Extensive Metabolic Remodeling Differentiates Non-pathogenic and Pathogenic Growth Forms of the Dimorphic Pathogen Talaromyces marneffei.

PubMed

Pasricha, Shivani; MacRae, James I; Chua, Hwa H; Chambers, Jenny; Boyce, Kylie J; McConville, Malcolm J; Andrianopoulos, Alex

2017-01-01

Fungal infections are an increasing public health problem, particularly in immunocompromised individuals. While these pathogenic fungi show polyphyletic origins with closely related non-pathogenic species, many undergo morphological transitions to produce pathogenic cell types that are associated with increased virulence. However, the characteristics of these pathogenic cells that contribute to virulence are poorly defined. Talaromyces marneffei grows as a non-pathogenic hyphal form at 25°C but undergoes a dimorphic transition to a pathogenic yeast form at 37°C in vitro and following inhalation of asexual conidia by a host. Here we show that this transition is associated with major changes in central carbon metabolism, and that these changes are correlated with increased virulence of the yeast form. Comprehensive metabolite profiling and 13 C-labeling studies showed that hyphal cells exhibited very active glycolytic metabolism and contain low levels of internal carbohydrate reserves. In contrast, yeast cells fully catabolized glucose in the mitochondrial TCA cycle, and store excess glucose in large intracellular pools of trehalose and mannitol. Inhibition of the yeast TCA cycle inhibited replication in culture and in host cells. Yeast, but not hyphae, were also able to use myo -inositol and amino acids as secondary carbon sources, which may support their survival in host macrophages. These analyses suggest that T. marneffei yeast cells exhibit a more efficient oxidative metabolism and are capable of utilizing a diverse range of carbon sources, which contributes to their virulence in animal tissues, highlighting the importance of dimorphic switching in pathogenic yeast.

In High-Light-Acclimated Coffee Plants the Metabolic Machinery Is Adjusted to Avoid Oxidative Stress Rather than to Benefit from Extra Light Enhancement in Photosynthetic Yield

PubMed Central

Martins, Samuel C. V.; Araújo, Wagner L.; Tohge, Takayuki; Fernie, Alisdair R.; DaMatta, Fábio M.

2014-01-01

Coffee (Coffea arabica L.) has been traditionally considered as shade-demanding, although it performs well without shade and even out-yields shaded coffee. Here we investigated how coffee plants adjust their metabolic machinery to varying light supply and whether these adjustments are supported by a reprogramming of the primary and secondary metabolism. We demonstrate that coffee plants are able to adjust its metabolic machinery to high light conditions through marked increases in its antioxidant capacity associated with enhanced consumption of reducing equivalents. Photorespiration and alternative pathways are suggested to be key players in reductant-consumption under high light conditions. We also demonstrate that both primary and secondary metabolism undergo extensive reprogramming under high light supply, including depression of the levels of intermediates of the tricarboxylic acid cycle that were accompanied by an up-regulation of a range of amino acids, sugars and sugar alcohols, polyamines and flavonoids such as kaempferol and quercetin derivatives. When taken together, the entire dataset is consistent with these metabolic alterations being primarily associated with oxidative stress avoidance rather than representing adjustments in order to facilitate the plants from utilizing the additional light to improve their photosynthetic performance. PMID:24733284

Enhanced oral absorption of 20(S)-protopanaxadiol by self-assembled liquid crystalline nanoparticles containing piperine: in vitro and in vivo studies

PubMed Central

Jin, Xin; Zhang, Zhen-hai; Sun, E; Tan, Xiao-bin; Li, Song-lin; Cheng, Xu-dong; You, Ming; Jia, Xiao-bin

2013-01-01

Background 20(S)-protopanaxadiol (PPD), similar to several other anticancer agents, has low oral absorption and is extensively metabolized. These factors limit the use of PPD for treatment of human diseases. Methods In this study, we used cubic nanoparticles containing piperine to improve the oral bioavailability of PPD and to enhance its absorption and inhibit its metabolism. Cubic nanoparticles loaded with PPD and piperine were prepared by fragmentation of glyceryl monoolein (GMO)/poloxamer 407 bulk cubic gel and verified using transmission electron microscopy and differential scanning calorimetry. We evaluated the in vitro release of PPD from these nanoparticles and its absorption across the Caco-2 cell monolayer model, and subsequently, we examined the bioavailability and metabolism of PPD and its nanoparticles in vivo. Results The in vitro release of PPD from these nanoparticles was less than 5% at 12 hours. PPD-cubosome and PPD-cubosome loaded with piperine (molar ratio PPD/piperine, 1:3) increased the apical to basolateral permeability values of PPD across the Caco-2 cell monolayer from 53% to 64%, respectively. In addition, the results of a pharmacokinetic study in rats showed that the relative bioavailabilities of PPD-cubosome [area under concentration–time curve (AUC)0–∞] and PPD-cubosome containing piperine (AUC0–∞) compared to that of raw PPD (AUC0–∞) were 166% and 248%, respectively. Conclusion The increased bioavailability of PPD-cubosome loaded with piperine is due to an increase in absorption and inhibition of metabolism of PPD by cubic nanoparticles containing piperine rather than because of improved release of PPD. The cubic nanoparticles containing piperine may be a promising oral carrier for anticancer drugs with poor oral absorption and that undergo extensive metabolism by cytochrome P450. PMID:23426652

In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms.

