereas roots are metabolically activated to enhance the uptake of water and nutrients, together buffering the effects of drought, at least at the short term.

  19. Cold exposure stimulates lipid metabolism, induces inflammatory response in the adipose tissue of mice and promotes the osteogenic differentiation of BMMSCs via the p38 MAPK pathway in vitro

    PubMed Central

    Nie, Yizhen; Yan, Zhaoqi; Yan, Wei; Xia, Qingyan; Zhang, Yina

    2015-01-01

    This study was to explore the effect of long-term cold exposure on morphological changes of WAT and BAT, metabolic changes and inflammatory responses in vivo. We also investigated the effect of cold exposure on the osteogenic differentiation of BMMSCs and the mechanism involved in vitro. At the end of the animal experiments, WAT and BAT were isolated and analyzed by HE staining. The results showed that both temperature and exposure time were associated with the degree of WAT browning. Then, peripheral blood samples were collected and centrifuged to obtain serum. Serum biochemical analysis was performed. After exposure to cold air for 21 d, cyclic adenosine monophosphate (cAMP) level in BAT was greatly upregulated. cAMP in WAT and glycerol levels were slightly increased. Cold exposure decreased triglyceride (TG) level and increased the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Whereas, high-density lipoprotein cholesterol (HDL-C) and free fatty acid (FFA) levels remains unchanged. Moreover, leptin and adiponectin (ADP) levels were remarkably downregulated. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 concentrations were significantly elevated. Furthermore, the results showed that cold exposure significantly elevated runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP), osteopontin (OPN) and collagen I levels and promoted the phosphorylation of p38 MAPK. However, the inducing effects were greatly inhibited by p38 MAPK inhibitor SB203580. These data suggest that long-term cold exposure activate BAT, increase lipolysis rate and enhance inflammatory response in mice. Furthermore, cold exposure promoted the osteogenic differentiation of BMMSCs partially via the p38 MAPK pathway. PMID:26617802

  20. Pregnancy-induced metabolic phenotype variations in maternal plasma.

    PubMed

    Luan, Hemi; Meng, Nan; Liu, Ping; Feng, Qiang; Lin, Shuhai; Fu, Jin; Davidson, Robert; Chen, Xiaomin; Rao, Weiqiao; Chen, Fang; Jiang, Hui; Xu, Xun; Cai, Zongwei; Wang, Jun

    2014-03-01

    Metabolic variations occur during normal pregnancy to provide the growing fetus with a supply of nutrients required for its development and to ensure the health of the woman during gestation. Mass spectrometry-based metabolomics was employed to study the metabolic phenotype variations in the maternal plasma that are induced by pregnancy in each of its three trimesters. Nontargeted metabolomics analysis showed that pregnancy significantly altered the profile of metabolites in maternal plasma. The levels of six metabolites were found to change significantly throughout pregnancy, with related metabolic pathway variations observed in biopterin metabolism, phospholipid metabolism, amino acid derivatives, and fatty acid oxidation. In particular, there was a pronounced elevation of dihydrobiopterin (BH₂), a compound produced in the synthesis of dopa, dopamine, norepinephrine, and epinephrine, in the second trimester, whereas it was markedly decreased in the third trimester. The turnover of BH₂ and tryptophan catabolites indicated that the fluctuations of neurotransmitters throughout pregnancy might reveal the metabolic adaption in the maternal body for the growth of the fetus. Furthermore, 11 lipid classes and 41 carnitine species were also determined and this showed variations in the presence of long-chain acylcarnitines and lysophospholipids in later pregnancy, suggesting changes of acylcarnitines and lysophospholipids to meet the energy demands in pregnant women. To our knowledge, this work is the first report of dynamic metabolic signatures and proposed related metabolic pathways in the maternal plasma for normal pregnancies and provided the basis for time-dependent metabolic trajectory against which disease-related disorders may be contrasted. PMID:24450375

  1. Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach.

    PubMed

    Ishii, Shun'ichi; Suzuki, Shino; Tenney, Aaron; Norden-Krichmar, Trina M; Nealson, Kenneth H; Bretschger, Orianna

    2015-01-01

    Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli. PMID:26443302

  2. Microbial metabolic networks in a complex electrogenic biofilm recovered from a stimulus-induced metatranscriptomics approach

    PubMed Central

    Ishii, Shun’ichi; Suzuki, Shino; Tenney, Aaron; Norden-Krichmar, Trina M.; Nealson, Kenneth H.; Bretschger, Orianna

    2015-01-01

    Microorganisms almost always exist as mixed communities in nature. While the significance of microbial community activities is well appreciated, a thorough understanding about how microbial communities respond to environmental perturbations has not yet been achieved. Here we have used a combination of metagenomic, genome binning, and stimulus-induced metatranscriptomic approaches to estimate the metabolic network and stimuli-induced metabolic switches existing in a complex microbial biofilm that was producing electrical current via extracellular electron transfer (EET) to a solid electrode surface. Two stimuli were employed: to increase EET and to stop EET. An analysis of cell activity marker genes after stimuli exposure revealed that only two strains within eleven binned genomes had strong transcriptional responses to increased EET rates, with one responding positively and the other responding negatively. Potential metabolic switches between eleven dominant members were mainly observed for acetate, hydrogen, and ethanol metabolisms. These results have enabled the estimation of a multi-species metabolic network and the associated short-term responses to EET stimuli that induce changes to metabolic flow and cooperative or competitive microbial interactions. This systematic meta-omics approach represents a next step towards understanding complex microbial roles within a community and how community members respond to specific environmental stimuli. PMID:26443302

  3. Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in acute lymphoblastic leukemia

    PubMed Central

    Herranz, Daniel; Ambesi-Impiombato, Alberto; Sudderth, Jessica; Sánchez-Martín, Marta; Belver, Laura; Tosello, Valeria; Xu, Luyao; Wendorff, Agnieszka A.; Castillo, Mireia; Haydu, J. Erika; Márquez, Javier; Matés, José M.; Kung, Andrew L.; Rayport, Stephen; Cordon-Cardo, Carlos; DeBerardinis, Ralph J.; Ferrando, Adolfo A.

    2015-01-01

    Activating mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (TALL). Here we identify glutaminolysis as a critical pathway for leukemia cell growth downstream of NOTCH1 and a key determinant of clinical response to anti-NOTCH1 therapies. Mechanistically, inhibition of NOTCH1 signaling in T-ALL induces a metabolic shutdown with prominent inhibition of glutaminolysis and triggers autophagy as a salvage pathway supporting leukemia cell metabolism. Consequently, both inhibition of glutaminolysis and inhibition of autophagy strongly and synergistically enhance the antileukemic effects of anti-NOTCH1 therapies. Moreover, we demonstrate that Pten loss induces increased glycolysis and consequently rescues leukemic cell metabolism abrogating the antileukemic effects of NOTCH1 inhibition. Overall, these results identify glutaminolysis as a major node in cancer metabolism controlled by NOTCH1 and as therapeutic target for the treatment of T-ALL. PMID:26390244

  4. Impaired cellular energy metabolism contributes to bluetongue-virus-induced autophagy.

    PubMed

    Lv, Shuang; Xu, Qingyuan; Sun, Encheng; Zhang, Jikai; Wu, Donglai

    2016-10-01

    Bluetongue virus (BTV) has been found to trigger autophagy to favor its replication, but the underlying mechanisms have not been clarified. Here, we show that cellular energy metabolism is involved in BTV-induced autophagy. Cellular ATP synthesis was impaired by BTV1 infection, causing metabolic stress, which was responsible for activation of autophagy, since the conversion of LC3 and aggregation of GFP-LC3 (autophagy markers) were suppressed when infection-caused energy depletion was reversed via MP (metabolic substrate) treatment. The reduced virus yields with MP further supported this view. Overall, our findings suggest that BTV1-induced disruption of cellular energy metabolism contributes to autophagy, and this provides new insights into BTV-host interactions. PMID:27379971

  5. Impairment of carbon metabolism induced by the herbicide glyphosate.

    PubMed

    Orcaray, Luis; Zulet, Amaia; Zabalza, Ana; Royuela, Mercedes

    2012-01-01

    The herbicide glyphosate reduces plant growth and causes plant death by inhibiting the biosynthesis of aromatic amino acids. The objective of this work was to determine whether glyphosate-treated plants show a carbon metabolism pattern comparable to that of plants treated with herbicides that inhibit branched-chain amino acid biosynthesis. Glyphosate-treated plants showed impaired carbon metabolism with an accumulation of carbohydrates in the leaves and roots. The growth inhibition detected after glyphosate treatment suggested impaired metabolism that impedes the utilization of available carbohydrates or energy at the expected rate. These effects were common to both types of amino acid biosynthesis inhibitors. Under aerobic conditions, ethanolic fermentative metabolism was enhanced in the roots of glyphosate-treated plants. This fermentative response was not related to changes in the respiratory rate or to a limitation of the energy charge. This response, which was similar for both types of herbicides, might be considered a general response to stress conditions. PMID:21944839

  6. Allergen-induced airway responses.

    PubMed

    Gauvreau, Gail M; El-Gammal, Amani I; O'Byrne, Paul M

    2015-09-01

    Environmental allergens are an important cause of asthma and can contribute to loss of asthma control and exacerbations. Allergen inhalation challenge has been a useful clinical model to examine the mechanisms of allergen-induced airway responses and inflammation. Allergen bronchoconstrictor responses are the early response, which reaches a maximum within 30 min and resolves by 1-3 h, and late responses, when bronchoconstriction recurs after 3-4 h and reaches a maximum over 6-12 h. Late responses are followed by an increase in airway hyperresponsiveness. These responses occur when IgE on mast cells is cross-linked by an allergen, causing degranulation and the release of histamine, neutral proteases and chemotactic factors, and the production of newly formed mediators, such as cysteinyl leukotrienes and prostaglandin D2. Allergen-induced airway inflammation consists of an increase in airway eosinophils, basophils and, less consistently, neutrophils. These responses are mediated by the trafficking and activation of myeloid dendritic cells into the airways, probably as a result of the release of epithelial cell-derived thymic stromal lymphopoietin, and the release of pro-inflammatory cytokines from type 2 helper T-cells. Allergen inhalation challenge has also been a widely used model to study potential new therapies for asthma and has an excellent negative predictive value for this purpose. PMID:26206871

  7. Metabolic response to exogenous ethanol in yeast: an in vivo NMR and mathematical modelling approach.

    PubMed

    Martini, Silvia; Ricci, Maso; Bartolini, Fiora; Bonechi, Claudia; Braconi, Daniela; Millucci, Lia; Santucci, Annalisa; Rossi, Claudio

    2006-03-20

    The understanding of the metabolic behaviour of complex systems such as eukaryotic cells needs the development of new approaches that are able to deal with the complexity due to a large number of interactions within the system. In this paper, we applied an approach based on the combined use of in vivo NMR experiments and mathematical modelling in order to analyze the metabolic response to ethanol stress in a wild-strain of Saccharomyces cerevisiae. Considering the cellular metabolic processes resulting from activation, inhibition, and feed-back activities, we developed a model able to describe the modulation of the whole system induced by an external stress due to increasing concentrations of exogenous ethanol. This approach was able to interpret the experimental results in terms of metabolic response to exogenous ethanol in the yeast. The robustness and flexibility of the model enables it to work correctly at different initial exogenous ethanol concentrations. PMID:16316719

  8. Metabolic acidosis-induced insulin resistance and cardiovascular risk.

    PubMed

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús; Adeva, Maria M

    2011-08-01

    Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosis worsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  9. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk

    PubMed Central

    Souto, Gema; Donapetry, Cristóbal; Calviño, Jesús

    2011-01-01

    Abstract Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosisworsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance. PMID:21352078

  10. Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

    SciTech Connect

    Xu, Aibin; Liu, Jingyi; Liu, Peilin; Jia, Min; Wang, Han; Tao, Ling

    2014-04-18

    Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H{sub 2}O{sub 2} led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H{sub 2}O{sub 2} and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the

  11. Metabolic phenotyping reveals a lipid mediator response to ionizing radiation.

    PubMed

    Laiakis, Evagelia C; Strassburg, Katrin; Bogumil, Ralf; Lai, Steven; Vreeken, Rob J; Hankemeier, Thomas; Langridge, James; Plumb, Robert S; Fornace, Albert J; Astarita, Giuseppe

    2014-09-01

    Exposure to ionizing radiation has dramatically increased in modern society, raising serious health concerns. The molecular response to ionizing radiation, however, is still not completely understood. Here, we screened mouse serum for metabolic alterations following an acute exposure to γ radiation using a multiplatform mass-spectrometry-based strategy. A global, molecular profiling revealed that mouse serum undergoes a series of significant molecular alterations following radiation exposure. We identified and quantified bioactive metabolites belonging to key biochemical pathways and low-abundance, oxygenated, polyunsaturated fatty acids (PUFAs) in the two groups of animals. Exposure to γ radiation induced a significant increase in the serum levels of ether phosphatidylcholines (PCs) while decreasing the levels of diacyl PCs carrying PUFAs. In exposed mice, levels of pro-inflammatory, oxygenated metabolites of arachidonic acid increased, whereas levels of anti-inflammatory metabolites of omega-3 PUFAs decreased. Our results indicate a specific serum lipidomic biosignature that could be utilized as an indicator of radiation exposure and as novel target for therapeutic intervention. Monitoring such a molecular response to radiation exposure might have implications not only for radiation pathology but also for countermeasures and personalized medicine. PMID:25126707

  12. Reproducibility of regional brain metabolic responses to lorazepam

    SciTech Connect

    Wang, G.J.; Volkow, N.D.; Overall, J. |

    1996-10-01

    Changes in regional brain glucose metabolism in response to benzodiazepine agonists have been used as indicators of benzodiazepine-GABA receptor function. The purpose of this study was to assess the reproducibility of these responses. Sixteen healthy right-handed men underwent scanning with PET and [{sup 18}F]fluorodeoxyglucose (FDG) twice: before placebo and before lorazepam (30 {mu}g/kg). The same double FDG procedure was repeated 6-8 wk later on the men to assess test-retest reproducibility. The regional absolute brain metabolic values obtained during the second evaluation were significantly lower than those obtained from the first evaluation regardless of condition (p {le} 0.001). Lorazepam significantly and consistently decreased both whole-brain metabolism and the magnitude. The regional pattern of the changes were comparable for both studies (12.3% {plus_minus} 6.9% and 13.7% {plus_minus} 7.4%). Lorazepam effects were the largest in the thalamus (22.2% {plus_minus} 8.6% and 22.4% {plus_minus} 6.9%) and occipital cortex (19% {plus_minus} 8.9% and 21.8% {plus_minus} 8.9%). Relative metabolic measures were highly reproducible both for pharmacolgic and replication condition. This study measured the test-retest reproducibility in regional brain metabolic responses, and although the global and regional metabolic values were significantly lower for the repeated evaluation, the response to lorazepam was highly reproducible. 1613 refs., 3 figs., 3 tabs.

  13. Secondary psychosis induced by metabolic disorders

    PubMed Central

    Bonnot, Olivier; Herrera, Paula M.; Tordjman, Sylvie; Walterfang, Mark

    2015-01-01

    Metabolic disorders are not well-recognized by psychiatrists as a possible source of secondary psychoses. Inborn errors of metabolism (IEMs) are not frequent. Although their prompt diagnosis may lead to suitable treatments. IEMs are well-known to pediatricians, in particular for their most serious forms, having an early expression most of the time. Recent years discoveries have unveiled later expression forms, and sometimes very discreet first physical signs. There is a growing body of evidence that supports the hypothesis that IEMs can manifest as atypical psychiatric symptoms, even in the absence of clear neurological symptoms. In the present review, we propose a detailed overview at schizophrenia-like and autism-like symptoms that can lead practitioners to bear in mind an IEM. Other psychiatric manifestations are also found, as behavioral, cognitive, learning, and mood disorders. However, they are less frequent. Ensuring an accurate IEM diagnosis, in front of these psychiatric symptoms should be a priority, in order to grant suitable and valuable treatment for these pathologies. PMID:26074754

  14. Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration

    PubMed Central

    Kurihara, Toshihide; Westenskow, Peter D; Gantner, Marin L; Usui, Yoshihiko; Schultz, Andrew; Bravo, Stephen; Aguilar, Edith; Wittgrove, Carli; Friedlander, Mollie SH; Paris, Liliana P; Chew, Emily; Siuzdak, Gary; Friedlander, Martin

    2016-01-01

    Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies. DOI: http://dx.doi.org/10.7554/eLife.14319.001 PMID:26978795

  15. Extracellular Adenosine Mediates a Systemic Metabolic Switch during Immune Response

    PubMed Central

    Bajgar, Adam; Kucerova, Katerina; Jonatova, Lucie; Tomcala, Ales; Schneedorferova, Ivana; Okrouhlik, Jan; Dolezal, Tomas

    2015-01-01

    Immune defense is energetically costly, and thus an effective response requires metabolic adaptation of the organism to reallocate energy from storage, growth, and development towards the immune system. We employ the natural infection of Drosophila with a parasitoid wasp to study energy regulation during immune response. To combat the invasion, the host must produce specialized immune cells (lamellocytes) that destroy the parasitoid egg. We show that a significant portion of nutrients are allocated to differentiating lamellocytes when they would otherwise be used for development. This systemic metabolic switch is mediated by extracellular adenosine released from immune cells. The switch is crucial for an effective immune response. Preventing adenosine transport from immune cells or blocking adenosine receptor precludes the metabolic switch and the deceleration of development, dramatically reducing host resistance. Adenosine thus serves as a signal that the “selfish” immune cells send during infection to secure more energy at the expense of other tissues. PMID:25915062

  16. Injury-induced immune responses in Hydra.

    PubMed

    Wenger, Yvan; Buzgariu, Wanda; Reiter, Silke; Galliot, Brigitte

    2014-08-01

    The impact of injury-induced immune responses on animal regenerative processes is highly variable, positive or negative depending on the context. This likely reflects the complexity of the innate immune system that behaves as a sentinel in the transition from injury to regeneration. Early-branching invertebrates with high regenerative potential as Hydra provide a unique framework to dissect how injury-induced immune responses impact regeneration. A series of early cellular events likely require an efficient immune response after amputation, as antimicrobial defence, epithelial cell stretching for wound closure, migration of interstitial progenitors toward the wound, cell death, phagocytosis of cell debris, or reconstruction of the extracellular matrix. The analysis of the injury-induced transcriptomic modulations of 2636 genes annotated as immune genes in Hydra identified 43 genes showing an immediate/early pulse regulation in all regenerative contexts examined. These regulations point to an enhanced cytoprotection via ROS signaling (Nrf, C/EBP, p62/SQSMT1-l2), TNFR and TLR signaling (TNFR16-like, TRAF2l, TRAF5l, jun, fos-related, SIK2, ATF1/CREB, LRRC28, LRRC40, LRRK2), proteasomal activity (p62/SQSMT1-l1, Ced6/Gulf, NEDD8-conjugating enzyme Ubc12), stress proteins (CRYAB1, CRYAB2, HSP16.2, DnaJB9, HSP90a1), all potentially regulating NF-κB activity. Other genes encoding immune-annotated proteins such as NPYR4, GTPases, Swap70, the antiproliferative BTG1, enzymes involved in lipid metabolism (5-lipoxygenase, ACSF4), secreted clotting factors, secreted peptidases are also pulse regulated upon bisection. By contrast, metalloproteinases and antimicrobial peptide genes largely follow a context-dependent regulation, whereas the protease inhibitor α2macroglobulin gene exhibits a sustained up-regulation. Hence a complex immune response to injury is linked to wound healing and regeneration in Hydra. PMID:25086685

  17. Genetic regulation of warfarin metabolism and response.

    PubMed

    Daly, Ann K; Aithal, Guruprasad P

    2003-08-01

    Genetic factors make an important contribution to the wide interindividual variation in warfarin dose requirement. Several cytochromes P450, each of which shows genetic polymorphism leading to interindividual variation in levels of activity, contribute to oxidative metabolism of warfarin. The most important of these is CYP2C9, which 7-hydroxylates S-warfarin. In clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in mean warfarin dose requirement in at least eight studies. Several studies also suggest that possession of a variant allele is associated with an increased risk of adverse events. Other genetic factors such as polymorphisms affecting CYP3A4 or CYP1A2 may also be relevant to warfarin dose requirement. The molecular basis of warfarin resistance remains unclear but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to abnormal vitamin K epoxide reductase (pharmacodynamic resistance). There is less information available on genetic factors affecting other anticoagulants, but the CYP2C9 genotype is also relevant to acenocoumarol dose. PMID:15199455

  18. Central and Peripheral Metabolic Changes Induced by Gamma-Hydroxybutyrate

    PubMed Central

    Luca, Gianina; Vienne, Julie; Vaucher, Angélique; Jimenez, Sonia; Tafti, Mehdi

    2015-01-01

    Study Objectives: Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone release in humans and induces weight loss in treated patients, suggesting an unexplored metabolic effect. In different experiments the effect of GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism, were evaluated in mice. Design: C57BL/6J, gamma-aminobutyric acid B (GABAB) knockout and obese (ob/ob) mice were acutely or chronically treated with GHB at 300 mg/kg. Measurements and Results: Respiratory ratio decreased under GHB treatment, independent of food intake, suggesting a shift in energy substrate from carbohydrates to lipids. GHB-treated C57BL/6J and GABAB null mice but not ob/ob mice gained less weight than matched controls. GHB dramatically increased the corticosterone level but did not affect growth hormone or prolactin. Metabolome profiling showed that an acute high dose of GHB did not increase the brain GABA level. In the brain and the liver, GHB was metabolized into succinic semialdehyde by hydroxyacid-oxoacid transhydrogenase. Chronic administration decreased glutamate, s-adenosylhomocysteine, and oxidized gluthathione, and increased omega-3 fatty acids. Conclusions: Our findings indicate large central and peripheral metabolic changes induced by gamma-hydroxybutyrate (GHB) with important relevance to its therapeutic use. Citation: Luca G, Vienne J, Vaucher A, Jimenez S, Tafti M. Central and peripheral metabolic changes induced by gamma-hydroxybutyrate. SLEEP 2015;38(2):305–313. PMID:25515097

  19. Metabolic Profile of Wound-Induced Changes in Primary Carbon Metabolism in Sugarbeet Root

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Injury to plant products induces respiration rate and increases the demand for respiratory substrates. Alterations in primary carbon metabolism are likely to support the elevated demand for respiratory substrates, although the nature of these alterations is unknown. To gain insight into the metabo...

  20. Autofluorescence Imaging of Living Pancreatic Islets Reveals Fibroblast Growth Factor-21 (FGF21)-Induced Metabolism

    PubMed Central

    Sun, Mark Y.; Yoo, Eunjong; Green, Brenda J.; Altamentova, Svetlana M.; Kilkenny, Dawn M.; Rocheleau, Jonathan V.

    2012-01-01

    Fibroblast growth factor-21 (FGF21) has therapeutic potential for metabolic syndrome due to positive effects on fatty acid metabolism in liver and white adipose tissue. FGF21 also improves pancreatic islet survival in excess palmitate; however, much less is known about FGF21-induced metabolism in this tissue. We first confirmed FGF21-dependent activity in islets by identifying expression of the cognate coreceptor Klothoβ, and by measuring a ligand-stimulated decrease in acetyl-CoA carboxylase expression. To further reveal the effect of FGF21 on metabolism, we employed a unique combination of two-photon and confocal autofluorescence imaging of the NAD(P)H and mitochondrial NADH responses while holding living islets stationary in a microfluidic device. These responses were further correlated to mitochondrial membrane potential and insulin secretion. Glucose-stimulated responses were relatively unchanged by FGF21. In contrast, responses to glucose in the presence of palmitate were significantly reduced compared to controls showing diminished NAD(P)H, mitochondrial NADH, mitochondrial membrane potential, and insulin secretion. Consistent with the glucose-stimulated responses being smaller due to continued fatty acid oxidation, mitochondrial membrane potential was increased in FGF21-treated islets by using the fatty acid transport inhibitor etomoxir. Citrate-stimulated NADPH responses were also significantly larger in FGF21-treated islets suggesting preference for citrate cycling rather than acetyl-CoA carboxylase-dependent fatty acid synthesis. Overall, these data show a reduction in palmitate-induced potentiation of glucose-stimulated metabolism and insulin secretion in FGF21-treated islets, and establish the use of autofluorescence imaging and microfluidic devices to investigate cell metabolism in a limited amount of living tissue. PMID:23283237

  1. Gender-specific metabolic responses in hepatopancreas of mussel Mytilus galloprovincialis challenged by Vibrio harveyi.

    PubMed

    Liu, Xiaoli; Sun, Hushan; Wang, Yiyan; Ma, Mengwen; Zhang, Yuemei

    2014-10-01

    Mussel Mytilus galloprovincialis is a marine aquaculture shellfish and frequently studied in shellfish immunology. In this work, the gender-specific metabolic responses induced by Vibrio harveyi in hepatopancreas from M. galloprovincialis were characterized using NMR-based metabolomics. In details, V. harveyi challenge increased the levels of amino acids including (valine, leucine, isoleucine, threonine, alanine, arginine and tyrosine) and ATP, and decreased the level of glucose in male mussel hepatopancreas. In V. harveyi-challenged female mussel hepatopancreas, both threonine and AMP were significantly elevated, and choline, phoshphocholine, sn-glycero-3-phosphocholine, taurine, betaine and ATP were depleted. Obviously, only threonine was similarly altered to that in V. harveyi-challenged male mussel hepatopancreas. These findings confirmed the gender-specific metabolic responses in mussels challenged by V. harveyi. Overall, V. harveyi induced an enhanced energy demand through activated glycolysis and immune response indicated by increased BCAAs in male mussel hepatopancreas. In female mussel hepatopancreas, V. harveyi basically caused disturbances in both osmotic regulation and energy metabolism through the metabolic pathways of conversions of phosphocholine and ADP to choline and ATP, and sn-glycero-3-phosphocholine and H2O into choline and sn-glycerol 3-phosphate. The altered mRNA expression levels of related genes (Cu/Zn-SOD, HSP90, lysozyme and defensin) suggested that V. harveyi induced obvious oxidative and immune stresses in both male and female mussel hepatopancreas. This work demonstrated that V. harveyi could induce gender-specific metabolic responses in mussel M. galloprovincialis hepatopancreas using NMR-based metabolomics. PMID:25123832

  2. Metabolic profiling reveals potential metabolic markers associated with Hypoxia Inducible Factor-mediated signalling in hypoxic cancer cells

    PubMed Central

    Armitage, Emily G.; Kotze, Helen L.; Allwood, J. William; Dunn, Warwick B.; Goodacre, Royston; Williams, Kaye J.

    2015-01-01

    Hypoxia inducible factors (HIFs) plays an important role in oxygen compromised environments and therefore in tumour survival. In this research, metabolomics has been applied to study HIFs metabolic function in two cell models: mouse hepatocellular carcinoma and human colon carcinoma, whereby the metabolism has been profiled for a range of oxygen potentials. Wild type cells have been compared to cells deficient in HIF signalling to reveal its effect on cellular metabolism under normal oxygen conditions as well as low oxygen, hypoxic and anoxic environments. Characteristic responses to hypoxia that were conserved across both cell models involved the anti-correlation between 2-hydroxyglutarate, 2-oxoglutarate, fructose, hexadecanoic acid, hypotaurine, pyruvate and octadecenoic acid with 4-hydroxyproline, aspartate, cysteine, glutamine, lysine, malate and pyroglutamate. Further to this, network-based correlation analysis revealed HIF specific pathway responses to each oxygen condition that were also conserved between cell models. From this, 4-hydroxyproline was revealed as a regulating hub in low oxygen survival of WT cells while fructose appeared to be in HIF deficient cells. Pathways surrounding these hubs were built from the direct connections of correlated metabolites that look beyond traditional pathways in order to understand the mechanism of HIF response to low oxygen environments. PMID:26508589

  3. Metabolic, immune, and gut microbial signals mount a systems response to Leishmania major infection.

    PubMed

    Lamour, Sabrina D; Veselkov, Kirill A; Posma, Joram M; Giraud, Emilie; Rogers, Matthew E; Croft, Simon; Marchesi, Julian R; Holmes, Elaine; Seifert, Karin; Saric, Jasmina

    2015-01-01

    Parasitic infections such as leishmaniasis induce a cascade of host physiological responses, including metabolic and immunological changes. Infection with Leishmania major parasites causes cutaneous leishmaniasis in humans, a neglected tropical disease that is difficult to manage. To understand the determinants of pathology, we studied L. major infection in two mouse models: the self-healing C57BL/6 strain and the nonhealing BALB/c strain. Metabolic profiling of urine, plasma, and feces via proton NMR spectroscopy was performed to discover parasite-specific imprints on global host metabolism. Plasma cytokine status and fecal microbiome were also characterized as additional metrics of the host response to infection. Results demonstrated differences in glucose and lipid metabolism, distinctive immunological phenotypes, and shifts in microbial composition between the two models. We present a novel approach to integrate such metrics using correlation network analyses, whereby self-healing mice demonstrated an orchestrated interaction between the biological measures shortly after infection. In contrast, the response observed in nonhealing mice was delayed and fragmented. Our study suggests that trans-system communication across host metabolism, the innate immune system, and gut microbiome is key for a successful host response to L. major and provides a new concept, potentially translatable to other diseases. PMID:25369177

  4. Erythropoietin Action in Stress Response, Tissue Maintenance and Metabolism

    PubMed Central

    Zhang, Yuanyuan; Wang, Li; Dey, Soumyadeep; Alnaeeli, Mawadda; Suresh, Sukanya; Rogers, Heather; Teng, Ruifeng; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin (EPO) regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR), suggest the potential for EPO response in metabolism and disease. PMID:24918289

  5. Erythropoietin action in stress response, tissue maintenance and metabolism.

    PubMed

    Zhang, Yuanyuan; Wang, Li; Dey, Soumyadeep; Alnaeeli, Mawadda; Suresh, Sukanya; Rogers, Heather; Teng, Ruifeng; Noguchi, Constance Tom

    2014-01-01

    Erythropoietin (EPO) regulation of red blood cell production and its induction at reduced oxygen tension provides for the important erythropoietic response to ischemic stress. The cloning and production of recombinant human EPO has led to its clinical use in patients with anemia for two and half decades and has facilitated studies of EPO action. Reports of animal and cell models of ischemic stress in vitro and injury suggest potential EPO benefit beyond red blood cell production including vascular endothelial response to increase nitric oxide production, which facilitates oxygen delivery to brain, heart and other non-hematopoietic tissues. This review discusses these and other reports of EPO action beyond red blood cell production, including EPO response affecting metabolism and obesity in animal models. Observations of EPO activity in cell and animal model systems, including mice with tissue specific deletion of EPO receptor (EpoR), suggest the potential for EPO response in metabolism and disease. PMID:24918289

  6. Divergent metabolic responses of Apostichopus japonicus suffered from skin ulceration syndrome and pathogen challenge.

    PubMed

    Shao, Yina; Li, Chenghua; Ou, Changrong; Zhang, Peng; Lu, Yali; Su, Xiurong; Li, Ye; Li, Taiwu

    2013-11-13

    Skin ulceration syndrome (SUS) is the main limitation in the development of Apostichopus japonicus culture industries, in which Vibrio splendidus has been well documented as one of the major pathogens. However, the intrinsic mechanisms toward pathogen challenge and disease outbreak remain largely unknown at the metabolic level. In this work, the metabolic responses were investigated in muscles of sea cucumber among natural SUS-diseased and V. splendidus-challenged samples. The pathogen did not induce obvious biological effects in A. japonicus samples after infection for the first 24 h. An enhanced energy storage (or reduced energy demand) and immune responses were observed in V. splendidus-challenged A. japonicus samples at 48 h, as marked by increased glucose and branched chain amino acids, respectively. Afterward, infection of V. splendidus induced significant increases in energy demand in A. japonicus samples at both 72 and 96 h, confirmed by decreased glucose and glycogen, and increased ATP. Surprisingly, high levels of glycogen and glucose and low levels of threonine, alanine, arginine, glutamate, glutamine, taurine and ATP were founded in natural SUS-diseased sea cucumber. Our present results provided essential metabolic information about host-pathogen interaction for sea cucumber, and informed that the metabolic biomarkers induced by V. splendidus were not usable for the prediction of SUS disease in practice. PMID:24127639

  7. Diabetes and hyperlipidemia induce dysfunction of VSMCs: contribution of the metabolic inflammation/miRNA pathway.

    PubMed

    Li, Tao; Yang, Guang-ming; Zhu, Yu; Wu, Yue; Chen, Xiang-yun; Lan, Dan; Tian, Kun-lun; Liu, Liang-ming

    2015-02-15

    Vascular endothelial cell injury is considered to be the major factor inducing vascular complications in metabolic diseases and plays an important role in other organ damage. With diabetic and hyperlipidemic rats and cultured VSMCs, the present study was aimed at investigating whether the early damage of VSMCs during metabolic diseases plays a critical role in vascular dysfunction and the underlying mechanisms and would be a promising treatment target. With diabetic and hyperlipidemic rats and cultured VSMCs, the changes and relationships of vascular relaxation and contractile function to the vital organ damage and the underlying mechanisms were investigated; meanwhile, the protective and preventive effects of lowering blood lipid and glucose and inhibition of diabetes and hyperlipidemia-induced vascular hyperreactivity were observed. Diabetic and hyperlipidemic rats presented hyperreactivity in vascular contractile response in the early stages. Hyperglycemia and hyperlipidemia directly affected the contractile function of VSMCs. Early application of fasudil, a specific antagonist of Rho kinase, significantly alleviated diabetes and hyperlipidemia-induced organ damage by inhibiting vascular hyperreactivity. Diabetes and hyperlipidemia-induced inflammatory response could upregulate the expression of connexins and Rho kinase by selective downregulation of the expression of miR-10a, miR-139b, miR-206, and miR-222. These findings suggest that hyperglucose and lipid may directly impair VSMCs and induce vascular hyperreactivity in the early stages. Metabolic inflammation-induced changes in the miRNA-connexin/Rho kinase regulatory pathway are the main mechanism for vascular hyperreactivity and organ damage. Measures inhibiting vascular hyperreactivity are promising for the prevention of organ damage induced by metabolic diseases. PMID:25425000

  8. Combined hormonal infusion simulates the metabolic response to injury.

    PubMed Central

    Bessey, P Q; Watters, J M; Aoki, T T; Wilmore, D W

    1984-01-01

    To investigate the role of hormones as mediators of the metabolic response to injury, nine normal male volunteers received a continuous 74-hour infusion of the three 'stress' hormones: cortisol, glucagon, and epinephrine. As a control, each subject received a saline infusion during another 4-day period. Diets were constant and matched on both occasions. Hormonal infusion achieved hormone concentrations similar to those seen following mild-moderate injury. With this alteration in the endocrine environment significant hypermetabolism, negative nitrogen and potassium balances, glucose intolerance, hyperinsulinemia, insulin resistance, sodium retention, and peripheral leukocytosis were observed. Additional studies with single hormone infusions indicated that these responses resulted from both additive and synergistic interactions of the hormones. Triple hormone infusion simulated many of the metabolic responses observed following mild-moderate injury and other catabolic illnesses. PMID:6431917

  9. Fetal and maternal metabolic responses to exercise during pregnancy.

    PubMed

    Mottola, Michelle F; Artal, Raul

    2016-03-01

    Pregnancy is characterized by physiological, endocrine and metabolic adaptations creating a pseudo-diabetogenic state of progressive insulin resistance. These adaptations occur to sustain continuous fetal requirements for nutrients and oxygen. Insulin resistance develops at the level of the skeletal muscle, and maternal exercise, especially activity involving large muscle groups improve glucose tolerance and insulin sensitivity. We discuss the maternal hormonal and metabolic changes associated with a normal pregnancy, the metabolic dysregulation that may occur leading to gestational diabetes mellitus (GDM), and the consequences to mother and fetus. We will then examine the acute and chronic (training) responses to exercise in the non-pregnant state and relate these alterations to maternal exercise in a low-risk pregnancy, how exercise can be used to regulate glucose tolerance in women at risk for or diagnosed with GDM. Lastly, we present key exercise guidelines to help maintain maternal glucose regulation and suggest future research directions. PMID:26803360

  10. Optimal Biofilm Featues: metabolic and geometric response to multiple oxidants

    NASA Astrophysics Data System (ADS)

    Kempes, C.; Okegbe, C.; Mears-Clarke, Z.; Follows, M. J.; Dietrich, L.

    2014-12-01

    An important challenge in understanding complex microbial mat communities is determining how groups of a single species balance metabolic requirements with the dynamics of resource supply. We have investigated this problem in the context of redox resources within a single-species bacterial biofilm. We developed a mathematical model of oxidant availability and metabolic response within biofilm features and we show that observed biofilm geometries maximize cellular reproduction and growth efficiency. Our model accurately predicts the measured distribution of two types of electron acceptors: oxygen, which is available from the environment, and phenazines, redox-active small molecules produced by the bacterium. Because our model is based on resource dynamics, we are also able to predict observed shifts in feature geometry based on changes in the availability of redox resources such as variations in the external availability of oxygen or the removal of phenazines. This analysis suggests various avenues for understanding microstructure and the evolution of spatial metabolism in microbial mats.

  11. Base substitution mutations induced by metabolically activated aflatoxin B1.

    PubMed

    Foster, P L; Eisenstadt, E; Miller, J H

    1983-05-01

    We have determined the base substitutions generated by metabolically activated aflatoxin B1 in the lacI gene of a uvrB- strain of Escherichia coli. By monitoring over 70 different nonsense mutation sites, we show that activated aflatoxin B1 specifically induced GxC leads to TxA transversions. One possible pathway leading to this base change involves depurination at guanine residues. We consider this mechanism of mutagenesis in the light of our other findings that the carcinogens benzo[a]pyrene diol epoxide and N-acetoxyacetylaminofluorene also specifically induce GxC leads to TxA transversions. PMID:6405385

  12. Sickness behavior is accentuated in rats with metabolic disorders induced by a fructose diet.

    PubMed

    Orlandi, Lidiane; Fonseca, Wesley F; Enes-Marques, Silvia; Paffaro, Valdemar A; Vilela, Fabiana C; Giusti-Paiva, Alexandre

    2015-12-15

    This study investigated behavioral responses to an immune challenge among animals with fructose-induced metabolic disorders. Adult male Wistar rats were provided either water or a fructose solution (10%) for 5 weeks. Sickness behaviors were assessed 2h following the injection of either a lipopolysaccharide (LPS) or vehicle. The rats were subjected to an open field test, a social interaction test, a food intake test and a fever evaluation. Cytokine expression was assessed in both adipose tissue and hypothalamus samples. The neural response was assessed in the forebrain immunohistochemistry for c-Fos. Compared with the control group, the fructose diet induced dyslipidemia and significantly higher plasma total cholesterol, HDL-cholesterol, triglyceride, and glucose levels as well as both epididymal and retroperitoneal adiposity. Furthermore, in response to LPS (1 mg/kg), the rats subjected to a fructose diet exhibited exacerbated sickness behaviors and accentuated febrile responses. LPS induced Fos protein expression in several areas of the brains of the control rats; however, higher numbers of Fos-positive cells were observed in the brains of the rats that were fed a fructose diet. Moreover, larger increases in cytokine expression were observed in both the hypothalamus and the adipose tissue of the obese rats compared with the control rats in response to LPS. In this study, fructose diets played an important role in both the induction of metabolic disorders and the modulation of sickness behaviors in response to an immunological challenge, most likely through the induction of cytokines in the hypothalamus. PMID:26616874

  13. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism.

    PubMed

    Chen, Minjiang; Zheng, Hong; Wei, Tingting; Wang, Dan; Xia, Huanhuan; Zhao, Liangcai; Ji, Jiansong; Gao, Hongchang

    2016-01-01

    Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID:27413747

  14. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism

    PubMed Central

    Chen, Minjiang; Zheng, Hong; Wei, Tingting; Wang, Dan; Xia, Huanhuan; Zhao, Liangcai; Ji, Jiansong

    2016-01-01

    Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID:27413747

  15. Metabolic Context Regulates Distinct Hypothalamic Transcriptional Responses to Antiaging Interventions

    PubMed Central

    Stranahan, Alexis M.; Martin, Bronwen; Chadwick, Wayne; Park, Sung-Soo; Wang, Liyun; Becker, Kevin G.; WoodIII, William H.; Zhang, Yongqing; Maudsley, Stuart

    2012-01-01

    The hypothalamus is an essential relay in the neural circuitry underlying energy metabolism that needs to continually adapt to changes in the energetic environment. The neuroendocrine control of food intake and energy expenditure is associated with, and likely dependent upon, hypothalamic plasticity. Severe disturbances in energy metabolism, such as those that occur in obesity, are therefore likely to be associated with disruption of hypothalamic transcriptomic plasticity. In this paper, we investigated the effects of two well-characterized antiaging interventions, caloric restriction and voluntary wheel running, in two distinct physiological paradigms, that is, diabetic (db/db) and nondiabetic wild-type (C57/Bl/6) animals to investigate the contextual sensitivity of hypothalamic transcriptomic responses. We found that, both quantitatively and qualitatively, caloric restriction and physical exercise were associated with distinct transcriptional signatures that differed significantly between diabetic and non-diabetic mice. This suggests that challenges to metabolic homeostasis regulate distinct hypothalamic gene sets in diabetic and non-diabetic animals. A greater understanding of how genetic background contributes to hypothalamic response mechanisms could pave the way for the development of more nuanced therapeutics for the treatment of metabolic disorders that occur in diverse physiological backgrounds. PMID:22934110

  16. Thermoregulatory and metabolic responses of Japanese quail to hypoxia

    PubMed Central

    Atchley, Dylan S.; Foster, Jennifer A.; Bavis, Ryan W.

    2008-01-01

    Common responses to hypoxia include decreased body temperature (Tb) and decreased energy metabolism. In this study, the effects of hypoxia and hypercapnia on Tb and metabolic oxygen consumption (V̇o2) were investigated in Japanese quail (Coturnix japonica). When exposed to hypoxia (15, 13, 11 and 9% O2), Tb decreased only at 11% and 9% O2 compared to normoxia; quail were better able to maintain Tb during acute hypoxia after a one-week acclimation to 10% O2. V̇o2 also decreased during hypoxia, but at 9% O2 this was partially offset by increased anaerobic metabolism. Tb and V̇o2 responses to 9% O2 were exaggerated at lower ambient temperature (Ta), reflecting a decreased lower critical temperature during hypoxia. Conversely, hypoxia had little effect on Tb or V̇o2 at higher Ta (36°C). We conclude that Japanese quail respond to hypoxia in much the same way as mammals, by reducing both Tb and V̇o2. No relationship was found between the magnitudes of decreases in Tb and V̇o2 during 9% O2, however. Since metabolism is the source of heat generation, this suggests that Japanese quail increase thermolysis to reduce Tb. During hypercapnia (3, 6 and 9% CO2), Tb was reduced only at 9% CO2 while V̇o2 was unchanged. PMID:18727957

  17. Metabolic PET Imaging in Cancer Detection and Therapy Response

    PubMed Central

    Zhu, Aizhi; Lee, Daniel; Shim, Hyunsuk

    2010-01-01

    Positron emission tomography (PET) is a noninvasive imaging technique that provides a functional or metabolic assessment of normal tissue or disease conditions. 18F-fluorodeoxyglucose PET imaging (FDG-PET) is widely used clinically for tumor imaging due to increased glucose metabolism in most types of tumors, and has been shown to improve the diagnosis and subsequent treatment of cancers. In this chapter, we review its use in cancer diagnosis, staging, restaging, and assessment of response to treatment. In addition, other metabolic PET imaging agents in research or clinical trial stages are discussed, including amino acid analogs based on increased protein synthesis, and choline, which is based on increased membrane lipid synthesis. Amino acid analogs and choline are more specific to tumor cells than FDG, so they play an important role in differentiating cancers from benign conditions and in the diagnosis of cancers with low FDG uptake or high background FDG uptake. For decades, researchers have shown that tumors have altered metabolic profiles and display elevated uptake of glucose, amino acids, and lipids, which can be used for cancer diagnosis and monitoring of the therapeutic response with excellent signal-to-noise ratios. PMID:21362516

  18. Induction of the Unfolded Protein Response Drives Enhanced Metabolism and Chemoresistance in Glioma Cells

    PubMed Central

    Merz, Andrea L.; Dechkovskaia, Anjelika M.; Herring, Matthew; Winston, Benjamin A.; Lencioni, Alex M.; Russell, Rae L.; Madsen, Helen; Nega, Meheret; Dusto, Nathaniel L.; White, Jason; Bigner, Darell D.; Nicchitta, Christopher V.; Serkova, Natalie J.; Graner, Michael W.

    2013-01-01

    The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-based cytoprotective mechanism acting to prevent pathologies accompanying protein aggregation. It is frequently active in tumors, but relatively unstudied in gliomas. We hypothesized that UPR stress effects on glioma cells might protect tumors from additional exogenous stress (ie, chemotherapeutics), postulating that protection was concurrent with altered tumor cell metabolism. Using human brain tumor cell lines, xenograft tumors, human samples and gene expression databases, we determined molecular features of glioma cell UPR induction/activation, and here report a detailed analysis of UPR transcriptional/translational/metabolic responses. Immunohistochemistry, Western and Northern blots identified elevated levels of UPR transcription factors and downstream ER chaperone targets in gliomas. Microarray profiling revealed distinct regulation of stress responses between xenograft tumors and parent cell lines, with gene ontology and network analyses linking gene expression to cell survival and metabolic processes. Human glioma samples were examined for levels of the ER chaperone GRP94 by immunohistochemistry and for other UPR components by Western blotting. Gene and protein expression data from patient gliomas correlated poor patient prognoses with increased expression of ER chaperones, UPR target genes, and metabolic enzymes (glycolysis and lipogenesis). NMR-based metabolomic studies revealed increased metabolic outputs in glucose uptake with elevated glycolytic activity as well as increased phospholipid turnover. Elevated levels of amino acids, antioxidants, and cholesterol were also evident upon UPR stress; in particular, recurrent tumors had overall higher lipid outputs and elevated specific UPR arms. Clonogenicity studies following temozolomide treatment of stressed or unstressed cells demonstrated UPR-induced chemoresistance. Our data characterize the UPR in glioma cells and human tumors, and

  19. Induction of the unfolded protein response drives enhanced metabolism and chemoresistance in glioma cells.

    PubMed

    Epple, Laura M; Dodd, Rebecca D; Merz, Andrea L; Dechkovskaia, Anjelika M; Herring, Matthew; Winston, Benjamin A; Lencioni, Alex M; Russell, Rae L; Madsen, Helen; Nega, Meheret; Dusto, Nathaniel L; White, Jason; Bigner, Darell D; Nicchitta, Christopher V; Serkova, Natalie J; Graner, Michael W

    2013-01-01

    The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-based cytoprotective mechanism acting to prevent pathologies accompanying protein aggregation. It is frequently active in tumors, but relatively unstudied in gliomas. We hypothesized that UPR stress effects on glioma cells might protect tumors from additional exogenous stress (ie, chemotherapeutics), postulating that protection was concurrent with altered tumor cell metabolism. Using human brain tumor cell lines, xenograft tumors, human samples and gene expression databases, we determined molecular features of glioma cell UPR induction/activation, and here report a detailed analysis of UPR transcriptional/translational/metabolic responses. Immunohistochemistry, Western and Northern blots identified elevated levels of UPR transcription factors and downstream ER chaperone targets in gliomas. Microarray profiling revealed distinct regulation of stress responses between xenograft tumors and parent cell lines, with gene ontology and network analyses linking gene expression to cell survival and metabolic processes. Human glioma samples were examined for levels of the ER chaperone GRP94 by immunohistochemistry and for other UPR components by Western blotting. Gene and protein expression data from patient gliomas correlated poor patient prognoses with increased expression of ER chaperones, UPR target genes, and metabolic enzymes (glycolysis and lipogenesis). NMR-based metabolomic studies revealed increased metabolic outputs in glucose uptake with elevated glycolytic activity as well as increased phospholipid turnover. Elevated levels of amino acids, antioxidants, and cholesterol were also evident upon UPR stress; in particular, recurrent tumors had overall higher lipid outputs and elevated specific UPR arms. Clonogenicity studies following temozolomide treatment of stressed or unstressed cells demonstrated UPR-induced chemoresistance. Our data characterize the UPR in glioma cells and human tumors, and

  20. Interplay between cold-responsive gene regulation, metabolism and RNA processing during plant cold acclimation.

    PubMed

    Zhu, Jianhua; Dong, Chun-Hai; Zhu, Jian-Kang

    2007-06-01

    Temperate plants are capable of developing freezing tolerance when they are exposed to low nonfreezing temperatures. Acquired freezing tolerance involves extensive reprogramming of gene expression and metabolism. Recent full-genome transcript profiling studies, in combination with mutational and transgenic plant analyses, have provided a snapshot of the complex transcriptional network that operates under cold stress. Ubiquitination-mediated proteosomal protein degradation has a crucial role in regulating one of the upstream transcription factors, INDUCER OF CBF EXPRESSION 1 (ICE1), and thus in controlling the cold-responsive transcriptome. The changes in expression of hundreds of genes in response to cold temperatures are followed by increases in the levels of hundreds of metabolites, some of which are known to have protective effects against the damaging effects of cold stress. Genetic analysis has revealed important roles for cellular metabolic signals, and for RNA splicing, export and secondary structure unwinding, in regulating cold-responsive gene expression and chilling and freezing tolerance. PMID:17468037

  1. Sirt1 protects against high-fat diet-induced metabolic damage

    PubMed Central

    Pfluger, Paul T.; Herranz, Daniel; Velasco-Miguel, Susana; Serrano, Manuel; Tschöp, Matthias H.