PubMed

Abbas, R; Chow, C P; Browder, N J; Thacker, D; Bramer, S L; Fu, C J; Forbes, W; Odomi, M; Flockhart, D A

2000-03-01

1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

Pharmacokinetics and N-acetylation metabolism of S-methyl-l-cysteine and trans-S-1-propenyl-l-cysteine in rats and dogs.

PubMed

Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

2016-11-01

1. Pharmacokinetics and N-acetylation metabolism of S-methyl-L-cysteine (SMC) and trans-S-1-propenyl-L-cysteine (S1PC) were examined in rats and dogs. SMC and S1PC (2-5 mg/kg) were well absorbed in both species with high bioavailability (88-100%). 2. SMC and S1PC were excreted only to a small extent in the urine of rats and dogs. The small renal clearance values (<0.03 l/h/kg) indicated the extensive renal reabsorption of SMC and S1PC, which potentially contributed to their long elimination half-lives (>5 h) in dogs. 3. S1PC, but not SMC, underwent N-acetylation extensively in vivo, which can be explained by the relative activities of N-acetylation of S1PC/SMC and deacetylation of their N-acetylated forms, N-acetyl-S1PC/N-acetyl-SMC, in the liver and kidney in vitro. The activities for S1PC N-acetylation were similar to or higher than those for N-acetyl-S1PC deacetylation in liver S9 fractions of rat and dog, whereas liver and kidney S9 fractions of rat and dog had little activity for SMC N-acetylation or considerably higher activities for N-acetyl-SMC deacetylation. 4. Our study demonstrated that the pharmacokinetics of SMC and S1PC in rats and dogs was characterized by high bioavailability and extensive renal reabsorption; however, the extent of undergoing the N-acetylation metabolism was extremely different between SMC and S1PC.

Pharmacokinetics of S-Allyl-l-cysteine in Rats Is Characterized by High Oral Absorption and Extensive Renal Reabsorption.

PubMed

Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

2016-02-01

S-Allylcysteine (SAC) is a key component of aged garlic extract, one of many garlic products. However, information on its pharmacokinetics has been scant except for data from a few animal studies. We designed this study to determine the overall pharmacokinetics of SAC in rats. After oral or intravenous administration of SAC to rats at a dose of 5 mg/kg, the plasma concentration-time profile of SAC and its metabolites, as well as the amounts excreted in bile and urine, were analyzed by using liquid chromatography tandem mass spectrometry. After oral administration, SAC was well absorbed with a bioavailability of 98%. Two major metabolites of SAC, N-acetyl-S-allylcysteine (NAc-SAC) and N-acetyl-S-allylcysteine sulfoxide (NAc-SACS), were detected in plasma, but their concentrations were markedly lower than those of SAC. SAC was metabolized to a limited extent, but most of the orally absorbed SAC was excreted into urine in the form of its N-acetylated metabolites. The amounts of SAC, NAc-SAC, and NAc-SACS excreted in urine over 24 h were 2.9%, 80%, and 11% of the orally administered SAC, respectively. The very low renal clearance (0.016 L ⋅ h(-1) ⋅ kg(-1)) of SAC indicated that it undergoes extensive renal reabsorption. These results collectively suggested that SAC was ultimately metabolized to NAc-SAC and NAc-SACS through the cycles of urinary excretion, renal reabsorption, and systemic recirculation. The pharmacokinetics of SAC in rats were characterized by high oral absorption, limited metabolism, and extensive renal reabsorption, all of which potentially contribute to its high and relatively long-lasting plasma concentrations. © 2016 American Society for Nutrition.

Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.

PubMed

Eichenbaum, Gary; Hsu, C-P; Subrahmanyam, Vangala; Chen, Jing; Scicinski, Jan; Galemmo, Robert A; Tuman, Robert W; Johnson, Dana L

2012-07-01

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed. Copyright © 2012 Wiley Periodicals, Inc.

The Effects of Physiological and Environmental Factors on Hepatic Perfusion and First-Pass Metabolism.