    2008-01-01

    The identification of new pharmacological approaches to effectively prevent, treat, and cure the metabolic syndrome is of crucial importance. Excessive exposure to dietary lipids causes inflammatory responses, deranges the homeostasis of cellular metabolism, and is believed to constitute a key initiator of the metabolic syndrome. Mammalian Sirt1 is a protein deacetylase that has been involved in resveratrol-mediated protection from high-fat diet-induced metabolic damage, but direct proof for the implication of Sirt1 has remained elusive. Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1α, and lower activation of proinflammatory cytokines, such as TNFα and IL-6, via down-modulation of NFκB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet. PMID:18599449

  2. Selective metabolic activation of the hippocampus during lidocaine-induced pre-seizure activity.

    PubMed

    Ingvar, M; Shapiro, H M

    1981-01-01

    Neurophysiologic studies indicate that local anesthetic-induced seizures are generated in subcortical brain structures. The authors utilized a quantitative autoradiographic technique to measure cerebral metabolism during lidocaine-induced seizure activity in rats anesthetized with nitrous oxide. Local cerebral metabolic rate for glucose (l-CMRg) was determined when lidocaine infusion resulted in sustained electroencephalographic patterns consisting of approximately 100--125-mu volt discharges with a frequency of about 9 Hz, lasting 1-2 sec, and superimposed upon almost isoelectric periods lasting 1-3 sec. Significant reductions in 1-CMRg (30-70 per cent decreases) occurred in 19 of 26 regions surveyed. All areas of cerebral cortex had decreased glucose uptake following lidocaine administration. The hippocampus developed a striking increase in 1-CMRg of 237 per cent, while the amygdala and other related nuclei sustained metabolic rates similar to those present before lidocaine was given. This study demonstrates a coupling of metabolic activity with functional activity in subcortical structures recognized to be involved in the generation of local anesthetic seizure activity. Additionally, it reveals a heterogeneous response of cerebral metabolism to lidocaine infusion in the presence of subcortically localized seizures. PMID:7457980

  3. A strong response to selection on mass-independent maximal metabolic rate without a correlated response in basal metabolic rate

    PubMed Central

    Wone, B W M; Madsen, P; Donovan, E R; Labocha, M K; Sears, M W; Downs, C J; Sorensen, D A; Hayes, J P

    2015-01-01

    Metabolic rates are correlated with many aspects of ecology, but how selection on different aspects of metabolic rates affects their mutual evolution is poorly understood. Using laboratory mice, we artificially selected for high maximal mass-independent metabolic rate (MMR) without direct selection on mass-independent basal metabolic rate (BMR). Then we tested for responses to selection in MMR and correlated responses to selection in BMR. In other lines, we antagonistically selected for mice with a combination of high mass-independent MMR and low mass-independent BMR. All selection protocols and data analyses included body mass as a covariate, so effects of selection on the metabolic rates are mass adjusted (that is, independent of effects of body mass). The selection lasted eight generations. Compared with controls, MMR was significantly higher (11.2%) in lines selected for increased MMR, and BMR was slightly, but not significantly, higher (2.5%). Compared with controls, MMR was significantly higher (5.3%) in antagonistically selected lines, and BMR was slightly, but not significantly, lower (4.2%). Analysis of breeding values revealed no positive genetic trend for elevated BMR in high-MMR lines. A weak positive genetic correlation was detected between MMR and BMR. That weak positive genetic correlation supports the aerobic capacity model for the evolution of endothermy in the sense that it fails to falsify a key model assumption. Overall, the results suggest that at least in these mice there is significant capacity for independent evolution of metabolic traits. Whether that is true in the ancestral animals that evolved endothermy remains an important but unanswered question. PMID:25604947

  4. Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome.

    PubMed

    Schinzari, Francesca; Iantorno, Micaela; Campia, Umberto; Mores, Nadia; Rovella, Valentina; Tesauro, Manfredi; Di Daniele, Nicola; Cardillo, Carmine

    2015-11-01

    Patients with metabolically healthy obesity (MHO) do not present the cluster of metabolic abnormalities that define the metabolic syndrome (MetS). Whether MHO is associated with lower impairment of vasoreactivity than the MetS is unknown. For this purpose, forearm blood flow (FBF) responses were measured by strain-gauge plethysmography during the intra-arterial infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and/or the selective endothelin type A (ETA) receptor blocker BQ-123 in 119 obese individuals with MHO (n = 34) or with the MetS (n = 85) and in healthy lean controls (n = 56). ACh and SNP caused a significant vasodilation in both obese and lean participants (all P < 0.001). However, the response to both agents was significantly lower in the obese than in the control group (both P < 0.001). Among the obese participants, the reactivity to ACh was higher in MHO than in MetS patients, whereas the responsiveness to SNP was equally impaired in both groups (P = 0.45). Infusion of BQ-123 significantly increased FBF in obese patients (P < 0001), but not in the lean participants; hence, FBF following ETA receptor blockade was higher in both obese groups than in controls (both P < 0.001). FBF response to BQ-123 was significantly higher in patients with the MetS than in those with MHO (P = 0.007). In conclusion, patients with MHO have abnormal vascular reactivity, although their endothelial dysfunction is less pronounced than in patients with the MetS. These findings indicate that obesity is associated with vascular damage independent of those metabolic abnormalities underlying the MetS. PMID:26374766

  5. Dynamic responses of reserve carbohydrate metabolism under carbon and nitrogen limitations in Saccharomyces cerevisiae.

    PubMed

    Parrou, J L; Enjalbert, B; Plourde, L; Bauche, A; Gonzalez, B; François, J

    1999-02-01

    The dynamic responses of reserve carbohydrates with respect to shortage of either carbon or nitrogen source was studied to obtain a sound basis for further investigations devoted to the characterization of mechanisms by which the yeast Saccharomyces cerevisiae can cope with nutrient limitation during growth. This study was carried out in well-controlled bioreactors which allow accurate monitoring of growth and frequent sampling without disturbing the culture. Under glucose limitation, genes involved in glycogen and trehalose biosynthesis (GLG1, GSY1, GSY2, GAC1, GLC3, TPS1), in their degradation (GPH1, NTHI), and the typical stress-responsive CTT1 gene were coordinately induced in parallel with glycogen, when the growth has left the pure exponential phase and while glucose was still plentiful in the medium. Trehalose accumulation was delayed until the diauxic shift, although TPS1 was induced much earlier, due to hydrolysis of trehalose by high trehalase activity. In contrast, under nitrogen limitation, both glycogen and trehalose began to accumulate at the precise time when the nitrogen source was exhausted from the medium, coincidentally with the transcriptional activation of genes involved in their metabolism. While this response to nitrogen starvation was likely mediated by the stress-responsive elements (STREs) in the promoter of these genes, we found that these elements were not responsible for the co-induction of genes involved in reserve carbohydrate metabolism during glucose limitation, since GLG1, which does not contain any STRE, was coordinately induced with GSY2 and TPS1. PMID:10077186

  6. Biofilm Shows Spatially Stratified Metabolic Responses to Contaminant Exposure

    SciTech Connect

    Cao, Bin; Majors, Paul D.; Ahmed, B.; Renslow, Ryan S.; Sylvia, Crystal P.; Shi, Liang; Kjelleberg, Staffan; Fredrickson, Jim K.; Beyenal, Haluk

    2012-11-01

    The objective of this study was to elucidate the spatiotemporal responses of live S. oneidensis MR-1 biofilms to U(VI) (uranyl, UO22+) and Cr(VI) (chromate, CrO42-), important environmental contaminants at DOE contaminated sites. Toward this goal, we applied noninvasive nuclear magnetic resonance (NMR) imaging, diffusion, relaxation and spectroscopy techniques to monitor in situ spatiotemporal responses of S. oneidensis biofilms to U(VI) and Cr(VI) exposure in terms of changes in biofilm structures, diffusion properties, and cellular metabolism. Exposure to U(VI) or Cr(VI) did not appear to change the overall biomass distribution but caused changes in the physicochemical microenvironments inside the biofilm as indicated by diffusion measurements. Changes in the diffusion properties of the biofilms in response to U(VI) and Cr(VI) exposure imply a novel function of the extracellular polymeric substances (EPS) affecting the biotransformation and transport of contaminants in the environment. In the presence of U(VI) or Cr(VI), the anaerobic metabolism of lactate was inhibited significantly, although the biofilms were still capable of reducing U(VI) and Cr(VI). Local concentrations of Cr(III)aq in the biofilm suggested relatively high Cr(VI) reduction activities at the top of the biofilm, near the medium-biofilm interface. The depth-resolved metabolic activities of the biofilm suggested higher diversion effects of gluconeogenesis and C1 metabolism pathways at the bottom of the biofilm and in the presence of U(VI). This study provides a noninvasive means to investigate spatiotemporal responses of biofilms, including surface-associated microbial communities in engineering, natural and medical settings, to various environmental perturbations including exposure to environmental contaminants and antimicrobials.

  7. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality

    PubMed Central

    McIntyre, Alan; Harris, Adrian L

    2015-01-01

    Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. PMID:25700172

  8. Cellulose Digestion and Metabolism Induced Biocatalytic Transitions in Anaerobic Microbial Ecosystems

    PubMed Central

    Yamazawa, Akira; Iikura, Tomohiro; Morioka, Yusuke; Shino, Amiu; Ogata, Yoshiyuki; Date, Yasuhiro; Kikuchi, Jun

    2013-01-01

    Anaerobic digestion of highly polymerized biomass by microbial communities present in diverse microbial ecosystems is an indispensable metabolic process for biogeochemical cycling in nature and for industrial activities required to maintain a sustainable society. Therefore, the evaluation of the complicated microbial metabolomics presents a significant challenge. We here describe a comprehensive strategy for characterizing the degradation of highly crystallized bacterial cellulose (BC) that is accompanied by metabolite production for identifying the responsible biocatalysts, including microorganisms and their metabolic functions. To this end, we employed two-dimensional solid- and one-dimensional solution-state nuclear magnetic resonance (NMR) profiling combined with a metagenomic approach using stable isotope labeling. The key components of biocatalytic reactions determined using a metagenomic approach were correlated with cellulose degradation and metabolic products. The results indicate that BC degradation was mediated by cellulases that contain carbohydrate-binding modules and that belong to structural type A. The degradation reactions induced the metabolic dynamics of the microbial community and produced organic compounds, such as acetic acid and propionic acid, mainly metabolized by clostridial species. This combinatorial, functional and structural metagenomic approach is useful for the comprehensive characterization of biomass degradation, metabolic dynamics and their key components in diverse ecosystems. PMID:24958386

  9. Thermal sensation and thermophysiological responses to metabolic step-changes

    NASA Astrophysics Data System (ADS)

    Goto, T.; Toftum, J.; de Dear, R.; Fanger, P. O.

    2006-05-01

    This study investigated the effect on thermal perception and thermophysiological variables of controlled metabolic excursions of various intensities and durations. Twenty-four subjects were alternately seated on a chair or exercised by walking on a treadmill at a temperature predicted to be neutral at sedentary activity. In a second experimental series, subjects alternated between rest and exercise as well as between exercise at different intensities at two temperature levels. Measurements comprised skin and oesophageal temperatures, heart rate and subjective responses. Thermal sensation started to rise or decline immediately (within 1 min) after a change of activity, which means that even moderate activity changes of short duration affect thermal perceptions of humans. After approximately 15 20 min under constant activity, subjective thermal responses approximated the steady-state response. The sensitivity of thermal sensation to changes in core temperature was higher for activity down-steps than for up-steps. A model was proposed that estimates transient thermal sensation after metabolic step-changes. Based on predictions by the model, weighting factors were suggested to estimate a representative average metabolic rate with varying activity levels, e.g. for the prediction of thermal sensation by steady-state comfort models. The activity during the most recent 5 min should be weighted 65%, during the prior 10 5 min 25% and during the prior 20 10 min 10%.

  10. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    PubMed

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-09-01

    Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by

  11. Role of Protein Farnesylation in Burn-Induced Metabolic Derangements and Insulin Resistance in Mouse Skeletal Muscle

    PubMed Central

    Tanaka, Tomokazu; Kramer, Joshua; Yu, Yong-Ming; Fischman, Alan J.; Martyn, J. A. Jeevendra; Tompkins, Ronald G.; Kaneki, Masao

    2015-01-01

    Objective Metabolic derangements, including insulin resistance and hyperlactatemia, are a major complication of major trauma (e.g., burn injury) and affect the prognosis of burn patients. Protein farnesylation, a posttranslational lipid modification of cysteine residues, has been emerging as a potential component of inflammatory response in sepsis. However, farnesylation has not yet been studied in major trauma. To study a role of farnesylation in burn-induced metabolic aberration, we examined the effects of farnesyltransferase (FTase) inhibitor, FTI-277, on burn-induced insulin resistance and metabolic alterations in mouse skeletal muscle. Methods A full thickness burn (30% total body surface area) was produced under anesthesia in male C57BL/6 mice at 8 weeks of age. After the mice were treated with FTI-277 (5 mg/kg/day, IP) or vehicle for 3 days, muscle insulin signaling, metabolic alterations and inflammatory gene expression were evaluated. Results Burn increased FTase expression and farnesylated proteins in mouse muscle compared with sham-burn at 3 days after burn. Simultaneously, insulin-stimulated phosphorylation of insulin receptor (IR), insulin receptor substrate (IRS)-1, Akt and GSK-3β was decreased. Protein expression of PTP-1B (a negative regulator of IR-IRS-1 signaling), PTEN (a negative regulator of Akt-mediated signaling), protein degradation and lactate release by muscle, and plasma lactate levels were increased by burn. Burn-induced impaired insulin signaling and metabolic dysfunction were associated with increased inflammatory gene expression. These burn-induced alterations were reversed or ameliorated by FTI-277. Conclusions Our data demonstrate that burn increased FTase expression and protein farnesylation along with insulin resistance, metabolic alterations and inflammatory response in mouse skeletal muscle, all of which were prevented by FTI-277 treatment. These results indicate that increased protein farnesylation plays a pivotal role in burn-induced

  12. Disrupted Tryptophan Metabolism Induced Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy.

    PubMed

    Gao, Rong; Kan, Ming-qiang; Wang, Shi-gang; Yang, Run-hua; Zhang, Shao-gang

    2016-04-01

    Sepsis-associated encephalopathy (SAE) is a common complication in critically ill patients and is associated with a poor prognosis. However, the precise mechanisms underlying sepsis-induced cognitive impairment remain largely to be elucidated. The aim of the present study was to investigate whether indoleamine 2, 3-dioxygenase (IDO) activation-mediated neurotoxicity is involved in the pathophysiology of sepsis-induced cognitive impairment. Sepsis was induced by cecal ligation/perforation (CLP). The animals were randomly divided into the following five groups: Sham + vehicle group; Sham + 1-methyl-D, L-tryptophan group; Sham + L-Kynurenine group; CLP + vehicle group; or CLP + 1-methyl-D, L-tryptophan group. The survival rate was estimated by the Kaplan-Meier method. Behavioral tests were performed by the open field and fear conditioning tests at days 13 and 14 after operation. In the present study, we demonstrated that sepsis induced a deficit in hippocampus-dependent cognitive impairment in a mouse model of SAE. Furthermore, a single peripheral kynurenine administration, the metabolic product of IDO, induced a deficit in the cognitive impairment in the sham mice. However, mice treated with IDO inhibitor 1-methyl-D, L-tryptophan were protected from sepsis-induced cognitive impairment. In conclusion, our study implicates IDO-dependent neurotoxic kynurenine metabolism as a critical factor responsible for the sepsis-induced cognitive impairment and a potential novel target for the treatment of SAE. PMID:26508338

  13. Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses.

    PubMed

    Webb, Tonya J; Carey, Gregory B; East, James E; Sun, Wenji; Bollino, Dominique R; Kimball, Amy S; Brutkiewicz, Randy R

    2016-08-01

    Natural killer T (NKT) cells play a critical role in the host's innate immune response. CD1d-mediated presentation of glycolipid antigens to NKT cells has been established; however, the mechanisms by which NKT cells recognize infected or cancerous cells remain unclear. 5(')-AMP activated protein kinase (AMPK) is a master regulator of lipogenic pathways. We hypothesized that activation of AMPK during infection and malignancy could alter the repertoire of antigens presented by CD1d and serve as a danger signal to NKT cells. In this study, we examined the effect of alterations in metabolism on CD1d-mediated antigen presentation to NKT cells and found that an infection with lymphocytic choriomeningitis virus rapidly increased CD1d-mediated antigen presentation. Hypoxia inducible factors (HIF) enhance T-cell effector functions during infection, therefore antigen presenting cells pretreated with pharmacological agents that inhibit glycolysis, induce HIF and activate AMPK were assessed for their ability to induce NKT-cell responses. Pretreatment with 2-deoxyglucose, cobalt chloride, AICAR and metformin significantly enhanced CD1d-mediated NKT-cell activation. In addition, NKT cells preferentially respond to malignant B cells and B-cell lymphomas express HIF-1α. These data suggest that targeting cellular metabolism may serve as a novel means of inducing innate immune responses. PMID:27297969

  14. Fumarate induces redox-dependent senescence by modifying glutathione metabolism

    PubMed Central

    Zheng, Liang; Cardaci, Simone; Jerby, Livnat; MacKenzie, Elaine D.; Sciacovelli, Marco; Johnson, T. Isaac; Gaude, Edoardo; King, Ayala; Leach, Joshua D. G.; Edrada-Ebel, RuAngelie; Hedley, Ann; Morrice, Nicholas A.; Kalna, Gabriela; Blyth, Karen; Ruppin, Eytan; Frezza, Christian; Gottlieb, Eyal

    2015-01-01

    Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers. PMID:25613188

  15. Comparative Proteomics Provides Insights into Metabolic Responses in Rat Liver to Isolated Soy and Meat Proteins.

    PubMed

    Song, Shangxin; Hooiveld, Guido J; Zhang, Wei; Li, Mengjie; Zhao, Fan; Zhu, Jing; Xu, Xinglian; Muller, Michael; Li, Chunbao; Zhou, Guanghong

    2016-04-01

    It has been reported that isolated dietary soy and meat proteins have distinct effects on physiology and liver gene expression, but the impact on protein expression responses are unknown. Because these may differ from gene expression responses, we investigated dietary protein-induced changes in liver proteome. Rats were fed for 1 week semisynthetic diets that differed only regarding protein source; casein (reference) was fully replaced by isolated soy, chicken, fish, or pork protein. Changes in liver proteome were measured by iTRAQ labeling and LC-ESI-MS/MS. A robust set totaling 1437 unique proteins was identified and subjected to differential protein analysis and biological interpretation. Compared with casein, all other protein sources reduced the abundance of proteins involved in fatty acid metabolism and Pparα signaling pathway. All dietary proteins, except chicken, increased oxidoreductive transformation reactions but reduced energy and essential amino acid metabolic pathways. Only soy protein increased the metabolism of sulfur-containing and nonessential amino acids. Soy and fish proteins increased translation and mRNA processing, whereas only chicken protein increased TCA cycle but reduced immune responses. These findings were partially in line with previously reported transcriptome results. This study further shows the distinct effects of soy and meat proteins on liver metabolism in rats. PMID:26886706

  16. IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism.

    PubMed

    Izquierdo-Garcia, Jose L; Viswanath, Pavithra; Eriksson, Pia; Cai, Larry; Radoul, Marina; Chaumeil, Myriam M; Blough, Michael; Luchman, H Artee; Weiss, Samuel; Cairncross, J Gregory; Phillips, Joanna J; Pieper, Russell O; Ronen, Sabrina M

    2015-08-01

    Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared with cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3, and levels of hypoxia inducible factor-1α. PDH activity was monitored in these cells by hyperpolarized (13)C-magnetic resonance spectroscopy ((13)C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-(13)C-pyruvate to 5-(13)C-glutamate, relative to cells expressing wild-type IDH1. (13)C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-(13)C-glutamate in IDH1 mutant cells. Furthermore, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism, which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications. PMID:26045167

  17. Bone metabolism induced by denture insertion in positron emission tomography.

    PubMed

    Suenaga, H; Chen, J; Yamaguchi, K; Sugazaki, M; Li, W; Swain, M; Li, Q; Sasaki, K

    2016-03-01

    18F-fluoride positron emission tomogra-phy (PET) can identify subtle functional variation prior to the major structural change detectable by X-ray. This study aims to investigate the mechanobiological bone reaction around the abutment tooth and in the residual ridge, induced by insertion of removable partial denture (RPD) within two different groups of patients: patients without denture experience (Group 1) and patients with denture experience before (Group 2), using 18F-fluoride PET imaging technique. 18F-fluoride PET/computerised tomography (CT) scan was performed to examine the bone metabolic change in mandible before and after the RPD treatment. Region of interests (ROIs) were placed in alveolar bone around abutment tooth and in residual bone beneath the RPD. Standardised uptake value (SUV), reflecting the accumulation of 18F-fluoride, was measured for each ROI. In all subjects of Group 1, SUVs after insertion were higher than before in both alveolar bone and residual bone, while there was less significant change in SUV in subjects of Group 2. This study demonstrated using longitudinal 18F-fluoride PET scans to effectively examine the bone metabolic change in mandible induced by occlusal loading after RPD insertion. Using this technique, within the six subjects in this study, it was shown that bone metabolism around abutment tooth and residual ridge increased after RPD insertion in case of first-time denture user, while there was no big change in the patient with experience of denture before. This study revealed the effectiveness of applying PET to evaluate bone metabolic activity as mechanobiolo-gical reaction. PMID:26431672

  18. Panorganismal metabolic response modeling of an experimental Echinostoma caproni infection in the mouse.

    PubMed

    Saric, Jasmina; Li, Jia V; Wang, Yulan; Keiser, Jennifer; Veselkov, Kirill; Dirnhofer, Stephan; Yap, Ivan K S; Nicholson, Jeremy K; Holmes, Elaine; Utzinger, Jürg

    2009-08-01

    Metabolic profiling of host tissues and biofluids during parasitic infections can reveal new biomarker information and aid the elucidation of mechanisms of disease. The multicompartmental metabolic effects of an experimental Echinostoma caproni infection have been characterized in 12 outbred female mice infected orally with 30 E. caproni metacercariae each, using a further 12 uninfected animals as a control group. Mice were killed 36 days postinfection and brain, intestine (colon, ileum, jejeunum), kidney, liver, and spleen were removed. Metabolic profiles of tissue samples were measured using high-resolution magic angle spinning (1)H NMR spectroscopy and biofluids measured by applying conventional (1)H NMR spectroscopy. Spectral data were analyzed via principal component analysis, partial least-squares-derived methods and hierarchical projection analyses. Infection-induced metabolic changes in the tissues were correlated with altered metabolite concentrations in the biofluids (urine, plasma, fecal water) using hierarchical modeling and correlation analyses. Metabolic descriptors of infection were identified in liver, renal cortex, intestinal tissues but not in spleen, brain or renal medulla. The main physiological change observed in the mouse was malabsorption in the small intestine, which was evidenced by decreased levels of various amino acids in the ileum, for example, alanine, taurine, glutamine, and branched chain amino acids. Furthermore, altered gut microbial activity or composition was reflected by increased levels of trimethylamine in the colon. Our modeling approach facilitated in-depth appraisal of the covariation of the metabolic profiles of different biological matrices and found that urine and plasma most closely reflected changes in ileal compartments. In conclusion, an E. caproni infection not only results in direct localized (ileum and jejenum) effects, but also causes remote metabolic changes (colon and several peripheral organs), and therefore

  19. Odorant Metabolism Catalyzed by Olfactory Mucosal Enzymes Influences Peripheral Olfactory Responses in Rats

    PubMed Central

    Thiebaud, Nicolas; Veloso Da Silva, Stéphanie; Jakob, Ingrid; Sicard, Gilles; Chevalier, Joëlle; Ménétrier, Franck; Berdeaux, Olivier; Artur, Yves; Heydel, Jean-Marie; Le Bon, Anne-Marie

    2013-01-01

    A large set of xenobiotic-metabolizing enzymes (XMEs), such as the cytochrome P450 monooxygenases (CYPs), esterases and transferases, are highly expressed in mammalian olfactory mucosa (OM). These enzymes are known to catalyze the biotransformation of exogenous compounds to facilitate elimination. However, the functions of these enzymes in the olfactory epithelium are not clearly understood. In addition to protecting against inhaled toxic compounds, these enzymes could also metabolize odorant molecules, and thus modify their stimulating properties or inactivate them. In the present study, we investigated the in vitro biotransformation of odorant molecules in the rat OM and assessed the impact of this metabolism on peripheral olfactory responses. Rat OM was found to efficiently metabolize quinoline, coumarin and isoamyl acetate. Quinoline and coumarin are metabolized by CYPs whereas isoamyl acetate is hydrolyzed by carboxylesterases. Electro-olfactogram (EOG) recordings revealed that the hydroxylated metabolites derived from these odorants elicited lower olfactory response amplitudes than the parent molecules. We also observed that glucurono-conjugated derivatives induced no olfactory signal. Furthermore, we demonstrated that the local application of a CYP inhibitor on rat olfactory epithelium increased EOG responses elicited by quinoline and coumarin. Similarly, the application of a carboxylesterase inhibitor increased the EOG response elicited by isoamyl acetate. This increase in EOG amplitude provoked by XME inhibitors is likely due to enhanced olfactory sensory neuron activation in response to odorant accumulation. Taken together, these findings strongly suggest that biotransformation of odorant molecules by enzymes localized to the olfactory mucosa may change the odorant’s stimulating properties and may facilitate the clearance of odorants to avoid receptor saturation. PMID:23555703

  20. Carotid body chemosensory excitation induced by nitric oxide: involvement of oxidative metabolism.

    PubMed

    Mosqueira, Matias; Iturriaga, Rodrigo

    2002-08-01

    Nitric oxide (NO) produces a dual effect on carotid body (CB) oxygen chemoreception. At low concentration, NO inhibits chemosensory response to hypoxia, while in normoxia, medium and high [NO] increases the frequency of carotid chemosensory discharges (f(x)). Since NO and peroxynitrite inhibit mitochondrial respiration, it is plausible that the NO-induced excitation may depend on the mitochondrial oxidative metabolism. To test this hypothesis, we studied the effects of oligomycin, FCCP and antimycin A that produce selective blockade of hypoxic and NaCN-induced chemosensory responses, leaving nicotinic response less affected. CBs excised from pentobarbitone-anaesthetised cats were perfused in vitro with Tyrode (P(O(2)) approximately 125 Torr, pH 7.40 at 38 degrees C). Hypoxia (P(O(2)) approximately equal 30 Torr), NaCN and nicotine (1-100 microg) and S-nitroso-N-acetylpenicillamide (SNAP, 300-600 microg) increased f(x). Oligomycin (12.5-25 microg), antimycin A (10 microg) and FCCP (5 microM) transiently increased f(x). Subsequently, chemosensory responses to hypoxia, NaCN and SNAP were reduced or abolished, while the response to nicotine was less affected. The electron donor system tetramethyl-p-phenylene diamide and ascorbate that bypasses the electron chain blockade produced by antimycin A, restores the excitatory responses to NaCN and SNAP. Present results suggest that the chemoexcitatory effect of NO depends on the integrity of mitochondrial metabolism. PMID:12126919

  1. Rapid flow-induced responses in endothelial cells

    NASA Technical Reports Server (NTRS)

    Stamatas, G. N.; McIntire, L. V.

    2001-01-01

    Endothelial cells alter their morphology, growth rate, and metabolism in response to fluid shear stress. To study rapid flow-induced responses in the 3D endothelial cell morphology and calcium distribution, coupled fluorescence microscopy with optical sectioning, digital imaging, and numerical deconvolution techniques have been utilized. Results demonstrate that within the first minutes of flow application nuclear calcium is increasing. In the same time frame whole cell height and nuclear height are reduced by about 1 microm. Whole cell height changes may facilitate reduction of shear stress gradients on the luminal surface, whereas nuclear structural changes may be important for modulating endothelial growth rate and metabolism. To study the role of the cytoskeleton in these responses, endothelial cells have been treated with specific disrupters (acrylamide, cytochalasin D, and colchicine) of each of the cytoskeleton elements (intermediate filaments, microfilaments, and microtubules, respectively). None of these compounds had any effect on the shear-induced calcium response. Cytochalasin D and acrylamide did not affect the shear-induced nuclear morphology changes. Colchicine, however, completely abrogated the response, indicating that microtubules may be implicated in force transmission from the plasma membrane to the nucleus. A pedagogical model based on tensegrity theory principles is presented that is consistent with the results on the 3D endothelial morphology.

  2. Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition

    PubMed Central

    Jiang, Lei; Xiao, Ling; Sugiura, Hidekazu; Huang, Xiumei; Ali, Aktar; Kuro-o, Makoto; Deberardinis, Ralph J.; Boothman, David A.

    2014-01-01

    Metastatic progression, including extravasation and micro-metastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1) induced Epithelial-to-Mesenchymal Transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Over-expressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knock-down was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis. PMID:25284588

  3. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats.

    PubMed

    Miller, Desinia B; Snow, Samantha J; Schladweiler, Mette C; Richards, Judy E; Ghio, Andrew J; Ledbetter, Allen D; Kodavanti, Urmila P

    2016-04-01

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway. PMID:26732886

  4. Shear stress induced stimulation of mammalian cell metabolism

    NASA Technical Reports Server (NTRS)

    Mcintire, L. V.; Frangos, J. A.; Eskin, S. G.

    1988-01-01

    A flow apparatus was developed for the study of the metabolic response of anchorage dependent cells to a wide range of steady and pulsatile shear stresses under well controlled conditions. Human umbilical vein endothelial cell monolayers were subjected to steady shear stresses of up to 24 dynes/sq cm, and the production of prostacyclin was determined. The onset of flow led to a burst in prostacyclin production which decayed to a long term steady state rate (SSR). The SSR of cells exposed to flow was greater than the basal release level, and increased linearly with increasing shear stress. It is demonstrated that shear stresses in certain ranges may not be detrimental to mammalian cell metabolism. In fact, throughout the range of shear stresses studied, metabolite production is maximized by maximizing shear stress.

  5. Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease

    PubMed Central

    Tsedensodnom, Orkhontuya; Vacaru, Ana M.; Howarth, Deanna L.; Yin, Chunyue; Sadler, Kirsten C.

    2013-01-01

    SUMMARY Secretory pathway dysfunction and lipid accumulation (steatosis) are the two most common responses of hepatocytes to ethanol exposure and are major factors in the pathophysiology of alcoholic liver disease (ALD). However, the mechanisms by which ethanol elicits these cellular responses are not fully understood. Recent data indicates that activation of the unfolded protein response (UPR) in response to secretory pathway dysfunction can cause steatosis. Here, we examined the relationship between alcohol metabolism, oxidative stress, secretory pathway stress and steatosis using zebrafish larvae. We found that ethanol was immediately internalized and metabolized by larvae, such that the internal ethanol concentration in 4-day-old larvae equilibrated to 160 mM after 1 hour of exposure to 350 mM ethanol, with an average ethanol metabolism rate of 56 μmol/larva/hour over 32 hours. Blocking alcohol dehydrogenase 1 (Adh1) and cytochrome P450 2E1 (Cyp2e1), the major enzymes that metabolize ethanol, prevented alcohol-induced steatosis and reduced induction of the UPR in the liver. Thus, we conclude that ethanol metabolism causes ALD in zebrafish. Oxidative stress generated by Cyp2e1-mediated ethanol metabolism is proposed to be a major culprit in ALD pathology. We found that production of reactive oxygen species (ROS) increased in larvae exposed to ethanol, whereas inhibition of the zebrafish CYP2E1 homolog or administration of antioxidants reduced ROS levels. Importantly, these treatments also blocked ethanol-induced steatosis and reduced UPR activation, whereas hydrogen peroxide (H2O2) acted as a pro-oxidant that synergized with low doses of ethanol to induce the UPR. Collectively, these data demonstrate that ethanol metabolism and oxidative stress are conserved mechanisms required for the development of steatosis and hepatic dysfunction in ALD, and that these processes contribute to ethanol-induced UPR activation and secretory pathway stress in hepatocytes. PMID

  6. Green and Black Cardamom in a Diet-Induced Rat Model of Metabolic Syndrome.

    PubMed

    Bhaswant, Maharshi; Poudyal, Hemant; Mathai, Michael L; Ward, Leigh C; Mouatt, Peter; Brown, Lindsay

    2015-09-01

    Both black (B) and green (G) cardamom are used as flavours during food preparation. This study investigated the responses to B and G in a diet-induced rat model of human metabolic syndrome. Male Wistar rats were fed either a corn starch-rich diet (C) or a high-carbohydrate, high-fat diet with increased simple sugars along with saturated and trans fats (H) for 16 weeks. H rats showed signs of metabolic syndrome leading to visceral obesity with hypertension, glucose intolerance, cardiovascular remodelling and nonalcoholic fatty liver disease. Food was supplemented with 3% dried B or G for the final eight weeks only. The major volatile components were the closely related terpenes, 1,8-cineole in B and α-terpinyl acetate in G. HB (high-carbohydrate, high-fat + black cardamom) rats showed marked reversal of diet-induced changes, with decreased visceral adiposity, total body fat mass, systolic blood pressure and plasma triglycerides, and structure and function of the heart and liver. In contrast, HG (high-carbohydrate, high-fat + green cardamom) rats increased visceral adiposity and total body fat mass, and increased heart and liver damage, without consistent improvement in the signs of metabolic syndrome. These results suggest that black cardamom is more effective in reversing the signs of metabolic syndrome than green cardamom. PMID:26378573

  7. Green and Black Cardamom in a Diet-Induced Rat Model of Metabolic Syndrome

    PubMed Central

    Bhaswant, Maharshi; Poudyal, Hemant; Mathai, Michael L.; Ward, Leigh C.; Mouatt, Peter; Brown, Lindsay

    2015-01-01

    Both black (B) and green (G) cardamom are used as flavours during food preparation. This study investigated the responses to B and G in a diet-induced rat model of human metabolic syndrome. Male Wistar rats were fed either a corn starch-rich diet (C) or a high-carbohydrate, high-fat diet with increased simple sugars along with saturated and trans fats (H) for 16 weeks. H rats showed signs of metabolic syndrome leading to visceral obesity with hypertension, glucose intolerance, cardiovascular remodelling and nonalcoholic fatty liver disease. Food was supplemented with 3% dried B or G for the final eight weeks only. The major volatile components were the closely related terpenes, 1,8-cineole in B and α-terpinyl acetate in G. HB (high-carbohydrate, high-fat + black cardamom) rats showed marked reversal of diet-induced changes, with decreased visceral adiposity, total body fat mass, systolic blood pressure and plasma triglycerides, and structure and function of the heart and liver. In contrast, HG (high-carbohydrate, high-fat + green cardamom) rats increased visceral adiposity and total body fat mass, and increased heart and liver damage, without consistent improvement in the signs of metabolic syndrome. These results suggest that black cardamom is more effective in reversing the signs of metabolic syndrome than green cardamom. PMID:26378573

  8. Dynamics of ceramide generation and metabolism in response to fenretinide--Diversity within and among leukemia.

    PubMed

    Morad, Samy A F; Davis, Traci S; Kester, Mark; Loughran, Thomas P; Cabot, Myles C

    2015-10-01

    Fenretinide, N-(4-hydroxyphenyl)retinamide, (4-HPR), a synthetic retinoid, owes its cancer-toxic effects in part to the generation of ceramide, a potent tumor-suppressing sphingolipid. As such, 4-HPR has garnered considerable interest as a chemotherapeutic. Cancer cells, however, via various metabolic routes, inactivate ceramide, and this can limit 4-HPR efficacy. As relatively little is known regarding 4-HPR-induced ceramide management in acute myelogeneous leukemia (AML), we undertook the present study to evaluate the impact of 4-HPR on ceramide production, metabolism, and cytotoxicity. In KG-1, HL-60, and HL-60/VCR (multidrug resistant) human leukemia cells, 4-HPR induced 15-, 2-, and 20-fold increases in ceramide (measured using [3H]palmitic acid), respectively. By use of specific inhibitors we show that ceramide was produced by sphingomyelinase and de novo pathways in response to 4-HPR exposure. HL-60/VCR cells metabolized ceramide to glucosylceramide (GC). 4-HPR exposure (1.25-10 μM) reduced viability in all cell lines, with approximate IC50's ranging from 1 to 8.0 μM. Reactive oxygen species (ROS) were generated in response to 4-HPR treatment, and the concomitant cytotoxicity was reversed by addition of vitamin E. 4-HPR was not cytotoxic nor did it elicit ceramide formation in K562, a chronic myeloid leukemia cell line; however, K562 cells were sensitive to a cell-deliverable form of ceramide, C6-ceramide. Treatment of Molt-3, an acute lymphoblastic leukemia cell line, with 4-HPR revealed moderate ceramide production (5-fold over control), robust conversion of ceramide to GC and sphingomyelin, and resistance to 4-HPR and C6-ceramide. In conclusion, this work demonstrates diversity within and among leukemia in 4-HPR sensitivity and ceramide generation and subsequent metabolism. As such, knowledge of these metabolic pathways can provide guidance for enhancing ceramide-driven effects of 4-HPR in treatment of leukemia. PMID:26220867

  9. Metabolomics reveals insect metabolic responses associated with fungal infection.

    PubMed

    Xu, Yong-Jiang; Luo, Feifei; Gao, Qiang; Shang, Yanfang; Wang, Chengshu

    2015-06-01

    The interactions between insects and pathogenic fungi are complex. We employed metabolomic techniques to profile insect metabolic dynamics upon infection by the pathogenic fungus Beauveria bassiana. Silkworm larvae were infected with fungal spores and microscopic observations demonstrated that the exhaustion of insect hemocytes was coupled with fungal propagation in the insect body cavity. Metabolomic analyses revealed that fungal infection could significantly alter insect energy and nutrient metabolisms as well as the immune defense responses, including the upregulation of carbohydrates, amino acids, fatty acids, and lipids, but the downregulation of eicosanoids and amines. The insect antifeedant effect of the fungal infection was evident with the reduced level of maclurin (a component of mulberry leaves) in infected insects but elevated accumulations in control insects. Insecticidal and cytotoxic mycotoxins like oosporein and beauveriolides were also detected in insects at the later stages of infection. Taken together, the metabolomics data suggest that insect immune responses are energy-cost reactions and the strategies of nutrient deprivation, inhibition of host immune responses, and toxin production would be jointly employed by the fungus to kill insects. The data obtained in this study will facilitate future functional studies of genes and pathways associated with insect-fungus interactions. PMID:25895944

  10. Sex differences in metabolic and adipose tissue responses to juvenile-onset obesity in sheep.

    PubMed

    Bloor, Ian D; Sébert, Sylvain P; Saroha, Vivek; Gardner, David S; Keisler, Duane H; Budge, Helen; Symonds, Michael E; Mahajan, Ravi P

    2013-10-01

    Sex is a major factor determining adipose tissue distribution and the subsequent adverse effects of obesity-related disease including type 2 diabetes. The role of gender on juvenile obesity and the accompanying metabolic and inflammatory responses is not well established. Using an ovine model of juvenile onset obesity induced by reduced physical activity, we examined the effect of gender on metabolic, circulatory, and related inflammatory and energy-sensing profiles of the major adipose tissue depots. Despite a similar increase in fat mass with obesity between genders, males demonstrated a higher storage capacity of lipids within perirenal-abdominal adipocytes and exhibited raised insulin. In contrast, obese females became hypercortisolemic, a response that was positively correlated with central fat mass. Analysis of gene expression in perirenal-abdominal adipose tissue demonstrated the stimulation of inflammatory markers in males, but not females, with obesity. Obese females displayed increased expression of genes involved in the glucocorticoid axis and energy sensing in perirenal-abdominal, but not omental, adipose tissue, indicating a depot-specific mechanism that may be protective from the adverse effects of metabolic dysfunction and inflammation. In conclusion, young males are at a greater risk than females to the onset of comorbidities associated with juvenile-onset obesity. These sex-specific differences in cortisol and adipose tissue could explain the earlier onset of the metabolic-related diseases in males compared with females after obesity. PMID:23885012

  11. Metabolic response of Clostridium ljungdahlii to oxygen exposure.

    PubMed

    Whitham, Jason M; Tirado-Acevedo, Oscar; Chinn, Mari S; Pawlak, Joel J; Grunden, Amy M

    2015-12-01

    Clostridium ljungdahlii is an important synthesis gas-fermenting bacterium used in the biofuels industry, and a preliminary investigation showed that it has some tolerance to oxygen when cultured in rich mixotrophic medium. Batch cultures not only continue to grow and consume H2, CO, and fructose after 8% O2 exposure, but fermentation product analysis revealed an increase in ethanol concentration and decreased acetate concentration compared to non-oxygen-exposed cultures. In this study, the mechanisms for higher ethanol production and oxygen/reactive oxygen species (ROS) detoxification were identified using a combination of fermentation, transcriptome sequencing (RNA-seq) differential expression, and enzyme activity analyses. The results indicate that the higher ethanol and lower acetate concentrations were due to the carboxylic acid reductase activity of a more highly expressed predicted aldehyde oxidoreductase (CLJU_c24130) and that C. ljungdahlii's primary defense upon oxygen exposure is a predicted rubrerythrin (CLJU_c39340). The metabolic responses of higher ethanol production and oxygen/ROS detoxification were found to be linked by cofactor management and substrate and energy metabolism. This study contributes new insights into the physiology and metabolism of C. ljungdahlii and provides new genetic targets to generate C. ljungdahlii strains that produce more ethanol and are more tolerant to syngas contaminants. PMID:26431975

  12. Gut microbiota dictates the metabolic response of Drosophila to diet

    PubMed Central

    Wong, Adam C.-N.; Dobson, Adam J.; Douglas, Angela E.

    2014-01-01

    Animal nutrition is profoundly influenced by the gut microbiota, but knowledge of the scope and core mechanisms of the underlying animal–microbiota interactions is fragmentary. To investigate the nutritional traits shaped by the gut microbiota of Drosophila, we determined the microbiota-dependent response of multiple metabolic and performance indices to systematically varied diet composition. Diet-dependent differences between Drosophila bearing its unmanipulated microbiota (conventional flies) and experimentally deprived of its microbiota (axenic flies) revealed evidence for: microbial sparing of dietary B vitamins, especially riboflavin, on low-yeast diets; microbial promotion of protein nutrition, particularly in females; and microbiota-mediated suppression of lipid/carbohydrate storage, especially on high sugar diets. The microbiota also sets the relationship between energy storage and body mass, indicative of microbial modulation of the host signaling networks that coordinate metabolism with body size. This analysis identifies the multiple impacts of the microbiota on the metabolism of Drosophila, and demonstrates that the significance of these different interactions varies with diet composition and host sex. PMID:24577449

  13. Metabolic Response of Clostridium ljungdahlii to Oxygen Exposure

    PubMed Central

    Whitham, Jason M.; Tirado-Acevedo, Oscar; Chinn, Mari S.; Pawlak, Joel J.

    2015-01-01

    Clostridium ljungdahlii is an important synthesis gas-fermenting bacterium used in the biofuels industry, and a preliminary investigation showed that it has some tolerance to oxygen when cultured in rich mixotrophic medium. Batch cultures not only continue to grow and consume H2, CO, and fructose after 8% O2 exposure, but fermentation product analysis revealed an increase in ethanol concentration and decreased acetate concentration compared to non-oxygen-exposed cultures. In this study, the mechanisms for higher ethanol production and oxygen/reactive oxygen species (ROS) detoxification were identified using a combination of fermentation, transcriptome sequencing (RNA-seq) differential expression, and enzyme activity analyses. The results indicate that the higher ethanol and lower acetate concentrations were due to the carboxylic acid reductase activity of a more highly expressed predicted aldehyde oxidoreductase (CLJU_c24130) and that C. ljungdahlii's primary defense upon oxygen exposure is a predicted rubrerythrin (CLJU_c39340). The metabolic responses of higher ethanol production and oxygen/ROS detoxification were found to be linked by cofactor management and substrate and energy metabolism. This study contributes new insights into the physiology and metabolism of C. ljungdahlii and provides new genetic targets to generate C. ljungdahlii strains that produce more ethanol and are more tolerant to syngas contaminants. PMID:26431975

  14. Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

    PubMed

    Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun; Gnana-Prakasam, Jaya P; Veeranan-Karmegam, Rajalakshmi; Huang, Lei; Ravishankar, Buvana; Bradley, Jillian; Kvirkvelia, Nino; McMenamin, Malgorzata; Xiao, Wei; Kleven, Daniel; Mellor, Andrew L; Madaio, Michael P; McGaha, Tracy L

    2015-06-15

    Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy. PMID:25980011

  15. Parasitic nematode-induced modulation of body weight and associated metabolic dysfunction in mouse models of obesity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity is associated with a chronic low grade inflammation characterized by high level of pro-inflammatory cytokines and mediators implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been shown to modulate immune-based pathol...

  16. Jasmonate-responsive transcription factors regulating plant secondary metabolism.

    PubMed

    Zhou, Meiliang; Memelink, Johan

    2016-01-01

    Plants produce a large variety of secondary metabolites including alkaloids, glucosinolates, terpenoids and phenylpropanoids. These compounds play key roles in plant-environment interactions and many of them have pharmacological activity in humans. Jasmonates (JAs) are plant hormones which induce biosynthesis of many secondary metabolites. JAs-responsive transcription factors (TFs) that regulate the JAs-induced accumulation of secondary metabolites belong to different families including AP2/ERF, bHLH, MYB and WRKY. Here, we give an overview of the types and functions of TFs that have been identified in JAs-induced secondary metabolite biosynthesis, and highlight their similarities and differences in regulating various biosynthetic pathways. We review major recent developments regarding JAs-responsive TFs mediating secondary metabolite biosynthesis, and provide suggestions for further studies. PMID:26876016

  17. PSR1 Is a Global Transcriptional Regulator of Phosphorus Deficiency Responses and Carbon Storage Metabolism in Chlamydomonas reinhardtii.