NASA Astrophysics Data System (ADS)

Modi, Marlene Woodruff

The interaction of three important parameters; hepatic blood flow (Q_{rm H} ), plasma protein binding (f), and hepatic intrinsic clearance (CL_{rm int}) determines the disposition of agents undergoing extensive first-pass metabolism. This collection of studies focuses on the interaction of these parameters in man and the rat in the presence and absence of a given physiological and environmental perturbation. Potential mechanisms implicated in the "Food Effect" phenomenon whereby concomitant food intake increases the bioavailability a basic lipophilic drug are examined. These investigations provide insight as to the physiological response of the liver in the face of nutritional, pharmacological and physiological perturbations. The measurement of hepatic blood flow is a necessary endeavor before and understanding of the hepatic circulation or hepatic clearance concepts can be realized. Preliminary studies were performed to improve our understanding of the factors affecting the interpretation of hepatic blood flow estimates. It has been postulated that this food effect is caused at least in part by a transient increase in Q _{rm H} with its associated decrease in hepatic first-pass metabolism. Posture was manipulated in such a manner as to simulate the hepatic blood flow pattern observed in postprandial subjects. Although transient changes in Q_{rm H } comparable in magnitude and duration to those encountered after food consumption were observed, the AUC _{rm oral} for propanolol was not affected. It is important to assess the free concentration being presented to the organ which is highly extracting the drug. Single macronutrient feedings of glucose and vitamin-free casein to male Sprague-Dawley rats did not produce significant changes in the serum protein binding of a model basic lipophilic drug (quinidine) in systemic or hepatic blood. It has been postulated that food intake may have a greater influence on the bioavailability of metoprolol (a high clearance drug) in extensive metabolizers of the drug. After a population of extensive and poor metabolizers of metoprolol were identified, the effect of chronic food intake on steady-state concentrations of metoprolol was examined in these two groups.

CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

PubMed

Fijal, Bonnie A; Guo, Yingying; Li, Si G; Ahl, Jonna; Goto, Taro; Tanaka, Yoko; Nisenbaum, Laura K; Upadhyaya, Himanshu P

2015-10-01

Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (≥5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine. © 2015, The American College of Clinical Pharmacology.

Impact of CYP2D6 polymorphisms on clinical efficacy & tolerability of metoprolol tartrate

PubMed Central

Hamadeh, Issam S.; Langaee, Taimour Y.; Dwivedi, Ruti; Garcia, Sofia; Burkley, Ben M.; Chapman, Arlene B.; Gums, John G.; Turner, Stephen T.; Gong, Yan; Cooper-DeHoff, Rhonda M.; Johnson, Julie A.

2014-01-01

Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol. PMID:24637943

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

PubMed Central

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment. PMID:23116312

Perspectives on new synthetic curcumin analogs and their potential anticancer properties.

PubMed

Vyas, Alok; Dandawate, Prasad; Padhye, Subhash; Ahmad, Aamir; Sarkar, Fazlul

2013-01-01

Curcumin is the active component of dried rhizome of Curcuma longa, a perennial herb belonging to ginger family, cultivated extensively in south and southeastern tropical Asia. It is widely consumed in the Indian subcontinent, south Asia and Japan in traditional food recipes. Extensive research over last few decades has shown that curcumin is a potent anti-inflammatory agent with powerful therapeutic potential against a variety of cancers. It suppresses proliferation and metastasis of human tumors through regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases and other enzymes. It induces apoptotic cell death and also inhibits proliferation of cancer cells by cell cycle arrest. Pharmacokinetic data has shown that curcumin undergoes rapid metabolism leading to glucuronidation and sulfation in the liver and excretion in the feces, which accounts for its poor systemic bioavailability. The compound has, therefore, been formulated and administered using different drug delivery systems such as liposomes, micelles, polysaccharides, phospholipid complexes and nanoparticles that can overcome the limitation of bioavailability to some extent. Attempts to avoid rapid metabolism of curcumin until now have been met with limited success. This has prompted researchers to look for new synthetic curcumin analogs in order to overcome the drawbacks of limited bioavailability and rapid metabolism, and gain efficacy with reduced toxicity. In this review we provide a summarized account of novel synthetic curcumin formulations and analogs, and the recent progress in the field of cancer prevention and treatment.

Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine

PubMed Central

Kirkwood, L. C.; Nation, R. L.; Somogyi, A. A.

1997-01-01

Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated. Methods The kinetics of formation of N- and O-demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied. Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N-demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N-demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N-demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O-demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O-demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer. Conclusions CYP2D6 is the major enzyme mediating O-demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. PMID:9431830

Reconstruction of biological pathways and metabolic networks from in silico labeled metabolites.