    PubMed

    Bajhaiya, Amit K; Dean, Andrew P; Zeef, Leo A H; Webster, Rachel E; Pittman, Jon K

    2016-03-01

    Many eukaryotic microalgae modify their metabolism in response to nutrient stresses such as phosphorus (P) starvation, which substantially induces storage metabolite biosynthesis, but the genetic mechanisms regulating this response are poorly understood. Here, we show that P starvation-induced lipid and starch accumulation is inhibited in a Chlamydomonas reinhardtii mutant lacking the transcription factor Pi Starvation Response1 (PSR1). Transcriptomic analysis identified specific metabolism transcripts that are induced by P starvation but misregulated in the psr1 mutant. These include transcripts for starch and triacylglycerol synthesis but also transcripts for photosynthesis-, redox-, and stress signaling-related proteins. To further examine the role of PSR1 in regulating lipid and starch metabolism, PSR1 complementation lines in the psr1 strain and PSR1 overexpression lines in a cell wall-deficient strain were generated. PSR1 expression in the psr1 lines was shown to be functional due to rescue of the psr1 phenotype. PSR1 overexpression lines exhibited increased starch content and number of starch granules per cell, which correlated with a higher expression of specific starch metabolism genes but reduced neutral lipid content. Furthermore, this phenotype was consistent in the presence and absence of acetate. Together, these results identify a key transcriptional regulator in global metabolism and demonstrate transcriptional engineering in microalgae to modulate starch biosynthesis. PMID:26704642

  18. PSR1 Is a Global Transcriptional Regulator of Phosphorus Deficiency Responses and Carbon Storage Metabolism in Chlamydomonas reinhardtii1[OPEN

    PubMed Central

    Bajhaiya, Amit K.; Dean, Andrew P.; Zeef, Leo A.H.; Webster, Rachel E.; Pittman, Jon K.

    2016-01-01

    Many eukaryotic microalgae modify their metabolism in response to nutrient stresses such as phosphorus (P) starvation, which substantially induces storage metabolite biosynthesis, but the genetic mechanisms regulating this response are poorly understood. Here, we show that P starvation-induced lipid and starch accumulation is inhibited in a Chlamydomonas reinhardtii mutant lacking the transcription factor Pi Starvation Response1 (PSR1). Transcriptomic analysis identified specific metabolism transcripts that are induced by P starvation but misregulated in the psr1 mutant. These include transcripts for starch and triacylglycerol synthesis but also transcripts for photosynthesis-, redox-, and stress signaling-related proteins. To further examine the role of PSR1 in regulating lipid and starch metabolism, PSR1 complementation lines in the psr1 strain and PSR1 overexpression lines in a cell wall-deficient strain were generated. PSR1 expression in the psr1 lines was shown to be functional due to rescue of the psr1 phenotype. PSR1 overexpression lines exhibited increased starch content and number of starch granules per cell, which correlated with a higher expression of specific starch metabolism genes but reduced neutral lipid content. Furthermore, this phenotype was consistent in the presence and absence of acetate. Together, these results identify a key transcriptional regulator in global metabolism and demonstrate transcriptional engineering in microalgae to modulate starch biosynthesis. PMID:26704642

  19. Liposoluble vitamins in Crustacean feed: Metabolic and Histological responses.

    PubMed

    Fernández-Gimenez, Analía Verónica

    2016-05-01

    Vitamins are vital for normal growth and survival of living organisms and they are distributed in feedstuffs in small quantities. This review is focused on the liposoluble vitamins (A, D, E and K) in the diets and metabolic responses of the Argentine penaeoid shrimps Pleoticus muelleri and Artemesia longinaris, distributed along the South American coast line. Growth, survival and histological analyses serve as indicators of the nutritional value derived from vitamin deficiency. Liposoluble vitamins are also related to stress, antioxidant defense and immune response of shrimps. Effective diet for shrimp culture that provide not only macronutrients including protein and lipid but also micronutrients such as vitamins for optimal growth is an ever improving subject. This review may help formulating suitable feeds for shrimps. PMID:27319048

  20. SU-C-303-02: Correlating Metabolic Response to Radiation Therapy with HIF-1alpha Expression

    SciTech Connect

    Campos, D; Peeters, W; Nickel, K; Eliceiri, K; Kimple, R; Van Der Kogel, A; Kissick, M

    2015-06-15

    Purpose: To understand radiation induced alterations in cellular metabolism which could be used to assess treatment or normal tissue response to aid in patient-specific adaptive radiotherapy. This work aims to compare the metabolic response of two head and neck cell lines, one malignant (UM-SCC-22B) and one benign (Normal Oral Keratinocyte), to ionizing radiation. Responses are compared to alterations in HIF-1alpha expression. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Measurements of metabolism and HIF-1alpha expression were taken before and X minutes after a 10 Gy dose of radiation delivered via an orthovoltage x-ray source. In vitro changes in metabolic activity were measured via fluorescence lifetime imaging (FLIM) to assess the mean lifetime of NADH autofluorescence following a dose of 10 Gy. HIF-1alpha expression was measured via immunohistochemical staining of in vitro treated cells and expression was quantified using the FIJI software package. Results: FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways for malignant cells; whereas this benign cell line showed little change in metabolic signature. Immunohistochemical analysis showed significant changes in HIF-1alpha expression in response to 10 Gy of radiation that correlate to metabolic profiles. Conclusion: Radiation induces significant changes in metabolic activity and HIF-1alpha expression. These alterations occur on time scales approximating the duration of common radiation treatments (approximately tens of minutes). Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

  1. Delicate Metabolic Control and Coordinated Stress Response Critically Determine Antifungal Tolerance of Candida albicans Biofilm Persisters

    PubMed Central

    Li, Peng; Alpi, Emanuele; Vizcaino, Juan A.

    2015-01-01

    Candida infection has emerged as a critical health care burden worldwide, owing to the formation of robust biofilms against common antifungals. Recent evidence shows that multidrug-tolerant persisters critically account for biofilm recalcitrance, but their underlying biological mechanisms are poorly understood. Here, we first investigated the phenotypic characteristics of Candida biofilm persisters under consecutive harsh treatments of amphotericin B. The prolonged treatments effectively killed the majority of the cells of biofilms derived from representative strains of Candida albicans, Candida glabrata, and Candida tropicalis but failed to eradicate a small fraction of persisters. Next, we explored the tolerance mechanisms of the persisters through an investigation of the proteomic profiles of C. albicans biofilm persister fractions by liquid chromatography-tandem mass spectrometry. The C. albicans biofilm persisters displayed a specific proteomic signature, with an array of 205 differentially expressed proteins. The crucial enzymes involved in glycolysis, the tricarboxylic acid cycle, and protein synthesis were markedly downregulated, indicating that major metabolic activities are subdued in the persisters. It is noteworthy that certain metabolic pathways, such as the glyoxylate cycle, were able to be activated with significantly increased levels of isocitrate lyase and malate synthase. Moreover, a number of important proteins responsible for Candida growth, virulence, and the stress response were greatly upregulated. Interestingly, the persisters were tolerant to oxidative stress, despite highly induced intracellular superoxide. The current findings suggest that delicate metabolic control and a coordinated stress response may play a crucial role in mediating the survival and antifungal tolerance of Candida biofilm persisters. PMID:26195524

  2. RAGE Regulates the Metabolic and Inflammatory Response to High-Fat Feeding in Mice

    PubMed Central

    Song, Fei; Hurtado del Pozo, Carmen; Rosario, Rosa; Zou, Yu Shan; Ananthakrishnan, Radha; Xu, Xiaoyuan; Patel, Payal R.; Benoit, Vivian M.; Yan, Shi Fang; Li, Huilin; Friedman, Richard A.; Kim, Jason K.; Ramasamy, Ravichandran; Ferrante, Anthony W.; Schmidt, Ann Marie

    2014-01-01

    In mammals, changes in the metabolic state, including obesity, fasting, cold challenge, and high-fat diets (HFDs), activate complex immune responses. In many strains of rodents, HFDs induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for HFD-induced phenotypes. We studied the function of the receptor for advanced glycation end products (RAGE) in the development of phenotypes associated with high-fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. We found that high-fat feeding induced expression of RAGE ligand HMGB1 and carboxymethyllysine-advanced glycation end product epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These findings demonstrate that high-fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention. PMID:24520121

  3. Transcriptional and Metabolic Analysis of Senescence Induced by Preventing Pollination in Maize1[W][OA

    PubMed Central

    Sekhon, Rajandeep S.; Childs, Kevin L.; Santoro, Nicholas; Foster, Cliff E.; Buell, C. Robin; de Leon, Natalia; Kaeppler, Shawn M.

    2012-01-01

    Transcriptional and metabolic changes were evaluated during senescence induced by preventing pollination in the B73 genotype of maize (Zea mays). Accumulation of free glucose and starch and loss of chlorophyll in leaf was manifested early at 12 d after anthesis (DAA), while global transcriptional and phenotypic changes were evident only at 24 DAA. Internodes exhibited major transcriptomic changes only at 30 DAA. Overlaying expression data onto metabolic pathways revealed involvement of many novel pathways, including those involved in cell wall biosynthesis. To investigate the overlap between induced and natural senescence, transcriptional data from induced senescence in maize was compared with that reported for Arabidopsis (Arabidopsis thaliana) undergoing natural and sugar-induced senescence. Notable similarities with natural senescence in Arabidopsis included up-regulation of senescence-associated genes (SAGs), ethylene and jasmonic acid biosynthetic genes, APETALA2, ethylene-responsive element binding protein, and no apical meristem transcription factors. However, differences from natural senescence were highlighted by unaltered expression of a subset of the SAGs, and cytokinin, abscisic acid, and salicylic acid biosynthesis genes. Key genes up-regulated during sugar-induced senescence in Arabidopsis, including a cysteine protease (SAG12) and three flavonoid biosynthesis genes (PRODUCTION OF ANTHOCYANIN PIGMENT1 (PAP1), PAP2, and LEUCOANTHOCYANIDIN DIOXYGENASE), were also induced, suggesting similarities in senescence induced by pollination prevention and sugar application. Coexpression analysis revealed networks involving known senescence-related genes and novel candidates; 82 of these were shared between leaf and internode networks, highlighting similarities in induced senescence in these tissues. Insights from this study will be valuable in systems biology of senescence in maize and other grasses. PMID:22732243

  4. Modular metabolic control analysis of large responses in branched systems--application to aspartate metabolism.

    PubMed

    Ortega, Fernando; Acerenza, Luis

    2011-07-01

    Organisms subject to changing environmental conditions or experimental protocols show complex patterns of responses. The design principles behind these patterns are still poorly understood. Here, modular metabolic control analysis is developed to deal with large changes in branched pathways. Modular aggregation of the system dramatically reduces the number of explicit variables and modulation sites. Thus, the resulting number of control coefficients, which describe system responses, is small. Three properties determine the pattern for large changes in the variables: the values of infinitesimal control coefficients, the effect of large rate changes on the control coefficients and the range of rate changes preserving feasible intermediate concentrations. Importantly, this pattern gives information about the possibility of obtaining large variable changes by changing parameters inside the module, without the need to perform any parameter modulations. The framework is applied to a detailed model of Asp metabolism. The system is aggregated in one supply module, producing Thr from Asp (SM1), and two demand modules, incorporating Thr (DM2) and Ile (DM3) into protein. Their fluxes are: J(1), J(2), and J(3), respectively. The analysis shows similar high infinitesimal control coefficients of J(2) by the rates of SM1 and DM2 (C(v1)(J2) = 0.6 and C(v2)(J2) = 0.7, respectively). In addition, these coefficients present only moderate decreases when the rates of the corresponding modules are increased. However, the range of feasible rate changes in SM1 is narrow. Therefore, for large increases in J(2) to be obtained, DM2 must be modulated. Of the rich network of allosteric interactions present, only two groups of inhibitions generate the control pattern for large responses. PMID:21592306

  5. Soybean Aphid Infestation Induces Changes in Fatty Acid Metabolism in Soybean

    PubMed Central

    Kanobe, Charles; McCarville, Michael T.; O’Neal, Matthew E.; Tylka, Gregory L.; MacIntosh, Gustavo C.

    2015-01-01

    The soybean aphid (Aphis glycines Matsumura) is one of the most important insect pests of soybeans in the North-central region of the US. It has been hypothesized that aphids avoid effective defenses by inhibition of jasmonate-regulated plant responses. Given the role fatty acids play in jasmonate-induced plant defenses, we analyzed the fatty acid profile of soybean leaves and seeds from aphid-infested plants. Aphid infestation reduced levels of polyunsaturated fatty acids in leaves with a concomitant increase in palmitic acid. In seeds, a reduction in polyunsaturated fatty acids was associated with an increase in stearic acid and oleic acid. Soybean plants challenged with the brown stem rot fungus or with soybean cyst nematodes did not present changes in fatty acid levels in leaves or seeds, indicating that the changes induced by aphids are not a general response to pests. One of the polyunsaturated fatty acids, linolenic acid, is the precursor of jasmonate; thus, these changes in fatty acid metabolism may be examples of “metabolic hijacking” by the aphid to avoid the induction of effective defenses. Based on the changes in fatty acid levels observed in seeds and leaves, we hypothesize that aphids potentially induce interference in the fatty acid desaturation pathway, likely reducing FAD2 and FAD6 activity that leads to a reduction in polyunsaturated fatty acids. Our data support the idea that aphids block jasmonate-dependent defenses by reduction of the hormone precursor. PMID:26684003

  6. Genotoxicity induced by a shale oil byproduct in Chinese hamster cells following metabolic activation

    SciTech Connect

    Okinaka, R.T.; Nickols, J.W.; Chen, D.J.; Strniste, G.F.

    1982-01-01

    A process water obtained from a holding tank during the surface retorting of oil shale has been shown to induce a linear dose response of 100 histidine revertants/sub ..mu../1 in the Ames/Salmonella test. The complex mixture has also previously been shown to induce genotoxicity in mammalian cells following activation by near ultraviolet light and natural sunlight. This report focuses on the effects of a particular oil shale retort process water on cultured Chinese hamster cells following metabolic activation by either rat liver homogenate or lethally irradiated but metabolically competent Syrian hamster embryonic cells. Cytotoxic and mutagenic responses induced by the process water and a fractionated sample from it containing the majority of the mutagenic activity (as assessed by the Salmonella test) were measured under conditions designed to optimally measure the mutagenic potency of the promutagen, benzo(a)pyrene. These results suggest a possible discrepancy in the genotoxic potential of this complex mixture when various methods are utilized to measure its potential.

  7. Stress-responsive hydroxycinnamate glycosyltransferase modulates phenylpropanoid metabolism in Populus

    PubMed Central

    Babst, Benjamin A.; Chen, Han-Yi; Wang, Hong-Qiang; Payyavula, Raja S.; Thomas, Tina P.; Harding, Scott A.; Tsai, Chung-Jui

    2014-01-01

    The diversity of phenylpropanoids offers a rich inventory of bioactive chemicals that can be exploited for plant improvement and human health. Recent evidence suggests that glycosylation may play a role in the partitioning of phenylpropanoid precursors for a variety of downstream uses. This work reports the functional characterization of a stress-responsive glycosyltransferase, GT1-316 in Populus. GT1-316 belongs to the UGT84A subfamily of plant glycosyltransferase family 1 and is designated UGT84A17. Recombinant protein analysis showed that UGT84A17 is a hydroxycinnamate glycosyltransferase and able to accept a range of unsubstituted and substituted cinnamic and benzoic acids as substrates in vitro. Overexpression of GT1-316 in transgenic Populus led to plant-wide increases of hydroxycinnamoyl-glucose esters, which were further elevated under N-limiting conditions. Levels of the two most abundant flavonoid glycosides, rutin and kaempferol-3-O-rutinoside, decreased, while levels of other less abundant flavonoid and phenylpropanoid conjugates increased in leaves of the GT1-316-overexpressing plants. Transcript levels of representative phenylpropanoid pathway genes were unchanged in transgenic plants, supporting a glycosylation-mediated redirection of phenylpropanoid carbon flow as opposed to enhanced phenylpropanoid pathway flux. The metabolic response of N-replete transgenic plants overlapped with that of N-stressed wild types, as the majority of phenylpropanoid derivatives significantly affected by GT1-316 overexpression were also significantly changed by N stress in the wild types. These results suggest that UGT84A17 plays an important role in phenylpropanoid metabolism by modulating biosynthesis of hydroxycinnamoyl-glucose esters and their derivatives in response to developmental and environmental cues. PMID:24803501

  8. A clickable glutathione approach for identification of protein glutathionylation in response to glucose metabolism.

    PubMed

    Samarasinghe, Kusal T G; Munkanatta Godage, Dhanushka N P; Zhou, Yani; Ndombera, Fidelis T; Weerapana, Eranthie; Ahn, Young-Hoon

    2016-07-19

    Glucose metabolism and mitochondrial function are closely interconnected with cellular redox-homeostasis. Although glucose starvation, which mimics ischemic conditions or insufficient vascularization, is known to perturb redox-homeostasis, global and individual protein glutathionylation in response to glucose metabolism or mitochondrial activity remains largely unknown. In this report, we use our clickable glutathione approach, which forms clickable glutathione (azido-glutathione) by using a mutant of glutathione synthetase (GS M4), for detection and identification of protein glutathionylation in response to glucose starvation. We found that protein glutathionylation is readily induced in HEK293 cells in response to low glucose concentrations when mitochondrial reactive oxygen species (ROS) are elevated in cells, and glucose is the major determinant for inducing reversible glutathionylation. Proteomic and biochemical analysis identified over 1300 proteins, including SMYD2, PP2Cα, and catalase. We further showed that PP2Cα is glutathionylated at C314 in a C-terminal domain, and PP2Cα C314 glutathionylation disrupts the interaction with mGluR3, an important glutamate receptor associated with synaptic plasticity. PMID:27216279

  9. Food odors trigger an endocrine response that affects food ingestion and metabolism.

    PubMed

    Lushchak, Oleh V; Carlsson, Mikael A; Nässel, Dick R

    2015-08-01

    Food odors stimulate appetite and innate food-seeking behavior in hungry animals. The smell of food also induces salivation and release of gastric acid and insulin. Conversely, sustained odor exposure may induce satiation. We demonstrate novel effects of food odors on food ingestion, metabolism and endocrine signaling in Drosophila melanogaster. Acute exposure to attractive vinegar odor triggers a rapid and transient increase in circulating glucose, and a rapid upregulation of genes encoding the glucagon-like hormone adipokinetic hormone (AKH), four insulin-like peptides (DILPs) and some target genes in peripheral tissues. Sustained exposure to food odors, however, decreases food intake. Hunger-induced strengthening of synaptic signaling from olfactory sensory neurons (OSNs) to brain neurons increases food-seeking behavior, and conversely fed flies display reduced food odor sensitivity and feeding. We show that increasing the strength of OSN signaling chronically by genetic manipulation of local peptide neuromodulation reduces feeding, elevates carbohydrates and diminishes lipids. Furthermore, constitutively strengthened odor sensitivity altered gene transcripts for AKH, DILPs and some of their targets. Thus, we show that food odor can induce a transient anticipatory endocrine response, and that boosted sensitivity to this odor affects food intake, as well as metabolism and hormonal signaling. PMID:25782410

  10. Biological and metabolic response in STS-135 space-flown mouse skin.

    PubMed

    Mao, X W; Pecaut, M J; Stodieck, L S; Ferguson, V L; Bateman, T A; Bouxsein, M L; Gridley, D S

    2014-08-01

    There is evidence that space flight condition-induced biological damage is associated with increased oxidative stress and extracellular matrix (ECM) remodeling. To explore possible mechanisms, changes in gene expression profiles implicated in oxidative stress and in ECM remodeling in mouse skin were examined after space flight. The metabolic effects of space flight in skin tissues were also characterized. Space Shuttle Atlantis (STS-135) was launched at the Kennedy Space Center on a 13-day mission. Female C57BL/6 mice were flown in the STS-135 using animal enclosure modules (AEMs). Within 3-5 h after landing, the mice were euthanized and skin samples were harvested for gene array analysis and metabolic biochemical assays. Many genes responsible for regulating production and metabolism of reactive oxygen species (ROS) were significantly (p < 0.05) altered in the flight group, with fold changes >1.5 compared to AEM control. For ECM profile, several genes encoding matrix and metalloproteinases involved in ECM remodeling were significantly up-/down-regulated following space flight. To characterize the metabolic effects of space flight, global biochemical profiles were evaluated. Of 332 named biochemicals, 19 differed significantly (p < 0.05) between space flight skin samples and AEM ground controls, with 12 up-regulated and 7 down-regulated including altered amino acid, carbohydrate metabolism, cell signaling, and transmethylation pathways. Collectively, the data demonstrated that space flight condition leads to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling. This indicates that astronauts may be at increased risk for pathophysiologic damage or carcinogenesis in cutaneous tissue. PMID:24796731

  11. Metabolic Response of the Cerebral Cortex Following Gentle Sleep Deprivation and Modafinil Administration

    PubMed Central

    Petit, Jean-Marie; Tobler, Irene; Kopp, Caroline; Morgenthaler, Florence; Borbély, Alexander A.; Magistretti, Pierre J.

    2010-01-01

    Study Objectives: The main energy reserve of the brain is glycogen, which is almost exclusively localized in astrocytes. We previously reported that cerebral expression of certain genes related to glycogen metabolism changed following instrumental sleep deprivation in mice. Here, we extended our investigations to another set of genes related to glycogen and glucose metabolism. We also compared the effect of instrumentally and pharmacologically induced prolonged wakefulness, followed (or not) by 3 hours of sleep recovery, on the expression of genes related to brain energy metabolism. Design: Sleep deprivation for 6–7 hours. Setting: Animal sleep research laboratory. Participants: Adults OF1 mice. Interventions: Wakefulness was maintained by “gentle sleep deprivation” method (GSD) or by administration of the wakefulness-promoting drug modafinil (MOD) (200 mg/kg i.p.). Measurements and Results: Levels of mRNAs encoding proteins related to energy metabolism were measured by quantitative real-time PCR in the cerebral cortex. The mRNAs encoding protein targeting to glycogen (PTG) and the glial glucose transporter were significantly increased following both procedures used to prolong wakefulness. Glycogenin mRNA levels were increased only after GSD, while neuronal glucose transporter mRNA only after MOD. These effects were reversed after sleep recovery. A significant enhancement of glycogen synthase activity without any changes in glycogen levels was observed in both conditions. Conclusions: These results indicate the existence of a metabolic adaptation of astrocytes aimed at maintaining brain energy homeostasis during the sleep-wake cycle. Citation: Petit, JM; Tobler I; Kopp C; Morgenthaler F; Borbély AA; Magistretti PJ. Metabolic response of the cerebral cortex following gentle sleep deprivation and modafinil administration. SLEEP 2010;33(7):901–908. PMID:20614850

  12. Sugar metabolism, redox balance and oxidative stress response in the respiratory yeast Kluyveromyces lactis

    PubMed Central

    González-Siso, M Isabel; García-Leiro, Ana; Tarrío, Nuria; Cerdán, M Esperanza

    2009-01-01

    A lot of studies have been carried out on Saccharomyces cerevisiae, an yeast with a predominant fermentative metabolism under aerobic conditions, which allows exploring the complex response induced by oxidative stress. S. cerevisiae is considered a eukaryote model for these studies. We propose Kluyveromyces lactis as a good alternative model to analyse variants in the oxidative stress response, since the respiratory metabolism in this yeast is predominant under aerobic conditions and it shows other important differences with S. cerevisiae in catabolic repression and carbohydrate utilization. The knowledge of oxidative stress response in K. lactis is still a developing field. In this article, we summarize the state of the art derived from experimental approaches and we provide a global vision on the characteristics of the putative K. lactis components of the oxidative stress response pathway, inferred from their sequence homology with the S. cerevisiae counterparts. Since K. lactis is also a well-established alternative host for industrial production of native enzymes and heterologous proteins, relevant differences in the oxidative stress response pathway and their potential in biotechnological uses of this yeast are also reviewed. PMID:19715615

  13. Remodeling of Glucose Metabolism Precedes Pressure Overload -Induced Left Ventricular Hypertrophy: Review of a Hypothesis

    PubMed Central

    Kundu, Bijoy K.; Zhong, Min; Sen, Shiraj; Davogustto, Giovanni; Keller, Susanna R.; Taegtmeyer, Heinrich

    2015-01-01

    When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[18F]-fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pre-treatment with rapamycin (mTOR inhibition) or metformin (enzyme 5′-AMP-activated protein kinase activation ). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH. PMID:25791172

  14. Effects of celecoxib and ibuprofen on metabolic disorders induced by Walker-256 tumor in rats.

    PubMed

    de Souza, Camila Oliveira; Kurauti, Mirian Ayumi; de Fatima Silva, Flaviane; de Morais, Hely; Borba-Murad, Glaucia Regina; de Andrade, Fábio Goulart; de Souza, Helenir Medri

    2015-01-01

    The contribution of anti-inflammatory property of celecoxib in the improvement of metabolic disorders in cancer is unknown. The purpose of this study was to compare the effects of celecoxib and ibuprofen, non-steroidal anti-inflammatory drugs (NSAIDs), on several metabolic changes observed in Walker-256 tumor-bearing rats. The effects of these NSAIDs on the tumor growth were also assessed. Celecoxib or ibuprofen (both at 25 mg/Kg) was administered orally for 12 days, beginning on the day the rats were inoculated with Walker-256 tumor cells. Celecoxib treatment prevented the losses in body mass and mass of retroperitoneal adipose tissue, gastrocnemius, and extensor digitorum longus muscles in tumor-bearing rats. Celecoxib also prevented the rise in blood levels of triacylglycerol, urea, and lactate, the inhibition of peripheral response to insulin and hepatic glycolysis, and tended to attenuate the decrease in the food intake, but had no effect on the reduction of glycemia induced by the tumor. In addition, celecoxib treatment increased the number of Walker-256 cells with signs of apoptosis and the tumor necrosis area and prevented the tumor growth. In contrast, ibuprofen treatment had no effect on metabolic parameters affected by the Walker-256 tumor or tumor growth. It can be concluded that celecoxib, unlike ibuprofen, ameliorated several metabolic changes in rats with Walker-256 tumor due to its anti-tumor effect and not its anti-inflammatory property. PMID:25359170

  15. Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats.

    PubMed

    Li, Da; Tian, Yan-Jie; Guo, Jing; Sun, Wu-Ping; Lun, Yong-Zhi; Guo, Ming; Luo, Ning; Cao, Yu; Cao, Ji-Min; Gong, Xiao-Jie; Zhou, Shi-Sheng

    2013-12-01

    Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine-homocysteine S-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities. PMID:23768418

  16. Interneurons contribute to the hemodynamic/metabolic response to epileptiform discharges.

    PubMed

    Saillet, Sandrine; Quilichini, Pascale P; Ghestem, Antoine; Giusiano, Bernard; Ivanov, Anton I; Hitziger, Sebastian; Vanzetta, Ivo; Bernard, Christophe; Bénar, Christian-G

    2016-03-01

    Interpretation of hemodynamic responses in epilepsy is hampered by an incomplete understanding of the underlying neurovascular coupling, especially the contributions of excitation and inhibition. We made simultaneous multimodal recordings of local field potentials (LFPs), firing of individual neurons, blood flow, and oxygen level in the somatosensory cortex of anesthetized rats. Epileptiform discharges induced by bicuculline injections were used to trigger large local events. LFP and blood flow were robustly coupled, as were LFP and tissue oxygen. In a parametric linear model, LFP and the baseline activities of cerebral blood flow and tissue partial oxygen tension contributed significantly to blood flow and oxygen responses. In an analysis of recordings from 402 neurons, blood flow/tissue oxygen correlated with the discharge of putative interneurons but not of principal cells. Our results show that interneuron activity is important in the vascular and metabolic responses during epileptiform discharges. PMID:26745250

  17. Irradiation Induced Injury Reduces Energy Metabolism in Small Intestine of Tibet Minipigs

    PubMed Central

    Song, Jun; Guo, Kun-Yuan; Wang, Gang; Wu, Qing-Hong; Gu, Wei-Wang

    2013-01-01

    Background The radiation-induced energy metabolism dysfunction related to injury and radiation doses is largely elusive. The purpose of this study is to investigate the early response of energy metabolism in small intestinal tissue and its correlation with pathologic lesion after total body X-ray irradiation (TBI) in Tibet minipigs. Methods and Results 30 Tibet minipigs were assigned into 6 groups including 5 experimental groups and one control group with 6 animals each group. The minipigs in these experimental groups were subjected to a TBI of 2, 5, 8, 11, and 14 Gy, respectively. Small intestine tissues were collected at 24 h following X-ray exposure and analyzed by histology and high performance liquid chromatography (HPLC). DNA contents in this tissue were also examined. Irradiation causes pathologic lesions and mitochondrial abnormalities. The Deoxyribonucleic acid (DNA) content-corrected and uncorrected adenosine-triphosphate (ATP) and total adenine nucleotides (TAN) were significantly reduced in a dose-dependent manner by 2–8 Gy exposure, and no further reduction was observed over 8 Gy. Conclusion TBI induced injury is highly dependent on the irradiation dosage in small intestine and inversely correlates with the energy metabolism, with its reduction potentially indicating the severity of injury. PMID:23527059

  18. Oxidative stress and metabolic responses to copper in freshwater- and seawater-acclimated killifish, Fundulus heteroclitus.

    PubMed

    Ransberry, Victoria E; Morash, Andrea J; Blewett, Tamzin A; Wood, Chris M; McClelland, Grant B

    2015-04-01

    In freshwater (FW), many of the main mechanisms of copper (Cu) toxicity have been characterized; however, toxicity mechanisms in seawater (SW) are less well understood. We investigated the effects of salinity on Cu-induced oxidative stress and metabolic responses in adult killifish, Fundulus heteroclitus. We exposed FW and SW-acclimated killifish to either low Cu (LC, 50 μg/L) or high Cu (HC, 200 μg/L) for 96 h and compared them to controls (CTRL) under the same salinities without added Cu. Cu exerted minimal influence on tissue ion levels in either FW or SW. Salinity generally protected against Cu bioaccumulation in the gills and liver, but not in the carcass. Hematocrit (Hct) and hemoglobin (Hb) levels were increased by LC and HC in both FW and SW, and blood lactate was reduced in FW-killifish exposed to LC and HC. Rates of oxygen consumption were similar across treatments. Salinity reduced Cu load in gill, liver and intestine at LC but only in the gills at HC. In general, Cu increased gill, liver, and intestine catalase (CAT) activity, while superoxide dismutase (SOD) either decreased or remained unchanged depending on tissue-type. These changes did not directly correlate with levels of protein carbonyls, used as an index of oxidative stress. Cu-induced changes in carbohydrate metabolic enzymes were low across tissues and the effect of salinity was variable. Thus, while salinity clearly protects against Cu bioaccumulation in some tissues, it is unclear whether salinity protects against Cu-induced oxidative stress and metabolic responses. PMID:25731683

  19. Cell Wall Metabolism in Response to Abiotic Stress

    PubMed Central

    Gall, Hyacinthe Le; Philippe, Florian; Domon, Jean-Marc; Gillet, Françoise; Pelloux, Jérôme; Rayon, Catherine

    2015-01-01

    This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic), transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i) an increased level in xyloglucan endotransglucosylase/hydrolase (XTH) and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii) an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions. PMID:27135320

  20. Cell Wall Metabolism in Response to Abiotic Stress.

    PubMed

    Le Gall, Hyacinthe; Philippe, Florian; Domon, Jean-Marc; Gillet, Françoise; Pelloux, Jérôme; Rayon, Catherine

    2015-01-01

    This review focuses on the responses of the plant cell wall to several abiotic stresses including drought, flooding, heat, cold, salt, heavy metals, light, and air pollutants. The effects of stress on cell wall metabolism are discussed at the physiological (morphogenic), transcriptomic, proteomic and biochemical levels. The analysis of a large set of data shows that the plant response is highly complex. The overall effects of most abiotic stress are often dependent on the plant species, the genotype, the age of the plant, the timing of the stress application, and the intensity of this stress. This shows the difficulty of identifying a common pattern of stress response in cell wall architecture that could enable adaptation and/or resistance to abiotic stress. However, in most cases, two main mechanisms can be highlighted: (i) an increased level in xyloglucan endotransglucosylase/hydrolase (XTH) and expansin proteins, associated with an increase in the degree of rhamnogalacturonan I branching that maintains cell wall plasticity and (ii) an increased cell wall thickening by reinforcement of the secondary wall with hemicellulose and lignin deposition. Taken together, these results show the need to undertake large-scale analyses, using multidisciplinary approaches, to unravel the consequences of stress on the cell wall. This will help identify the key components that could be targeted to improve biomass production under stress conditions. PMID:27135320

  1. Functional and metabolic properties of alveolar macrophages in response to the gas phase of tobacco smoke.

    PubMed Central

    Drath, D B; Shorey, J M; Huber, G L

    1981-01-01

    The effect of whole tobacco smoke and the gas phase of tobacco smoke on the metabolism and phagocytic ability of alveolar macrophages was monitored over a 30-day exposure period. It was demonstrated that both the gas phase and whole tobacco smoke induced a weight loss in exposed rats. Alveolar macrophage oxygen consumption was markedly increased by both exposure regimens. Superoxide generation was not affected by whole tobacco smoke exposure but was increased in response to the filtered gas phase. Hexose monophosphate shunt activity was not altered by either treatment. When metabolic alterations were seen in response to the separate exposures, they were seen only after a phagocytic challenge to the macrophage and not when the cell was unchallenged. Neither whole tobacco smoke nor the gas phase had any significant effect on the ability of alveolar macrophages to phagocytize a viable challenge of Staphylococcus aureus. Our results suggest that many of the metabolic and functional effects of tobacco smoke on alveolar macrophages can be attributed to the gas-phase component of whole tobacco smoke. PMID:6271676

  2. Functional and metabolic properties of alveolar macrophages in response to the gas phase of tobacco smoke.

    PubMed

    Drath, D B; Shorey, J M; Huber, G L

    1981-10-01

    The effect of whole tobacco smoke and the gas phase of tobacco smoke on the metabolism and phagocytic ability of alveolar macrophages was monitored over a 30-day exposure period. It was demonstrated that both the gas phase and whole tobacco smoke induced a weight loss in exposed rats. Alveolar macrophage oxygen consumption was markedly increased by both exposure regimens. Superoxide generation was not affected by whole tobacco smoke exposure but was increased in response to the filtered gas phase. Hexose monophosphate shunt activity was not altered by either treatment. When metabolic alterations were seen in response to the separate exposures, they were seen only after a phagocytic challenge to the macrophage and not when the cell was unchallenged. Neither whole tobacco smoke nor the gas phase had any significant effect on the ability of alveolar macrophages to phagocytize a viable challenge of Staphylococcus aureus. Our results suggest that many of the metabolic and functional effects of tobacco smoke on alveolar macrophages can be attributed to the gas-phase component of whole tobacco smoke. PMID:6271676

  3. The phosphotransferase system of Lactobacillus casei: regulation of carbon metabolism and connection to cold shock response.

    PubMed

    Monedero, Vicente; Mazé, Alain; Boël, Grégory; Zúñiga, Manuel; Beaufils, Sophie; Hartke, Axel; Deutscher, Josef

    2007-01-01

    Genome sequencing of two different Lactobacillus casei strains (ATCC334 and BL23) is presently going on and preliminary data revealed that this lactic acid bacterium possesses numerous carbohydrate transport systems probably reflecting its capacity to proliferate under varying environmental conditions. Many carbohydrate transporters belong to the phosphoenolpyruvate:sugar phosphotransferase system (PTS), but all different kinds of non-PTS transporters are present as well and their substrates are known in a few cases. In L. casei regulation of carbohydrate transport and carbon metabolism is mainly achieved by PTS proteins. Carbon catabolite repression (CCR) is mediated via several mechanisms, including the major P-Ser-HPr/catabolite control protein A (CcpA)-dependent mechanism. Catabolite response elements, the target sites for the P-Ser-HPr/CcpA complex, precede numerous genes and operons. PTS regulation domain-containing antiterminators and transcription activators are also present in both L. casei strains. Their activity is usually controlled by two PTS-mediated phosphorylation reactions exerting antagonistic effects on the transcription regulators: P~EIIB-dependent phosphorylation regulates induction of the corresponding genes and P~His-HPr-mediated phosphorylation plays a role in CCR. Carbohydrate transport of L. casei is also regulated via inducer exclusion and inducer expulsion. The presence of glucose, fructose, etc. leads to inhibition of the transport or metabolism of less favorable carbon sources (inducer exclusion) or to the export of accumulated non-metabolizable carbon sources (inducer expulsion). While P-Ser-HPr is essential for inducer exclusion of maltose, it is not necessary for the expulsion of accumulated thio-methyl-beta-D-galactopyranoside. Surprisingly, recent evidence suggests that the PTS of L. casei also plays a role in cold shock response. PMID:17183208

  4. Role of Akt and Ca2+ on cell permeabilization via connexin43 hemichannels induced by metabolic inhibition.

    PubMed

    Salas, Daniela; Puebla, Carlos; Lampe, Paul D; Lavandero, Sergio; Sáez, Juan C

    2015-07-01

    Connexin hemichannels are regulated under physiological and pathological conditions. Metabolic inhibition, a model of ischemia, promotes surface hemichannel activation associated, in part, with increased surface hemichannel levels, but little is known about its underlying mechanism. Here, we investigated the role of Akt on the connexin43 hemichannel's response induced by metabolic inhibition. In HeLa cells stably transfected with rat connexin43 fused to EGFP (HeLa43 cells), metabolic inhibition induced a transient Akt activation necessary to increase the amount of surface connexin43. The increase in levels of surface connexin43 was also found to depend on an intracellular Ca2+ signal increase that was partially mediated by Akt activation. However, the metabolic inhibition-induced Akt activation was not significantly affected by intracellular Ca2+ chelation. The Akt-dependent increase in connexin43 hemichannel activity in HeLa43 cells also occurred after oxygen-glucose deprivation, another ischemia-like condition, and in cultured cortical astrocytes (endogenous connexin43 expression system) under metabolic inhibition. Since opening of hemichannels has been shown to accelerate cell death, inhibition of Akt-dependent phosphorylation of connexin43 hemichannels could reduce cell death induced by ischemia/reperfusion. PMID:25779082

  5. Interdependence of tetrapyrrole metabolism, the generation of oxidative stress and the mitigative oxidative stress response.

    PubMed

    Busch, Andrea W U; Montgomery, Beronda L

    2015-01-01

    Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS) associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms. PMID:25618582

  6. Interdependence of tetrapyrrole metabolism, the generation of oxidative stress and the mitigative oxidative stress response

    PubMed Central

    Busch, Andrea W.U.; Montgomery, Beronda L.

    2015-01-01

    Tetrapyrroles are involved in light harvesting and light perception, electron-transfer reactions, and as co-factors for key enzymes and sensory proteins. Under conditions in which cells exhibit stress-induced imbalances of photosynthetic reactions, or light absorption exceeds the ability of the cell to use photoexcitation energy in synthesis reactions, redox imbalance can occur in photosynthetic cells. Such conditions can lead to the generation of reactive oxygen species (ROS) associated with alterations in tetrapyrrole homeostasis. ROS accumulation can result in cellular damage and detrimental effects on organismal fitness, or ROS molecules can serve as signals to induce a protective or damage-mitigating oxidative stress signaling response in cells. Induced oxidative stress responses include tetrapyrrole-dependent and -independent mechanisms for mitigating ROS generation and/or accumulation. Thus, tetrapyrroles can be contributors to oxidative stress, but are also essential in the oxidative stress response to protect cells by contributing to detoxification of ROS. In this review, we highlight the interconnection and interdependence of tetrapyrrole metabolism with the occurrence of oxidative stress and protective oxidative stress signaling responses in photosynthetic organisms. PMID:25618582

  7. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

    PubMed Central

    Azzam, Edouard I.; Jay-Gerin, Jean-Paul; Pain, Debkumar

    2013-01-01

    Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes. PMID:22182453

  8. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces peripheral metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for ozone-induced systemic metabolic effects and lung injury. Male Wis...

  9. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#

    EPA Science Inventory

    Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats ...

  10. Baking soda induced severe metabolic alkalosis in a haemodialysis patient.

    PubMed

    Solak, Yalcin; Turkmen, Kultigin; Atalay, Huseyin; Turk, Suleyman

    2009-08-01

    Metabolic alkalosis is a rare occurence in hemodialysis population compared to metabolic acidosis unless some precipitating factors such as nasogastric suction, vomiting and alkali ingestion or infusion are present. When metabolic alkalosis develops, it may cause serious clinical consequences among them are sleep apnea, resistent hypertension, dysrhythmia and seizures. Here, we present a 54-year-old female hemodialysis patient who developed a severe metabolic alkalosis due to baking soda ingestion to relieve dyspepsia. She had sleep apnea, volume overload and uncontrolled hypertension due to metabolic alkalosis. Metabolic alkalosis was corrected and the patient's clinical condition was relieved with negative-bicarbonate hemodialysis. PMID:25984015

  11. Metabolic Imaging to Assess Treatment Response to Cytotoxic and Cytostatic Agents

    PubMed Central

    Serkova, Natalie J.; Eckhardt, S. Gail

    2016-01-01

    For several decades, cytotoxic chemotherapeutic agents were considered the basis of anticancer treatment for patients with metastatic tumors. A decrease in tumor burden, assessed by volumetric computed tomography and magnetic resonance imaging, according to the response evaluation criteria in solid tumors (RECIST), was considered as a radiological response to cytotoxic chemotherapies. In addition to RECIST-based dimensional measurements, a metabolic response to cytotoxic drugs can be assessed by positron emission tomography (PET) using 18F-fluoro-thymidine (FLT) as a radioactive tracer for drug-disrupted DNA synthesis. The decreased 18FLT-PET uptake is often seen concurrently with increased apparent diffusion coefficients by diffusion-weighted imaging due to chemotherapy-induced changes in tumor cellularity. Recently, the discovery of molecular origins of tumorogenesis led to the introduction of novel signal transduction inhibitors (STIs). STIs are targeted cytostatic agents; their effect is based on a specific biological inhibition with no immediate cell death. As such, tumor size is not anymore a sensitive end point for a treatment response to STIs; novel physiological imaging end points are desirable. For receptor tyrosine kinase inhibitors as well as modulators of the downstream signaling pathways, an almost immediate inhibition in glycolytic activity (the Warburg effect) and phospholipid turnover (the Kennedy pathway) has been seen by metabolic imaging in the first 24 h of treatment. The quantitative imaging end points by magnetic resonance spectroscopy and metabolic PET (including 18F-fluoro-deoxy-glucose, FDG, and total choline) provide an early treatment response to targeted STIs, before a reduction in tumor burden can be seen. PMID:27471678

  12. Microbial nitrogen metabolism: response to warming and resource supply

    NASA Astrophysics Data System (ADS)

    Buckeridge, K. M.; Min, K.; Lehmeier, C.; Ballantyne, F.; Billings, S. A.

    2013-12-01

    Ecosystem nitrogen (N) dynamics are dependent on microbial metabolic responses to a changing climate. Most studies that investigate soil microbial N dynamics in response to temperature employ measurements reflective of many interacting and confounding phenomena, as altering soil temperature can simultaneously alter moisture regime, substrate availability, and competitive dynamics between microbial populations. As a result, it is difficult to discern how temperature alone can alter patterns of microbial N metabolism using whole soils. Without that knowledge, it is impossible to parse temperature effects on soil N fluxes from other drivers. We address this issue by exploring the sensitivity of microbial partitioning of N between assimilation (growing biomass) and dissimilation (releasing N to the environment) in response to changes in temperature and quality (C:N ratio) of substrate, using a chemostat approach in which a microbial population is maintained at steady state. We perform our experiments using a Gram-negative bacterium (Pseudomonas fluorescens), ubiquitous in soils and dependent on organic compounds to satisfy its resource demand. Individual chemostat runs, all conducted at similar microbial growth rates, generate data describing microbial biomass N, solution N pools and microbial biomass and solution d15N. With these data we can calculate d15N enrichment (d15N microbial biomass - d15N nutrient solution) a proxy for microbial N partitioning. From a recently published model of microbial biomass d15N drivers, fractionation of N occurs with both uptake and excretion of NH3+ so that microbes with a net dissimilation become 15N enriched relative to their source. Because a related study has demonstrated increased microbial C demand with temperature, we predict that in a warming environment microorganisms will become relatively C limited. Accordingly, we hypothesize that warming will enhance microbial dissimilation, and that this N release will be exacerbated as

  13. Type 1 Interferons Induce Changes in Core Metabolism that Are Critical for Immune Function.

    PubMed

    Wu, Duojiao; Sanin, David E; Everts, Bart; Chen, Qiongyu; Qiu, Jing; Buck, Michael D; Patterson, Annette; Smith, Amber M; Chang, Chih-Hao; Liu, Zhiping; Artyomov, Maxim N; Pearce, Erika L; Cella, Marina; Pearce, Edward J

    2016-06-21

    Greater understanding of the complex host responses induced by type 1 interferon (IFN) cytokines could allow new therapeutic approaches for diseases in which these cytokines are implicated. We found that in response to the Toll-like receptor-9 agonist CpGA, plasmacytoid dendritic cells (pDC) produced type 1 IFNs, which, through an autocrine type 1 IFN receptor-dependent pathway, induced changes in cellular metabolism characterized by increased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Direct inhibition of FAO and of pathways that support this process, such as fatty acid synthesis, prevented full pDC activation. Type 1 IFNs also induced increased FAO and OXPHOS in non-hematopoietic cells and were found to be responsible for increased FAO and OXPHOS in virus-infected cells. Increased FAO and OXPHOS in response to type 1 IFNs was regulated by PPARα. Our findings reveal FAO, OXPHOS and PPARα as potential targets to therapeutically modulate downstream effects of type 1 IFNs. PMID:27332732

  14. Metabolic enhancement and increase of alveolar macrophages induced by ozone

    SciTech Connect

    Mochitate, K.; Miura, T.

    1989-06-01

    Male Wistar rats were exposed to 0.2 ppm ozone (O3) for 14 days and at intervals alveolar macrophages were collected by bronchoalveolar lavage to examine the effects of O3. The specific activities of glucose-6-phosphate dehydrogenase and glutathione peroxidase of alveolar macrophages increased to 1.6-fold (on the 3rd day) and 1.5-fold (on the 5th day), respectively, those of the control values. Similarly, the specific activities of pyruvate kinase, lactate dehydrogenase, and hexokinase also increased to 1.6-fold, 1.4-fold, and 1.2-fold, respectively, those of the control values on the 3rd day. The activities of all enzymes tested were maintained at significantly higher levels until the 14th day. Furthermore, the incorporation of (14C)thymidine into alveolar macrophages increased twice the control values on the 1st and 3rd days and was almost completely inhibited by the addition of 1.23 x 10(-4) M aphidicolin, a competitive inhibitor of DNA polymerase alpha. The number of alveolar macrophages collected from exposed animals also increased to 1.5-fold that of the control value on the 3rd day and was maintained at significantly higher level until the 14th day. It was noted that alveolar macrophages of small size preferentially increased between the 5th and 14th days. These results show that exposures to 0.2 ppm O3 induced a metabolic enhancement of the peroxidative metabolism, glycolysis, and DNA synthesis in alveolar macrophages and increased the macrophages of small size.