PubMed

Hadadi, Noushin; Hafner, Jasmin; Soh, Keng Cher; Hatzimanikatis, Vassily

2017-01-01

Reaction atom mappings track the positional changes of all of the atoms between the substrates and the products as they undergo the biochemical transformation. However, information on atom transitions in the context of metabolic pathways is not widely available in the literature. The understanding of metabolic pathways at the atomic level is of great importance as it can deconvolute the overlapping catabolic/anabolic pathways resulting in the observed metabolic phenotype. The automated identification of atom transitions within a metabolic network is a very challenging task since the degree of complexity of metabolic networks dramatically increases when we transit from metabolite-level studies to atom-level studies. Despite being studied extensively in various approaches, the field of atom mapping of metabolic networks is lacking an automated approach, which (i) accounts for the information of reaction mechanism for atom mapping and (ii) is extendable from individual atom-mapped reactions to atom-mapped reaction networks. Hereby, we introduce a computational framework, iAM.NICE (in silico Atom Mapped Network Integrated Computational Explorer), for the systematic atom-level reconstruction of metabolic networks from in silico labelled substrates. iAM.NICE is to our knowledge the first automated atom-mapping algorithm that is based on the underlying enzymatic biotransformation mechanisms, and its application goes beyond individual reactions and it can be used for the reconstruction of atom-mapped metabolic networks. We illustrate the applicability of our method through the reconstruction of atom-mapped reactions of the KEGG database and we provide an example of an atom-level representation of the core metabolic network of E. coli. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Analysis of optimality in natural and perturbed metabolic networks

PubMed Central

Segrè, Daniel; Vitkup, Dennis; Church, George M.

2002-01-01

An important goal of whole-cell computational modeling is to integrate detailed biochemical information with biological intuition to produce testable predictions. Based on the premise that prokaryotes such as Escherichia coli have maximized their growth performance along evolution, flux balance analysis (FBA) predicts metabolic flux distributions at steady state by using linear programming. Corroborating earlier results, we show that recent intracellular flux data for wild-type E. coli JM101 display excellent agreement with FBA predictions. Although the assumption of optimality for a wild-type bacterium is justifiable, the same argument may not be valid for genetically engineered knockouts or other bacterial strains that were not exposed to long-term evolutionary pressure. We address this point by introducing the method of minimization of metabolic adjustment (MOMA), whereby we test the hypothesis that knockout metabolic fluxes undergo a minimal redistribution with respect to the flux configuration of the wild type. MOMA employs quadratic programming to identify a point in flux space, which is closest to the wild-type point, compatibly with the gene deletion constraint. Comparing MOMA and FBA predictions to experimental flux data for E. coli pyruvate kinase mutant PB25, we find that MOMA displays a significantly higher correlation than FBA. Our method is further supported by experimental data for E. coli knockout growth rates. It can therefore be used for predicting the behavior of perturbed metabolic networks, whose growth performance is in general suboptimal. MOMA and its possible future extensions may be useful in understanding the evolutionary optimization of metabolism. PMID:12415116

Pathways of metabolism of [1'-14C]-trans-anethole in the rat and mouse.

PubMed

Bounds, S V; Caldwell, J

1996-07-01

This study describes the metabolic fate of trans-4'-methoxyprop-[1-14C]enylbenzene, the natural flavor compound trans-anethole, in rats and mice given single doses of 250 mg/kg body weight. In both rats and mice, an essentially quantitative (> 95% of dose) recovery of 14C was obtained with the majority in the 0-24 hr urine. Separation and identification of 18 urinary anethole metabolites were achieved by radio-HPLC, chemical derivatization, and GC/ MS. Anethole undergoes three primary oxidation pathways-O-demethylation, omega-side chain oxidation, and side chain epoxidation-followed by a variety of secondary pathways of oxidation and hydration, the products of which are extensively conjugated with sulfate, glucuronic acid, glycine, and glutathione. A novel major metabolite has been characterized in the rat, apparently originating from conjugation of the epoxide with glutathione, namely S-[1-(4'-methoxyphenyl)-2-hydroxypropane]-N-acetylcysteine. These metabolites are discussed in terms of the pathways responsible for and the toxicological consequences of their formation.

Influence of negative energy balance on cyclicity and fertility in the high producing dairy cow.

PubMed

Wathes, D C; Fenwick, M; Cheng, Z; Bourne, N; Llewellyn, S; Morris, D G; Kenny, D; Murphy, J; Fitzpatrick, R

2007-09-01

The peripartum period is of critical importance to subsequent health and fertility. Most cows enter a state of negative energy balance (NEB) associated with many metabolic changes which have carry over effects on the resumption and normality of estrous cyclicity and the success of subsequent inseminations. A dataset on 500 lactations explored the relationships between metabolic traits measured before and after calving with fertility. Stepwise multiple regression analysis showed that longer calving to conception intervals were associated with altered profiles of IGF-I, urea and body condition score. These relationships between metabolic profiles and fertility differed between first lactation cows (which are still growing but produce less milk) and mature animals. Early postpartum the liver undergoes extensive biochemical and morphological modifications to adapt to NEB, the uterus is extensively remodeled and must clear bacterial infections, and the ovary must resume ovulatory cycles. RNA isolated from liver and uterine tissues harvested 2 weeks postpartum from cows in mild (MNEB) and severe (SNEB) energy balance was used to screen the Affymetrix 23K bovine microarray. In liver, SNEB resulted in differential expression of key genes involved in lipid catabolism, gluconeogenesis, and the synthesis and stability of IGF-I. This was accompanied by reduced systemic concentrations of IGF-I which is likely to impact on ovarian function and early embryo development. Within endometrium, cows in SNEB showed histological evidence for higher levels of inflammation and the microarray analysis identified groups of differentially expressed genes involved in tissue remodeling and immune response. This may delay uterine repair after calving, likely contributing to the observed reduction in fertility.

In vitro metabolism of [14C]-benalaxyl in hepatocytes of rats, dogs and humans.

PubMed

Nallani, Gopinath C; ElNaggar, Shaaban F; Shen, Li; Chandrasekaran, Appavu

2017-03-01

The in vitro comparative animal metabolism study is now a data requirement under EU Directive 1107/2009 for registration of plant protection products. This type of study helps determine the extent of metabolism of a chemical in each surrogate species and whether any unique human metabolite(s) are formed. In the present study, metabolism of racemic [ 14 C]-benalaxyl, a fungicide was investigated in cryopreserved rat, dog and human hepatocytes. The metabolites generated were identified/characterized by LC/MS/MS with radiometric detection and comparison with reference standards. [ 14 C]-glucuronide conjugates of benalaxyl metabolites in rat, dog and human hepatocytes were confirmed via additional experiments in which known reference standards were incubated with dog liver microsomes in the presence of UDPGA. After 4 h of incubation, benalaxyl was extensively metabolized in all the species with the following trend: dog (100%) > human (86%) > rat (75%). In all species, the major metabolic pathways consisted of hydroxylation of the methyl group in the xylene moiety to 2-hydroxymethyl-benalaxyl, further oxidation to its carboxylic acid analogue (benalaxyl-2-benzoic acid), and hydrolysis of the methyl ester to yield benalaxyl acid or 2-hydroxymethyl benalaxyl acid. In addition, glucuronidation of phase I metabolites occurred in all species, to a higher extent in dog hepatocytes in which 2-hydroxymethyl-benalaxyl-glucuronide conjugate constituted the most significant metabolite. No major unique metabolite was observed in human hepatocytes. Also, benalaxyl did not undergo stereo-selective metabolism in rat or human hepatocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism.

PubMed

Eltzschig, Holger K; Thompson, Linda F; Karhausen, Jorn; Cotta, Richard J; Ibla, Juan C; Robson, Simon C; Colgan, Sean P

2004-12-15

Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A(2A) and A(2B) receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5'-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation.

The effect of grapefruit juice on drug disposition

PubMed Central

Hanley, Michael J.; Cancalon, Paul; Widmer, Wilbur W.; Greenblatt, David J.

2011-01-01

Introduction Since their initial discovery in 1989, grapefruit juice-drug interactions have received extensive interest from the scientific, medical, regulatory, and lay communities. Although knowledge regarding the effects of grapefruit juice on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. Areas covered This article reviews the in vitro effects of grapefruit juice and its constituents on the activity of cytochrome P450 enzymes, organic anion-transporting polypeptides, P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported area under the plasma concentration-time curve ratios for available grapefruit juice-drug interaction studies are also provided. Relevant investigations were identified by searching the Pubmed electronic database from 1989 to 2010. Expert opinion Grapefruit juice increases the bioavailability of some orally-administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, grapefruit juice can decrease the oral absorption of a few drugs that rely on organic anion-transporting polypeptides in the gastrointestinal tract for their uptake. The number of drugs shown to interact with grapefruit juice in vitro is far greater than the number of clinically relevant grapefruit juice-drug interactions. For the majority of patients, complete avoidance of grapefruit juice is unwarranted. PMID:21254874

Prevalence of unrecognized diabetes, prediabetes and metabolic syndrome in patients undergoing elective percutaneous coronary intervention.

PubMed

Balakrishnan, Revathi; Berger, Jeffrey S; Tully, Lisa; Vani, Anish; Shah, Binita; Burdowski, Joseph; Fisher, Edward; Schwartzbard, Arthur; Sedlis, Steven; Weintraub, Howard; Underberg, James A; Danoff, Ann; Slater, James A; Gianos, Eugenia