  15. Exercise-induced albuminuria is related to metabolic syndrome.

    PubMed

    Greenberg, Sharon; Shenhar-Tsarfaty, Shani; Rogowski, Ori; Shapira, Itzhak; Zeltser, David; Weinstein, Talia; Lahav, Dror; Vered, Jaffa; Tovia-Brodie, Oholi; Arbel, Yaron; Berliner, Shlomo; Milwidsky, Assi

    2016-06-01

    Microalbuminuria (MA) is a known marker for endothelial dysfunction and future cardiovascular events. Exercise-induced albuminuria (EiA) may precede the appearance of MA. Associations between EiA and metabolic syndrome (MS) have not been assessed so far. Our aim was to investigate this association in a large sample of apparently healthy individuals with no baseline albuminuria. This was a cross-sectional study of 2,027 adults with no overt cardiovascular diseases who took part in a health survey program and had no baseline MA. Diagnosis of MS was based on harmonized criteria. All patients underwent an exercise test (Bruce protocol), and urinary albumin was measured before and after the examination. Urinary albumin-to-creatinine ratio (ACR) values before and after exercise were 0.40 (0.21-0.89) and 1.06 (0.43-2.69) mg/g for median (interquartile range) respectively. A total of 394 (20%) subjects had EiA; ACR rose from normal rest values (0.79 mg/g) to 52.28 mg/g after exercise (P < 0.001); this effect was not shown for the rest of the study population. EiA was related to higher prevalence of MS (13.8% vs. 27.1%, P < 0.001), higher metabolic equivalents (P < 0.001), higher baseline blood pressure (P < 0.001), and higher levels of fasting plasma glucose, triglycerides, and body mass index (P < 0.001). Multivariate binary logistic regression model showed that subjects with MS were 98% more likely to have EiA (95% confidence interval: 1.13-3.46, P = 0.016). In conclusion, EiA in the absence of baseline MA is independently related to MS. PMID:27076648

  16. Fasciola hepatica: motility response to metabolic inhibitors in vitro.

    PubMed

    Holmes, S D; Fairweather, I

    1985-06-01

    The effects of metabolic inhibitors on the in vitro motility of Fasciola hepatica have been determined by means of an isometric transducer system. Sodium fluoride, an inhibitor of glycolysis, causes a long-term suppression of motility; this is also the effect of sodium iodoacetate (another glycolysis inhibitor) at low concentrations (1 X 10(-5) M and below). However, higher concentrations of iodoacetate induce a rapid inhibition of activity leading to a spastic paralysis. Both rotenone and oligomycin, which act as inhibitors of oxidative phosphorylation, produce a long-term suppression of movement. Carbonylcyanide-p-trifluoromethoxyphenylhydrazone and carbonylcyanide-m-chlorophenylhydrazone, which are uncouplers of oxidative phosphorylation, induce a spastic paralysis of the fluke; this is rapid at high concentrations (1 X 10(-4) and 1 X 10(-5) M). A brief stimulation of activity is evident at 1 X 10(-5) M and lasts longer at 1 X 10(-6) and 1 X 10(-7) M, before inhibition sets in. There is no stimulation at low concentrations of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (1 X 10(-8) and 1 X 10(-9) M), only inhibition leading to a medium-term spastic paralysis. In contrast, a third uncoupler, 2,4-dinitrophenol, causes a flaccid paralysis and the effect is rapid only at high concentrations, being accompanied by an initial increase in muscle tone at 1 X 10(-2) M and a brief stimulation of motility at 1 X 10(-3) M. Stimulation lasts longer at 1 X 10(-4) and 1 X 10(-5) M, but is not evident at concentrations below this. The effects on motility at these lower concentrations are essentially long term in nature. That the rapid effects of the uncouplers on muscle tone and motility are not due primarily to uncoupling is shown by 2,4,6-trinitrophenol and hydroquinone, compounds structurally related to 2,4-dinitrophenol. 2,4,6-Trinitrophenol is a membrane-impermeable compound devoid of uncoupling activity; at 1 X 10(-3) M, it causes an immediate inhibition of activity

  17. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast.

    PubMed

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida; Sanvito, Rossella; Magni, Fulvio; Coccetti, Paola; Rocchetti, Marcella; Nielsen, Jens; Alberghina, Lilia; Vanoni, Marco

    2016-01-01

    Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage. PMID:27305947

  18. Respiratory metabolism and calorie restriction relieve persistent endoplasmic reticulum stress induced by calcium shortage in yeast

    PubMed Central

    Busti, Stefano; Mapelli, Valeria; Tripodi, Farida; Sanvito, Rossella; Magni, Fulvio; Coccetti, Paola; Rocchetti, Marcella; Nielsen, Jens; Alberghina, Lilia; Vanoni, Marco

    2016-01-01

    Calcium homeostasis is crucial to eukaryotic cell survival. By acting as an enzyme cofactor and a second messenger in several signal transduction pathways, the calcium ion controls many essential biological processes. Inside the endoplasmic reticulum (ER) calcium concentration is carefully regulated to safeguard the correct folding and processing of secretory proteins. By using the model organism Saccharomyces cerevisiae we show that calcium shortage leads to a slowdown of cell growth and metabolism. Accumulation of unfolded proteins within the calcium-depleted lumen of the endoplasmic reticulum (ER stress) triggers the unfolded protein response (UPR) and generates a state of oxidative stress that decreases cell viability. These effects are severe during growth on rapidly fermentable carbon sources and can be mitigated by decreasing the protein synthesis rate or by inducing cellular respiration. Calcium homeostasis, protein biosynthesis and the unfolded protein response are tightly intertwined and the consequences of facing calcium starvation are determined by whether cellular energy production is balanced with demands for anabolic functions. Our findings confirm that the connections linking disturbance of ER calcium equilibrium to ER stress and UPR signaling are evolutionary conserved and highlight the crucial role of metabolism in modulating the effects induced by calcium shortage. PMID:27305947

  19. Radiation-induced gene responses

    SciTech Connect

    Woloschak, G.E.; Paunesku, T.; Shearin-Jones, P.; Oryhon, J.

    1996-12-31

    In the process of identifying genes that are differentially regulated in cells exposed to ultraviolet radiation (UV), we identified a transcript that was repressed following the exposure of cells to a combination of UV and salicylate, a known inhibitor of NF-kappaB. Sequencing this band determined that it has identify to lactate dehydrogenase, and Northern blots confirmed the initial expression pattern. Analysis of the sequence of the LDH 5` region established the presence of NF-kappaB, Sp1, and two Ap-2 elements; two partial AP- 1; one partial RE, and two halves of E-UV elements were also found. Electromobility shift assays were then performed for the AP-1, NF- kappaB, and E-UV elements. These experiments revealed that binding to NF-kappaB was induced by UV but repressed with salicylic acid; UV did not affect AP-1 binding, but salicylic acid inhibited it alone or following UV exposure; and E-UV binding was repressed by UV, and salicylic acid had little effect. Since the binding of no single element correlated with the expression pattern of LDH, it is likely that multiple elements govern UV/salicylate-mediated expression.

  20. Cattle temperament influences metabolism: metabolic response to glucose tolerance and insulin sensitivity tests in beef steers.

    PubMed

    Burdick Sanchez, N C; Carroll, J A; Broadway, P R; Hughes, H D; Roberts, S L; Richeson, J T; Schmidt, T B; Vann, R C

    2016-07-01

    Cattle temperament, defined as the reactivity of cattle to humans or novel environments, can greatly influence several physiological systems in the body, including immunity, stress, and most recently discovered, metabolism. Greater circulating concentrations of nonesterified fatty acids (NEFAs) found in temperamental cattle suggest that temperamental cattle are metabolically different than calm cattle. Further, elevated NEFA concentrations have been reported to influence insulin sensitivity. Therefore, the objective of this study was to determine whether cattle temperament would influence the metabolic response to a glucose tolerance test (GTT) and insulin sensitivity test (IST). Angus-cross steers (16 calm and 15 temperamental; 216 ± 6 kg BW) were selected based on temperament score measured at weaning. On day 1, steers were moved into indoor stanchions to allow measurement of individual ad libitum feed intake. On day 6, steers were fitted with indwelling rectal temperature probes and jugular catheters. At 9 AM on day 7, steers received the GTT (0.5-mL/kg BW of a 50% dextrose solution), and at 2 PM on day 7, steers received the IST (2.5 IU bovine insulin/kg BW). Blood samples were collected and serum isolated at -60, -45, -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, and 150 min relative to each challenge. Serum was stored at -80°C until analyzed for cortisol, glucose, NEFA, and blood urea nitrogen concentrations. All variables changed over time (P < 0.01). For the duration of the study, temperamental steers maintained greater (P < 0.01) serum NEFA and less (P ≤ 0.01) serum blood urea nitrogen and insulin sensitivity (calculated using Revised Quantitative Insulin Sensitivity Check Index) compared with calm steers. During the GTT, temperamental steers had greater (P < 0.01) serum glucose, yet decreased (P = 0.03) serum insulin and (P < 0.01) serum insulin: serum glucose compared to calm cattle. During the IST, temperamental steers had greater (P < 0.01) serum

  1. Transmural Distribution of Metabolic Abnormalities and Glycolytic Activity during Dobutamine Induced Demand Ischemia

    PubMed Central

    Jameel, Mohammad N; Wang, Xiaohong; Eijgelshoven, Marcel H.J.; Mansoor, Abdul; Zhang, Jianyi

    2008-01-01

    The heterogeneity across the LV wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high energy phosphate (HEP) and 2-deoxyglucose-6-phosphate (2DGP) levels and myocardial blood flow (MBF) were determined under basal conditions (B), during dobutamine infusion (DOB: 20 μg/kg/min iv.), and during coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting subendocardial to subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion RPP, ischemic zone (IZ) MBF and ENDO/EPI decreased significantly. IZ PCr/ATP decreased significantly (2.30 +/- 0.14, 2.06 +/- 0.13 and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11 and 1.72 +/- 0.12; EPI, MID and ENDO, respectively) and 2DG6P accumulated in all layers as evidenced by the 2DG6P/PCr (0.55 +/- 0.12, 0.52 +/- 0.10 and 0.37 +/- 0.08; EPI, MID and ENDO respectively; p<0.05, EPI>ENDO). In the IZ the wet weight/dry weight ratio was significantly increased as compared to the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; p<0.05). Thus, in stenotic perfused bed, during dobutamine induced high cardiac workstate, despite higher blood flow the subepicardial layers showed the greater metabolic changes that characterized by a shift toward higher carbohydrate metabolism suggesting a homeostatic responses to high cardiac workstate is characterized by more glucose utilization in energy metabolism. PMID:18424629

  2. Arsenic induces structural and compositional colonic microbiome change and promotes host nitrogen and amino acid metabolism.

    PubMed

    Dheer, Rishu; Patterson, Jena; Dudash, Mark; Stachler, Elyse N; Bibby, Kyle J; Stolz, Donna B; Shiva, Sruti; Wang, Zeneng; Hazen, Stanley L; Barchowsky, Aaron; Stolz, John F

    2015-12-15

    Chronic exposure to arsenic in drinking water causes cancer and non-cancer diseases. However, mechanisms for chronic arsenic-induced pathogenesis, especially in response to lower exposure levels, are unclear. In addition, the importance of health impacts from xeniobiotic-promoted microbiome changes is just being realized and effects of arsenic on the microbiome with relation to disease promotion are unknown. To investigate impact of arsenic exposure on both microbiome and host metabolism, the stucture and composition of colonic microbiota, their metabolic phenotype, and host tissue and plasma metabolite levels were compared in mice exposed for 2, 5, or 10weeks to 0, 10 (low) or 250 (high) ppb arsenite (As(III)). Genotyping of colonic bacteria revealed time and arsenic concentration dependent shifts in community composition, particularly the Bacteroidetes and Firmicutes, relative to those seen in the time-matched controls. Arsenic-induced erosion of bacterial biofilms adjacent to the mucosal lining and changes in the diversity and abundance of morphologically distinct species indicated changes in microbial community structure. Bacterical spores increased in abundance and intracellular inclusions decreased with high dose arsenic. Interestingly, expression of arsenate reductase (arsA) and the As(III) exporter arsB, remained unchanged, while the dissimilatory nitrite reductase (nrfA) gene expression increased. In keeping with the change in nitrogen metabolism, colonic and liver nitrite and nitrate levels and ratios changed with time. In addition, there was a concomitant increase in pathogenic arginine metabolites in the mouse circulation. These data suggest that arsenic exposure impacts the microbiome and microbiome/host nitrogen metabolism to support disease enhancing pathogenic phenotypes. PMID:26529668

  3. AKR1B7 Is Induced by the Farnesoid X Receptor and Metabolizes Bile Acids*

    PubMed Central

    Schmidt, Daniel R.; Schmidt, Samuel; Holmstrom, Sam R.; Makishima, Makoto; Yu, Ruth T.; Cummins, Carolyn L.; Mangelsdorf, David J.; Kliewer, Steven A.

    2011-01-01

    Although bile acids are crucial for the absorption of lipophilic nutrients in the intestine, they are cytotoxic at high concentrations and can cause liver damage and promote colorectal carcinogenesis. The farnesoid X receptor (FXR), which is activated by bile acids and abundantly expressed in enterohepatic tissues, plays a crucial role in maintaining bile acids at safe concentrations. Here, we show that FXR induces expression of Akr1b7 (aldo-keto reductase 1b7) in murine small intestine, colon, and liver by binding directly to a response element in the Akr1b7 promoter. We further show that AKR1B7 metabolizes 3-keto bile acids to 3β-hydroxy bile acids that are less toxic to cultured cells than their 3α-hydroxy precursors. These findings reveal a feed-forward, protective pathway operative in murine enterohepatic tissues wherein FXR induces AKR1B7 to detoxify bile acids. PMID:21081494

  4. Optical Metabolic Imaging of Treatment Response in Human Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Shah, Amy T.; Demory Beckler, Michelle; Walsh, Alex J.; Jones, William P.; Pohlmann, Paula R.; Skala, Melissa C.

    2014-01-01

    Optical metabolic imaging measures fluorescence intensity and lifetimes from metabolic cofactors nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD). These molecular level measurements provide unique biomarkers for early cellular responses to cancer treatments. Head and neck squamous cell carcinoma (HNSCC) is an attractive target for optical imaging because of easy access to the site using fiber optic probes. Two HNSCC cell lines, SCC25 and SCC61, were treated with Cetuximab (anti-EGFR antibody), BGT226 (PI3K/mTOR inhibitor), or cisplatin (chemotherapy) for 24 hours. Results show increased redox ratio, NADH α1 (contribution from free NADH), and FAD α1 (contribution from protein-bound FAD) for malignant cells compared with the nonmalignant cell line OKF6 (p<0.05). In SCC25 and SCC61 cells, the redox ratio is unaffected by cetuximab treatment and decreases with BGT226 and cisplatin treatment (p<0.05), and these results agree with standard measurements of proliferation rates after treatment. For SCC25, NADH α1 is reduced with BGT226 and cisplatin treatment. For SCC61, NADH α1 is reduced with cetuximab, BGT226, and cisplatin treatment. Trends in NADH α1 are statistically similar to changes in standard measurements of glycolytic rates after treatment. FAD α1 is reduced with cisplatin treatment (p<0.05). These shifts in optical endpoints reflect early metabolic changes induced by drug treatment. Overall, these results indicate that optical metabolic imaging has potential to detect early response to cancer treatment in HNSCC, enabling optimal treatment regimens and improved patient outcomes. PMID:24595244

  5. High levels of glucose induce "metabolic memory" in cardiomyocyte via epigenetic histone H3 lysine 9 methylation.

    PubMed

    Yu, Xi-Yong; Geng, Yong-Jian; Liang, Jia-Liang; Zhang, Saidan; Lei, He-Ping; Zhong, Shi-Long; Lin, Qiu-Xiong; Shan, Zhi-Xin; Lin, Shu-Guang; Li, Yangxin

    2012-09-01

    Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients. PMID:22707199

  6. Inhibition of murine splenic T lymphocyte proliferation by 2-deoxy-D-glucose-induced metabolic stress

    NASA Technical Reports Server (NTRS)

    Miller, E. S.; Klinger, J. C.; Akin, C.; Koebel, D. A.; Sonnenfeld, G.

    1994-01-01

    Female Swiss-Webster mice were injected with the glucose analogue 2-deoxy-D-glucose (2-DG), which when administered to rodents induces acute periods of metabolic stress. A single or multiple injections of 2-DG invoked a stress response, as evidenced by increases in serum corticosterone levels. The influence of this metabolic stressor on the blastogenic potential of splenic T lymphocytes was then examined. It was found that one, two, or three injections of 2-DG resulted in depressed T cell proliferative responses, with an attenuation of the effect occurring by the fifth injection. The 2-DG-induced inhibition of T cell proliferation was not attributable to 2-DG-induced cytolysis, as in vitro incubation of naive T cells with varying concentrations of 2-DG did not result in a reduction in cell number or viability, and flow cytometric analysis demonstrated that percentages of CD3, CD4, and CD8 splenic T cells were not altered as a result of 2-DG-induced stress. Incubating naive T cells in varying concentrations of 2-DG resulted in a dose-dependent inhibition of T cell blastogenic potential. Following in vivo exposure to 2-DG, T cell proliferation did not return to normal levels until 3 days after the cessation of 2-DG injections. Administering the beta-adrenergic receptor antagonist propranolol did not reverse the inhibited lymphoproliferation in 2-DG-treated mice. The inhibition in T cell proliferation was not observed, however, in mice that had been adrenalectomized or hypophysectomized and injected with 2-DG.(ABSTRACT TRUNCATED AT 250 WORDS).

  7. The metabolic response to postnatal leptin in rats varies with age and may be litter dependent.

    PubMed

    Granado, M; Diaz, F; Fuente-Martín, E; García-Cáceres, C; Argente, J; Chowen, J A

    2014-06-01

    Hyperleptinemia during postnatal life induces long-term effects on metabolism. However, these effects are controversial as both increased and decreased propensity towards obesity has been reported. To further analyze the effects of chronic neonatal hyperleptinemia on the subsequent metabolic profile, male Wistar rats proceeding from 18 different litters (8 pups/litter) received a daily subcutaneous injection of either saline (10 ml/kg, n=36) or leptin (3 μg/g, n=36) from postnatal day (PND) 2 to PND9. Rats were sacrificed at 10, 40, or 150 days of age. At 10 days of age, leptin treated rats had decreased body weight (p<0.001) and body fat (p<0.05). Leptin levels and glycemia were increased (p<0.01), whereas insulin, total lipids, triglycerides and glycerol levels were decreased (p<0.05). At PND40 rats receiving leptin had increased glycemia (p<0.01) and plasma HDL and LDL levels, but decreased total lipids (p<0.05). At PND150 neonatal leptin treatment induced different effects in rats raised in different litters. Rats from litter 1 had increased body weight (p<0.05), body fat (p<0.01), and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), total lipid (p<0.001), LDL (p<0.05), and glycerol (p<0.001) levels. In rats from litter 2 these parameters did not differ from controls. Rats from litter 3 had decreased body weight (p<0.05), visceral fat (p<0.01) and plasma leptin (p<0.001), cholesterol (p<0.001), triglyceride (p<0.001), glycerol (p<0.001), and HDL (p<0.001) levels. In conclusion, the metabolic response to postnatal leptin varies with age, with the response in adulthood being variable and most likely influenced by other factors, including the genetic make-up. PMID:24446159

  8. Poly(ADP-ribose) metabolism in young and old cells: response to cellular stresses

    SciTech Connect

    Gracy, R.W.; Sims, J.L.; Cini, J.

    1986-05-01

    The authors have examined the effect of several cellular stresses on poly(ADP-ribose) metabolism in human fibroblasts of low passage number derived from young and old donors. Poly(ADP-ribose) was synthesized in response to alkylation of DNA caused by N-methyl-N'-nitro-N-nitroguanidine and by hyperthermic treatment at 43 /sup 0/C or 45 /sup 0/C. Ethanol is able to potentiate poly(ADP-ribose) accumulation following these treatments. There was little if any difference in the response of young and old cells to these stresses. Amino acid analogs are thought to induce a response in mammalian cells similar to that caused by hyperthermia and ethanol. However, amino acid analogs such as L-azetidine did not produce effects on poly(ADP-ribose) metabolism like those produced by ethanol or hyperthermia. The authors have also examined the poly(ADP-ribose) content of bovine eye lens. Each eye lens contains populations of young and old cells that are distributed in a fixed graduated manner. Thus, the eye lens allows the study of aging cells with identical genetic backgrounds without the complications of serial passage of young cultures in in vitro aging systems.

  9. Rain influences the physiological and metabolic responses to exercise in hot conditions.

    PubMed

    Ito, Ryo; Yamashita, Naoyuki; Suzuki, Eiko; Matsumoto, Takaaki

    2015-01-01

    Outdoor exercise often proceeds in rainy conditions. However, the cooling effects of rain on human physiological responses have not been systematically studied in hot conditions. The present study determined physiological and metabolic responses using a climatic chamber that can precisely simulate hot, rainy conditions. Eleven healthy men ran on a treadmill at an intensity of 70% VO2max for 30 min in the climatic chamber at an ambient temperature of 33°C in the presence (RAIN) or absence (CON) of 30 mm · h(-1) of precipitation and a headwind equal to the running velocity of 3.15 ± 0.19 m · s(-1). Oesophageal temperature, mean skin temperature, heart rate, rating of perceived exertion, blood parameters, volume of expired air and sweat loss were measured. Oesophageal and mean skin temperatures were significantly lower from 5 to 30 min, and heart rate was significantly lower from 20 to 30 min in RAIN than in CON (P < 0.05 for all). Plasma lactate and epinephrine concentrations (30 min) and sweat loss were significantly lower (P < 0.05) in RAIN compared with CON. Rain appears to influence physiological and metabolic responses to exercise in heat such that heat-induced strain might be reduced. PMID:25555077

  10. Requirement for metabolic activation of acetylaminofluorene to induce multidrug gene expression.

    PubMed Central

    Gant, T W; Schrenk, D; Silverman, J A; Thorgeirsson, S S

    1994-01-01

    Previously we have demonstrated that several xenobiotics can induce multidrug (mdr) gene expression in cultures of primary isolated hepatocytes. One of the best of these xenobiotic inducers in rat hepatocytes is 2-acetylaminofluorene (2-AAF), which induces mdr expression by an enhancement of mdr gene transcription. In all species studied to date, AAF is extensively and variously metabolized. In this study we have sought to determine if AAF per se or a metabolite is responsible for mediating the increase in mdr gene transcription and expression. This study demonstrates that AAF per se is not active, but that the effect of AAF we have observed on mdr gene transcription and expression in the rat is due to the formation of a reactive metabolite(s). Our data indicate that this reactive metabolite is probably N-acetoxy-2-aminofluorene or the sulfate ester of N-hydroxy-AAF. The requirement for the formation of one of these metabolites may explain the differences in species response to AAF, in terms of mdr gene expression, that we have observed. We hypothesize that the mechanism by which mdr gene transcription is increased in response to AAF involves a covalent interaction between a reactive metabolite and an mdr gene regulatory protein. Our current work is concerned with the exploration of this hypothesis. PMID:7889850

  11. Expression analysis in response to drought stress in soybean: Shedding light on the regulation of metabolic pathway genes.