2015-09-01

Diabetes mellitus (DM) and metabolic syndrome are important targets for secondary prevention in cardiovascular disease. However, the prevalence in patients undergoing elective percutaneous coronary intervention is not well defined. We aimed to analyse the prevalence and characteristics of patients undergoing percutaneous coronary intervention with previously unrecognized prediabetes, diabetes and metabolic syndrome. Data were collected from 740 patients undergoing elective percutaneous coronary intervention between November 2010 and March 2013 at a tertiary referral center. Prevalence of DM and prediabetes was evaluated using Haemoglobin A1c (A1c ≥ 6.5% for DM, A1c 5.7-6.4% for prediabetes). A modified definition was used for metabolic syndrome [three or more of the following criteria: body mass index ≥30 kg/m2; triglycerides ≥ 150 mg/dL; high density lipoprotein <40 mg/dL in men and <50 mg/dL in women; systolic blood pressure ≥ 130 mmHg and/or diastolic ≥ 85 mmHg; and A1c ≥ 5.7% or on therapy]. Mean age was 67 years, median body mass index was 28.2 kg/m(2) and 39% had known DM. Of those without known DM, 8.3% and 58.5% met A1c criteria for DM and for prediabetes at time of percutaneous coronary intervention. Overall, 54.9% met criteria for metabolic syndrome (69.2% of patients with DM and 45.8% of patients without DM). Among patients undergoing elective percutaneous coronary intervention, a substantial number were identified with a new DM, prediabetes, and/or metabolic syndrome. Routine screening for an abnormal glucometabolic state at the time of revascularization may be useful for identifying patients who may benefit from additional targeting of modifiable risk factors. Copyright © 2015 John Wiley & Sons, Ltd.

Metabolic engineering of Clostridium cellulolyticum for the production of n-butanol from crystalline cellulose.

PubMed

Gaida, Stefan Marcus; Liedtke, Andrea; Jentges, Andreas Heinz Wilhelm; Engels, Benedikt; Jennewein, Stefan

2016-01-13

Sustainable alternatives for the production of fuels and chemicals are needed to reduce our dependency on fossil resources and to avoid the negative impact of their excessive use on the global climate. Lignocellulosic feedstock from agricultural residues, energy crops and municipal solid waste provides an abundant and carbon-neutral alternative, but it is recalcitrant towards microbial degradation and must therefore undergo extensive pretreatment to release the monomeric sugar units used by biofuel-producing microbes. These pretreatment steps can be reduced by using microbes such as Clostridium cellulolyticum that naturally digest lignocellulose, but this limits the range of biofuels that can be produced. We therefore developed a metabolic engineering approach in C. cellulolyticum to expand its natural product spectrum and to fine tune the engineered metabolic pathways. Here we report the metabolic engineering of C. cellulolyticum to produce n-butanol, a next-generation biofuel and important chemical feedstock, directly from crystalline cellulose. We introduced the CoA-dependent pathway for n-butanol synthesis from C. acetobutylicum and measured the expression of functional enzymes (using targeted proteomics) and the abundance of metabolic intermediates (by LC-MS/MS) to identify potential bottlenecks in the n-butanol biosynthesis pathway. We achieved yields of 40 and 120 mg/L n-butanol from cellobiose and crystalline cellulose, respectively, after cultivating the bacteria for 6 and 20 days. The analysis of enzyme activities and key intracellular metabolites provides a robust framework to determine the metabolic flux through heterologous pathways in C. cellulolyticum, allowing further improvements by fine tuning individual steps to improve the yields of n-butanol.

Muscle glucose metabolism in chronic obstructive pulmonary disease patients.

PubMed

Sancho-Muñoz, Antonio; Trampal, Carlos; Pascual, Sergi; Martínez-Llorens, Juana; Chalela, Roberto; Gea, Joaquim; Orozco-Levi, Mauricio

2014-06-01

Muscle dysfunction is one of the most extensively studied manifestations of COPD. Metabolic changes in muscle are difficult to study in vivo, due to the lack of non-invasive techniques. Our aim was to evaluate metabolic activity simultaneously in various muscle groups in COPD patients. Thirty-nine COPD patients and 21 controls with normal lung function, due to undergo computed axial and positron emission tomography for staging of localized lung lesions were included. After administration of 18-fluordeoxyglucose, images of 2 respiratory muscles (costal and crural diaphragm, and rectus abdominus) and 2 peripheral muscles (brachial biceps and quadriceps) were obtained, using the standard uptake value as the glucose metabolism index. Standard uptake value was higher in both portions of the diaphragm than in the other muscles of all subjects. Moreover, the crural diaphragm and rectus abdominus showed greater activity in COPD patients than in the controls (1.8±0.7 vs 1.4±0.8; and 0.78±0.2 vs 0.58±0.1; respectively, P<.05). A similar trend was observed with the quadriceps. In COPD patients, uptake in the two respiratory muscles and the quadriceps correlated directly with air trapping (r=0.388, 0.427 and 0.361, respectively, P<.05). There is greater glucose uptake and metabolism in the human diaphragm compared to other muscles when the subject is at rest. Increased glucose metabolism in the respiratory muscles (with a similar trend in their quadriceps) of COPD patients is confirmed quantitatively, and is directly related to the mechanical loads confronted. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

Predicting the extent of metabolism using in vitro permeability rate measurements and in silico permeability rate predictions

PubMed Central

Hosey, Chelsea M; Benet, Leslie Z

2015-01-01

The Biopharmaceutics Drug Disposition Classification System (BDDCS) can be utilized to predict drug disposition, including interactions with other drugs and transporter or metabolizing enzyme effects based on the extent of metabolism and solubility of a drug. However, defining the extent of metabolism relies upon clinical data. Drugs exhibiting high passive intestinal permeability rates are extensively metabolized. Therefore, we aimed to determine if in vitro measures of permeability rate or in silico permeability rate predictions could predict the extent of metabolism, to determine a reference compound representing the permeability rate above which compounds would be expected to be extensively metabolized, and to predict the major route of elimination of compounds in a two-tier approach utilizing permeability rate and a previously published model predicting the major route of elimination of parent drug. Twenty-two in vitro permeability rate measurement data sets in Caco-2 and MDCK cell lines and PAMPA were collected from the literature, while in silico permeability rate predictions were calculated using ADMET Predictor™ or VolSurf+. The potential for permeability rate to differentiate between extensively and poorly metabolized compounds was analyzed with receiver operating characteristic curves. Compounds that yielded the highest sensitivity-specificity average were selected as permeability rate reference standards. The major route of elimination of poorly permeable drugs was predicted by our previously published model and the accuracies and predictive values were calculated. The areas under the receiver operating curves were >0.90 for in vitro measures of permeability rate and >0.80 for the VolSurf+ model of permeability rate, indicating they were able to predict the extent of metabolism of compounds. Labetalol and zidovudine predicted greater than 80% of extensively metabolized drugs correctly and greater than 80% of poorly metabolized drugs correctly in Caco-2 and MDCK, respectively, while theophylline predicted greater than 80% of extensively and poorly metabolized drugs correctly in PAMPA. A two-tier approach predicting elimination route predicts 72±9%, 49±10%, and 66±7% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly when the permeability rate is predicted in silico and 74±7%, 85±2%, and 73±8% of extensively metabolized, biliarily eliminated, and renally eliminated parent drugs correctly, respectively when the permeability rate is determined in vitro. PMID:25816851

Metabolites characterization of chamaechromone in vivo and in vitro by using ultra-performance liquid chromatography/Xevo G2 quadrupole time-of-flight tandem mass spectrometry.

PubMed

Lou, Yan; Zheng, Jinqi; Wang, Baohong; Zhang, Xingguo; Zhang, Xia; Zeng, Su

2014-01-01

Stellera chamaejasme L. (Thymelaeaceae) was a toxic perennial herb and widely used as pesticide and dermatological agents in China. Chamaechromone was a major component in the dried roots of Stellera chamaejasme with anti-HBV and insecticidal activity. Analysis of metabolic profile in vivo and in vitro plays a pivotal role to unravel how TCM works. And the metabolites of chamaechromone might influence the effects and toxicity of Stellera chamaejasme. Moreover, the metabolic routes of chamaechromone provide an important basis for toxicological safety evaluation. Until now, little is known about the metabolism of chamaechromone. The current study was designed to characterize the whole metabolic pathways of chamaechromone in vitro and in vivo. Twenty-four rats were randomly divided into four groups, including two oral administration groups (100mgkg(-1)), one intravenous injection group (5 mgkg(-1)), and one control group. The metabolites in rat urine and feces and bile were identified by UPLC/Q-TOF MS analysis and β-glucuronidase hydrolysis. Moreover, the possible metabolic mechanism was further confirmed by Phase I and Phase II metabolism and catechol-O-methyltransferase methylation in rat liver S9 fraction and degradation in rat intestinal bacteria. A total of 24 metabolites from chamaechromone were detected and identified in vivo and in vitro, 20 of which were novel. And the major metabolic processes were hydroxylation, methylation, glucuronation, acetylation, dehydroxylation and degradation. The present study revealed the whole metabolic pathways of chamaechromone in rat through both in vitro and in vivo experiments for the first time. And chamaechromone could undergo extensive phase I and phase II metabolism in rat. These findings would provide an important basis for the further study and clinical application of chamaechromone. In addition, the results of this work have showed the feasibility of the UPLC/Q-TOF-MS approach for rapid and reliable characterization of metabolites. © 2013 Elsevier Ireland Ltd. All rights reserved.

Discrimination of healthy and cancer cells of the bladder by metabolic state, based on autofluorescence

NASA Astrophysics Data System (ADS)

Palmer, S.; Litvinova, Karina; Rafailov, E. U.; Nabi, G.