    PubMed

    Guimarães-Dias, Fábia; Neves-Borges, Anna Cristina; Viana, Antonio Americo Barbosa; Mesquita, Rosilene Oliveira; Romano, Eduardo; de Fátima Grossi-de-Sá, Maria; Nepomuceno, Alexandre Lima; Loureiro, Marcelo Ehlers; Alves-Ferreira, Márcio

    2012-06-01

    Metabolomics analysis of wild type Arabidopsis thaliana plants, under control and drought stress conditions revealed several metabolic pathways that are induced under water deficit. The metabolic response to drought stress is also associated with ABA dependent and independent pathways, allowing a better understanding of the molecular mechanisms in this model plant. Through combining an in silico approach and gene expression analysis by quantitative real-time PCR, the present work aims at identifying genes of soybean metabolic pathways potentially associated with water deficit. Digital expression patterns of Arabidopsis genes, which were selected based on the basis of literature reports, were evaluated under drought stress condition by Genevestigator. Genes that showed strong induction under drought stress were selected and used as bait to identify orthologs in the soybean genome. This allowed us to select 354 genes of putative soybean orthologs of 79 Arabidopsis genes belonging to 38 distinct metabolic pathways. The expression pattern of the selected genes was verified in the subtractive libraries available in the GENOSOJA project. Subsequently, 13 genes from different metabolic pathways were selected for validation by qPCR experiments. The expression of six genes was validated in plants undergoing drought stress in both pot-based and hydroponic cultivation systems. The results suggest that the metabolic response to drought stress is conserved in Arabidopsis and soybean plants. PMID:22802708

  12. Expression analysis in response to drought stress in soybean: Shedding light on the regulation of metabolic pathway genes

    PubMed Central

    Guimarães-Dias, Fábia; Neves-Borges, Anna Cristina; Viana, Antonio Americo Barbosa; Mesquita, Rosilene Oliveira; Romano, Eduardo; de Fátima Grossi-de-Sá, Maria; Nepomuceno, Alexandre Lima; Loureiro, Marcelo Ehlers; Alves-Ferreira, Márcio

    2012-01-01

    Metabolomics analysis of wild type Arabidopsis thaliana plants, under control and drought stress conditions revealed several metabolic pathways that are induced under water deficit. The metabolic response to drought stress is also associated with ABA dependent and independent pathways, allowing a better understanding of the molecular mechanisms in this model plant. Through combining an in silico approach and gene expression analysis by quantitative real-time PCR, the present work aims at identifying genes of soybean metabolic pathways potentially associated with water deficit. Digital expression patterns of Arabidopsis genes, which were selected based on the basis of literature reports, were evaluated under drought stress condition by Genevestigator. Genes that showed strong induction under drought stress were selected and used as bait to identify orthologs in the soybean genome. This allowed us to select 354 genes of putative soybean orthologs of 79 Arabidopsis genes belonging to 38 distinct metabolic pathways. The expression pattern of the selected genes was verified in the subtractive libraries available in the GENOSOJA project. Subsequently, 13 genes from different metabolic pathways were selected for validation by qPCR experiments. The expression of six genes was validated in plants undergoing drought stress in both pot-based and hydroponic cultivation systems. The results suggest that the metabolic response to drought stress is conserved in Arabidopsis and soybean plants. PMID:22802708

  13. Induced phenylpropanoid metabolism during suberization and lignification: a comparative analysis

    NASA Technical Reports Server (NTRS)

    Bernards, M. A.; Susag, L. M.; Bedgar, D. L.; Anterola, A. M.; Lewis, N. G.

    2000-01-01

    Induction of the biosynthesis of phenylpropanoids was monitored at the enzyme level through measurement of the temporal change in the activity of two marker enzymes of phenylpropanoid metabolism, phenylalanine ammonia-lyase, (PAL, E.C. 4.1.3.5) and 4-coumaryl-CoA ligase (4-CL, E.C. 6.2.1.12) and two marker enzymes for hydroxycinnamyl alcohol biosynthesis, cinnamoyl-CoA:NADP+ oxidoreductase (CCR, E.C. 1.2.1.44) and cinnamyl alcohol dehydrogenase (CAD, E.C. 1.1.1.195) in both suberizing potato (Solanum tuberosum) tubers and lignifying loblolly pine (Pinus taeda) cell cultures. While measurable activities of PAL, 4-CL and CAD increased upon initiation of suberization in potato tubers, that of CCR did not. By contrast, all four enzymes were induced upon initiation of lignification in pine cell cultures. The lack of CCR induction in potato by wound treatment is consistent with the channelling of hydroxycinnamoyl-CoA derivatives away from monolignol formation and toward other hydroxycinnamoyl derivatives such as those that accumulate during suberization.

  14. 2-deoxy-D-glucose-induced metabolic stress enhances resistance to Listeria monocytogenes infection in mice

    NASA Technical Reports Server (NTRS)

    Miller, E. S.; Bates, R. A.; Koebel, D. A.; Fuchs, B. B.; Sonnenfeld, G.

    1998-01-01

    Exposure to different forms of psychological and physiological stress can elicit a host stress response, which alters normal parameters of neuroendocrine homeostasis. The present study evaluated the influence of the metabolic stressor 2-deoxy-D-glucose (2-DG; a glucose analog, which when administered to rodents, induces acute periods of metabolic stress) on the capacity of mice to resist infection with the facultative intracellular bacterial pathogen Listeria monocytogenes. Female BDF1 mice were injected with 2-DG (500 mg/kg b. wt.) once every 48 h prior to, concurrent with, or after the onset of a sublethal dose of virulent L. monocytogenes. Kinetics of bacterial growth in mice were not altered if 2-DG was applied concurrently or after the start of the infection. In contrast, mice exposed to 2-DG prior to infection demonstrated an enhanced resistance to the listeria challenge. The enhanced bacterial clearance in vivo could not be explained by 2-DG exerting a toxic effect on the listeria, based on the results of two experiments. First, 2-DG did not inhibit listeria replication in trypticase soy broth. Second, replication of L. monocytogenes was not inhibited in bone marrow-derived macrophage cultures exposed to 2-DG. Production of neopterin and lysozyme, indicators of macrophage activation, were enhanced following exposure to 2-DG, which correlated with the increased resistance to L. monocytogenes. These results support the contention that the host response to 2-DG-induced metabolic stress can influence the capacity of the immune system to resist infection by certain classes of microbial pathogens.

  15. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

    PubMed Central

    Wicks, Shawna E.; Vandanmagsar, Bolormaa; Haynie, Kimberly R.; Fuller, Scott E.; Warfel, Jaycob D.; Stephens, Jacqueline M.; Wang, Miao; Han, Xianlin; Zhang, Jingying; Noland, Robert C.; Mynatt, Randall L.

    2015-01-01

    The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity. PMID:26056297

  16. Calcium-regulated nuclear enzymes: potential mediators of phytochrome-induced changes in nuclear metabolism?

    NASA Technical Reports Server (NTRS)

    Roux, S. J.

    1992-01-01

    Calcium ions have been proposed to serve as important regulatory elements in stimulus-response coupling for phytochrome responses. An important test of this hypothesis will be to identify specific targets of calcium action that are required for some growth or development process induced by the photoactivated form of phytochrome (Pfr). Initial studies have revealed that there are at least two enzymes in pea nuclei that are stimulated by Pfr in a Ca(2+)-dependent fashion, a calmodulin-regulated nucleoside triphosphatase and a calmodulin-independent but Ca(2+)-dependent protein kinase. The nucleoside triphosphatase appears to be associated with the nuclear envelope, while the protein kinase co-purifies with a nuclear fraction highly enriched for chromatin. This short review summarizes the latest findings on these enzymes and relates them to what is known about Pfr-regulated nuclear metabolism.

  17. Minimal Peroxide Exposure of Neuronal Cells Induces Multifaceted Adaptive Responses

    PubMed Central

    Chadwick, Wayne; Zhou, Yu; Park, Sung-Soo; Wang, Liyun; Mitchell, Nicholas; Stone, Matthew D.; Becker, Kevin G.; Martin, Bronwen; Maudsley, Stuart

    2010-01-01

    Oxidative exposure of cells occurs naturally and may be associated with cellular damage and dysfunction. Protracted low level oxidative exposure can induce accumulated cell disruption, affecting multiple cellular functions. Accumulated oxidative exposure has also been proposed as one of the potential hallmarks of the physiological/pathophysiological aging process. We investigated the multifactorial effects of long-term minimal peroxide exposure upon SH-SY5Y neural cells to understand how they respond to the continued presence of oxidative stressors. We show that minimal protracted oxidative stresses induce complex molecular and physiological alterations in cell functionality. Upon chronic exposure to minimal doses of hydrogen peroxide, SH-SY5Y cells displayed a multifactorial response to the stressor. To fully appreciate the peroxide-mediated cellular effects, we assessed these adaptive effects at the genomic, proteomic and cellular signal processing level. Combined analyses of these multiple levels of investigation revealed a complex cellular adaptive response to the protracted peroxide exposure. This adaptive response involved changes in cytoskeletal structure, energy metabolic shifts towards glycolysis and selective alterations in transmembrane receptor activity. Our analyses of the global responses to chronic stressor exposure, at multiple biological levels, revealed a viable neural phenotype in-part reminiscent of aged or damaged neural tissue. Our paradigm indicates how cellular physiology can subtly change in different contexts and potentially aid the appreciation of stress response adaptations. PMID:21179406

  18. Acute metabolic and physiologic response of goats to narcosis

    NASA Technical Reports Server (NTRS)

    Schatte, C. L.; Bennett, P. B.

    1973-01-01

    Assessment of the metabolic consequences of exposure to elevated partial pressures of nitrogen and helium under normobaric and hyperbaric conditions in goats. The results include the finding that hyperbaric nitrogen causes and increase in metabolic rate and a general decrease in blood constituent levels which is interpreted as reflecting a shift toward fatty acid metabolism at the expense of carbohydrates. A similar but more pronounced pattern was observed with hyperbaric helium.

  19. Metabolic and Cardiovascular Response to Shallow Water Exercise in Young and Older Women.

    ERIC Educational Resources Information Center

    Campbell, Jennifer A.; D'Acquisto, Leo J.; D'Acquisto, Debra M.; Cline, Michael G.

    2003-01-01

    Compared the metabolic and cardiovascular responses of young and older women while performing shallow water exercise (SWE). Overall, SWE elicited metabolic and cardiovascular responses that met American College of Sports Medicine's guidelines for establishing health benefits. Older females self-selected a greater relative exercise intensity during…

  20. Lactose-Inducible System for Metabolic Engineering of Clostridium ljungdahlii

    SciTech Connect

    Banerjee, A; Leang, C; Ueki, T; Nevin, KP; Lovley, DR

    2014-03-25

    The development of tools for genetic manipulation of Clostridium ljungdahlii has increased its attractiveness as a chassis for autotrophic production of organic commodities and biofuels from syngas and microbial electrosynthesis and established it as a model organism for the study of the basic physiology of acetogenesis. In an attempt to expand the genetic toolbox for C. ljungdahlii, the possibility of adapting a lactose-inducible system for gene expression, previously reported for Clostridium perfringens, was investigated. The plasmid pAH2, originally developed for C. perfringens with a gusA reporter gene, functioned as an effective lactose-inducible system in C. ljungdahlii. Lactose induction of C. ljungdahlii containing pB1, in which the gene for the aldehyde/alcohol dehydrogenase AdhE1 was downstream of the lactose-inducible promoter, increased expression of adhE1 30-fold over the wild-type level, increasing ethanol production 1.5-fold, with a corresponding decrease in acetate production. Lactose-inducible expression of adhE1 in a strain in which adhE1 and the adhE1 homolog adhE2 had been deleted from the chromosome restored ethanol production to levels comparable to those in the wild-type strain. Inducing expression of adhE2 similarly failed to restore ethanol production, suggesting that adhE1 is the homolog responsible for ethanol production. Lactose-inducible expression of the four heterologous genes necessary to convert acetyl coenzyme A (acetyl-CoA) to acetone diverted ca. 60% of carbon flow to acetone production during growth on fructose, and 25% of carbon flow went to acetone when carbon monoxide was the electron donor. These studies demonstrate that the lactose-inducible system described here will be useful for redirecting carbon and electron flow for the biosynthesis of products more valuable than acetate. Furthermore, this tool should aid in optimizing microbial electrosynthesis and for basic studies on the physiology of acetogenesis.

  1. Lactose-Inducible System for Metabolic Engineering of Clostridium ljungdahlii

    PubMed Central

    Ueki, Toshiyuki; Nevin, Kelly P.; Lovley, Derek R.

    2014-01-01

    The development of tools for genetic manipulation of Clostridium ljungdahlii has increased its attractiveness as a chassis for autotrophic production of organic commodities and biofuels from syngas and microbial electrosynthesis and established it as a model organism for the study of the basic physiology of acetogenesis. In an attempt to expand the genetic toolbox for C. ljungdahlii, the possibility of adapting a lactose-inducible system for gene expression, previously reported for Clostridium perfringens, was investigated. The plasmid pAH2, originally developed for C. perfringens with a gusA reporter gene, functioned as an effective lactose-inducible system in C. ljungdahlii. Lactose induction of C. ljungdahlii containing pB1, in which the gene for the aldehyde/alcohol dehydrogenase AdhE1 was downstream of the lactose-inducible promoter, increased expression of adhE1 30-fold over the wild-type level, increasing ethanol production 1.5-fold, with a corresponding decrease in acetate production. Lactose-inducible expression of adhE1 in a strain in which adhE1 and the adhE1 homolog adhE2 had been deleted from the chromosome restored ethanol production to levels comparable to those in the wild-type strain. Inducing expression of adhE2 similarly failed to restore ethanol production, suggesting that adhE1 is the homolog responsible for ethanol production. Lactose-inducible expression of the four heterologous genes necessary to convert acetyl coenzyme A (acetyl-CoA) to acetone diverted ca. 60% of carbon flow to acetone production during growth on fructose, and 25% of carbon flow went to acetone when carbon monoxide was the electron donor. These studies demonstrate that the lactose-inducible system described here will be useful for redirecting carbon and electron flow for the biosynthesis of products more valuable than acetate. Furthermore, this tool should aid in optimizing microbial electrosynthesis and for basic studies on the physiology of acetogenesis. PMID:24509933

  2. Metabolic Context of the Competence-Induced Checkpoint for Cell Replication in Streptococcus suis

    PubMed Central

    Zaccaria, Edoardo; Wells, Jerry M.

    2016-01-01

    Natural genetic transformation is a transient, rapidly progressing energy-consuming process characterized by expression of the transformasome and competence-associated regulatory genes. This transient state is tightly controlled to avoid potentially adverse effects of genetic recombination on genome integrity during cell division. We investigated the global response of Streptococcus suis to exposure to the SigX competence-inducing peptide (XIP), and thus to the activation of the competence machinery, using time series analysis together with PCA analysis, gene clustering followed by heatmap visualisation, and GO enrichment analysis. We explored the possible regulatory link between metabolism and competence, and predicted the physiological adaptation of S. suis during competence induction, progression and exit using transcriptome analysis. We showed that competence development is associated with a suppression of basal metabolism, which may have consequences for the microbe's resilience to fluctuations in the environment, as competence is costly in terms of use of energy and protein translation. Furthermore our data suggest that several basal metabolic pathways are incompatible with activation of competence in S. suis. This study also showed that targeting specific pathways during the development of competence, might render S. suis more vulnerable toward novel antibiotic therapies. PMID:27149631

  3. Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model

    PubMed Central

    Milara, Javier; Morcillo, Esteban; Monleon, Daniel; Tenor, Herman; Cortijo, Julio

    2015-01-01

    Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile. PMID:26192616

  4. Does amifostine reduce metabolic rate? Effect of the drug on gas exchange and acute ventilatory hypoxic response in humans.

    PubMed

    Pandit, Jaideep J; Allen, Caroline; Little, Evelyn; Formenti, Federico; Harris, Adrian L; Robbins, Peter A

    2015-01-01

    Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain. PMID:25894815

  5. Human Skeletal Muscle Protein Metabolism Responses to Amino Acid Nutrition.

    PubMed

    Mitchell, W Kyle; Wilkinson, Daniel J; Phillips, Bethan E; Lund, Jonathan N; Smith, Kenneth; Atherton, Philip J

    2016-07-01

    Healthy individuals maintain remarkably constant skeletal muscle mass across much of adult life, suggesting the existence of robust homeostatic mechanisms. Muscle exists in dynamic equilibrium whereby the influx of amino acids (AAs) and the resulting increases in muscle protein synthesis (MPS) associated with the intake of dietary proteins cancel out the efflux of AAs from muscle protein breakdown that occurs between meals. Dysregulated proteostasis is evident with aging, especially beyond the sixth decade of life. Women and men aged 75 y lose muscle mass at a rate of ∼0.7% and 1%/y, respectively (sarcopenia), and lose strength 2- to 5-fold faster (dynapenia) as muscle "quality" decreases. Factors contributing to the disruption of an otherwise robust proteostatic system represent targets for potential therapies that promote healthy aging. Understanding age-related impairments in anabolic responses to AAs and identifying strategies to mitigate these factors constitute major areas of interest. Numerous studies have aimed to identify 1) the influence of distinct protein sources on absorption kinetics and muscle anabolism, 2) the latency and time course of MPS responses to protein/AAs, 3) the impacts of protein/AA intake on muscle microvascular recruitment, and 4) the role of certain AAs (e.g., leucine) as signaling molecules, which are able to trigger anabolic pathways in tissues. This review aims to discuss these 4 issues listed, to provide historical and modern perspectives of AAs as modulators of human skeletal muscle protein metabolism, to describe how advances in stable isotope/mass spectrometric approaches and instrumentation have underpinned these advances, and to highlight relevant differences between young adults and older individuals. Whenever possible, observations are based on human studies, with additional consideration of relevant nonhuman studies. PMID:27422520

  6. Metabolic response to dietary fibre composition in horses.

    PubMed

    Brøkner, C; Austbø, D; Næsset, J A; Blache, D; Bach Knudsen, K E; Tauson, A H

    2016-07-01

    The hypothesis for this study was that a higher dietary proportion of soluble fibre would result in stable and constant plasma metabolite and regulatory hormone concentrations. The study was a 4×4 Latin Square design with a sequence of 17 days adaptation to the ration followed by 8 sampling days. The feed rations consisted of only timothy hay (H), hay plus molassed sugar beet pulp combined with either whole oats (OB) or barley (BB) and hay plus a loose chaff-based concentrate (M). Four horses were fitted with permanent caecal cannulas and liquid caecal content was withdrawn manually and blood was drawn from the jugular vein at 0, 3 and 9 h postprandial. The horses were exercised daily at medium level for about 1 h. Samples were analysed for short-chain fatty acids (SCFA) and metabolic traits. Caecal SCFA and propionic acid concentrations increased with increased dietary starch and soluble fibre. The diet highest in soluble fibre (M) resulted in the highest plasma glucose and insulin concentrations in the morning, which then remained stable and constant throughout the day. A strong interaction (P<0.01) between time and diet was measured for plasma urea, glucose, insulin and leptin. The greatest variations in plasma glycaemic and insulinaemic responses were associated with the cereal grain diets (OB and BB). There were indications of a negative energy balance, which was reflected in a significantly higher plasma β-hydroxybutyrate concentration and a numerically higher non-esterified fatty acid concentration. In conclusion, this study found that inclusion of soluble fibre resulted in increased total caecal SCFA and propionic acid concentrations. This consequently resulted in stable and constant plasma glycaemic and insulinaemic responses. Diets with a high content of soluble fibre provided enough energy for horses at medium work level. PMID:26755337

  7. PINK1-Parkin-Mediated Mitophagy Protects Mitochondrial Integrity and Prevents Metabolic Stress-Induced Endothelial Injury.

    PubMed

    Wu, Weiwei; Xu, Hao; Wang, Zemin; Mao, Yun; Yuan, Liangshuai; Luo, Wei; Cui, Zhaoqiang; Cui, Taixing; Wang, Xing Li; Shen, Ying H

    2015-01-01

    Mitochondrial injury and dysfunction, a significant feature in metabolic syndrome, triggers endothelial cell dysfunction and cell death. Increasing evidence suggests that mitophagy, a process of autophagic turnover of damaged mitochondria, maintains mitochondrial integrity. PINK1 (phosphatase and tensin homolog (PTEN)-induced putative kinase 1) and Parkin signaling is a key pathway in mitophagy control. In this study, we examined whether this pathway could protect mitochondria under metabolic stress. We found that palmitic acid (PA) induced significant mitophagy and activated PINK1 and Parkin in endothelial cells. Knocking down PINK1 or Parkin reduced mitophagy, leading to impaired clearance of damaged mitochondria and intracellular accumulation of mitochondrial fragments. Furthermore, PINK1 and Parkin prevented PA-induced mitochondrial dysfunction, ROS production and apoptosis. Finally, we show that PINK1 and Parkin were up-regulated in vascular wall of obese mice and diabetic mice. Our study demonstrates that PINK1-Parkin pathway is activated in response to metabolic stress. Through induction of mitophagy, this pathway protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury. PMID:26161534

  8. Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice

    PubMed Central

    Battiprolu, Pavan K.; Hojayev, Berdymammet; Jiang, Nan; Wang, Zhao V.; Luo, Xiang; Iglewski, Myriam; Shelton, John M.; Gerard, Robert D.; Rothermel, Beverly A.; Gillette, Thomas G.; Lavandero, Sergio; Hill, Joseph A.

    2012-01-01

    The leading cause of death in diabetic patients is cardiovascular disease; diabetic cardiomyopathy is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. However, the molecular mechanism that links diabetes to cardiomyopathy is incompletely understood. Insulin resistance is a hallmark feature of diabetes, and the FoxO family of transcription factors, which regulate cell size, viability, and metabolism, are established targets of insulin and growth factor signaling. Here, we set out to evaluate a possible role of FoxO proteins in diabetic cardiomyopathy. We found that FoxO proteins were persistently activated in cardiac tissue in mice with diabetes induced either genetically or by high-fat diet (HFD). FoxO activity was critically linked with development of cardiomyopathy: cardiomyocyte-specific deletion of FoxO1 rescued HFD-induced declines in cardiac function and preserved cardiomyocyte insulin responsiveness. FoxO1-depleted cells displayed a shift in their metabolic substrate usage, from free fatty acids to glucose, associated with decreased accumulation of lipids in the heart. Furthermore, we found that FoxO1-dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance. Together, these data suggest that activation of FoxO1 is an important mediator of diabetic cardiomyopathy and is a promising therapeutic target for the disease. PMID:22326951

  9. Metabolomic analysis of wild and transgenic Nicotiana langsdorffii plants exposed to abiotic stresses: unraveling metabolic responses.

    PubMed

    Scalabrin, Elisa; Radaelli, Marta; Rizzato, Giovanni; Bogani, Patrizia; Buiatti, Marcello; Gambaro, Andrea; Capodaglio, Gabriele

    2015-08-01

    Nicotiana langsdorffii plants, wild and transgenic for the Agrobacterium rhizogenes rol C gene and the rat glucocorticoid receptor (GR) gene, were exposed to different abiotic stresses (high temperature, water deficit, and high chromium concentrations). An untargeted metabolomic analysis was carried out in order to investigate the metabolic effects of the inserted genes in response to the applied stresses and to obtain a comprehensive profiling of metabolites induced during abiotic stresses. High-performance liquid chromatography separation (HPLC) coupled to high-resolution mass spectrometry (HRMS) enabled the identification of more than 200 metabolites, and statistical analysis highlighted the most relevant compounds for each plant treatment. The plants exposed to heat stress showed a unique set of induced secondary metabolites, some of which were known while others were not previously reported for this kind of stress; significant changes were observed especially in lipid composition. The role of trichome, as a protection against heat stress, is here suggested by the induction of both acylsugars and glykoalkaloids. Water deficit and Cr(VI) stresses resulted mainly in enhanced antioxidant (HCAs, polyamine) levels and in the damage of lipids, probably as a consequence of reactive oxygen species (ROS) production. Moreover, the ability of rol C expression to prevent oxidative burst was confirmed. The results highlighted a clear influence of GR modification on plant stress response, especially to water deficiency-a phenomenon whose applications should be further investigated. This study provides new insights into the field of system biology and demonstrates the importance of metabolomics in the study of plant functioning. Graphical Abstract Untargeted metabolomic analysis was applied to wild type, GR and RolC modified Nicotiana Langsdorffii plants exposed to heat, water and Cr(VI) stresses. The key metabolites, highly affected by stress application, were identified

  10. Triplex-Induced DNA Damage Response

    PubMed Central

    Rogers, Faye A.; Tiwari, Meetu Kaushik

    2013-01-01

    Cellular DNA damage response is critical to preserving genomic integrity following exposure to genotoxic stress. A complex series of networks and signaling pathways become activated after DNA damage and trigger the appropriate cellular response, including cell cycle arrest, DNA repair, and apoptosis. The response elicited is dependent upon the type and extent of damage sustained, with the ultimate goal of preventing propagation of the damaged DNA. A major focus of our studies is to determine the cellular pathways involved in processing damage induced by altered helical structures, specifically triplexes. Our lab has demonstrated that the TFIIH factor XPD occupies a central role in triggering apoptosis in response to triplex-induced DNA strand breaks. We have shown that XPD co-localizes with γH2AX, and its presence is required for the phosphorylation of H2AX tyrosine142, which stimulates the signaling pathway to recruit pro-apoptotic factors to the damage site. Herein, we examine the cellular pathways activated in response to triplex formation and discuss our finding that suggests that XPD-dependent apoptosis plays a role in preserving genomic integrity in the presence of excessive structurally induced DNA damage. PMID:24348211