2015-02-01

Bladder cancer is among the most common cancers worldwide (4th in men). It is responsible for high patient morbidity and displays rapid recurrence and progression. Lack of sensitivity of gold standard techniques (white light cystoscopy, voided urine cytology) means many early treatable cases are missed. The result is a large number of advanced cases of bladder cancer which require extensive treatment and monitoring. For this reason, bladder cancer is the single most expensive cancer to treat on a per patient basis. In recent years, autofluorescence spectroscopy has begun to shed light into disease research. Of particular interest in cancer research are the fluorescent metabolic cofactors NADH and FAD. Early in tumour development, cancer cells often undergo a metabolic shift (the Warburg effect) resulting in increased NADH. The ratio of NADH to FAD ("redox ratio") can therefore be used as an indicator of the metabolic status of cells. Redox ratio measurements have been used to differentiate between healthy and cancer breast cells and to monitor cellular responses to therapies. Here, we have demonstrated, using healthy and bladder cancer cell lines, a statistically significant difference in the redox ratio of bladder cancer cells, indicative of a metabolic shift. To do this we customised a standard flow cytometer to excite and record fluorescence specifically from NADH and FAD, along with a method for automatically calculating the redox ratio of individual cells within large populations. These results could inform the design of novel probes and screening systems for the early detection of bladder cancer.

Metabolic profile of naringenin in the stomach and colon using liquid chromatography/electrospray ionization linear ion trap quadrupole-Orbitrap-mass spectrometry (LC-ESI-LTQ-Orbitrap-MS) and LC-ESI-MS/MS.

PubMed

Orrego-Lagarón, Naiara; Vallverdú-Queralt, Anna; Martínez-Huélamo, Miriam; Lamuela-Raventos, Rosa M; Escribano-Ferrer, Elvira

2016-02-20

Several biological activities (antioxidant, anti-inflammatory, anticarcinogenic) are attributed to naringenin (NAR)-a predominant flavonoid of citrus fruit and tomato-despite its low bioavailability after ingestion. NAR undergoes extensive metabolism when crossing the gastrointestinal tract, resulting in enteric, hepatic and microbial metabolites, some of them with recognized beneficial effects on human health. This study sought to provide new insights into the metabolism of NAR in regions of the gastrointestinal tract where it has been less studied: the stomach and colon. With this purpose, liquid chromatography coupled with an electrospray ionization hybrid linear ion trap quadrupole Orbitrap mass spectrometry technique (LC-ESI-LTQ-Orbitrap-MS) was used for an accurate identification of NAR metabolites, and liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) on a triple quadrupole was used for their identification and quantification. The combination of both analytical techniques provided a broader metabolic profile of NAR. As far as we know, this is the first in-depth metabolic profiling study of NAR in the stomach of mice. Three of the metabolites determined using the LC-LTQ-Orbitrap could not be identified by LC-ESI-MS/MS in stomach perfusion samples: apigenin, 3-(4-hydroxyphenyl) propionic acid and phloroglucinol. The number of colonic metabolites determined using the LTQ-Orbitrap-MS was more than twice the number identified by LC-ESI-MS/MS. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19.

PubMed

Yu, K S; Yim, D S; Cho, J Y; Park, S S; Park, J Y; Lee, K H; Jang, I J; Yi, S Y; Bae, K S; Shin, S G

2001-04-01

Moclobemide, an antidepressant with selective monoamine oxidase-A inhibitory action, is known to be metabolized by CYP2C19 and is also reported to be an inhibitor of CYP2C19, CYP2D6, and CYP1A2. To confirm the involvement of CYP2C19, we performed a pharmacokinetic interaction study. The effect of omeprazole on the pharmacokinetics of moclobemide was studied in 16 healthy volunteers. The volunteer group comprised 8 extensive metabolizers and 8 poor metabolizers of CYP2C19, which was confirmed by genotyping. Subjects were randomly allocated into two sequence groups, and a single-blind, placebo-controlled, two-period crossover study was performed. In study I, a placebo was orally administered for 7 days. On the eighth morning, 300 mg of moclobemide and 40 mg of placebo were coadministered with 200 mL of water, and a pharmacokinetic study was performed. During study II, 40 mg of omeprazole was given each morning instead of placebo, and pharmacokinetic studies were performed on the first and eighth day with 300 mg of moclobemide coadministration. The inhibition of moclobemide metabolism was significant in extensive metabolizers even after a single dose of omeprazole. After daily administration of omeprazole for 1 week, the pharmacokinetic parameters of moclobemide and its metabolites in extensive metabolizers changed to values similar to those in poor metabolizers. In poor metabolizers, no remarkable changes in the pharmacokinetic parameters were observed. Our results show that CYP2C19 is an important enzyme in the elimination of moclobemide and that it is extensively inhibited by omeprazole in extensive metabolizers, but not in poor metabolizers.

A broken krebs cycle in macrophages.

PubMed

O'Neill, Luke A J

2015-03-17

Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states. Copyright © 2015 Elsevier Inc. All rights reserved.

LC–MS Proteomics Analysis of the Insulin/IGF-1-Deficient Caenorhabditis elegans daf-2(e1370) Mutant Reveals Extensive Restructuring of Intermediary Metabolism

PubMed Central

2015-01-01

The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity, and metabolism in Caenorhabditis elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including the expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass spectrometry (LC–MS)-based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2);daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the upregulation of many core intermediary metabolic pathways. These include glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid β-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complexes I, II, III, and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative of spatiotemporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. This restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves and possibly also shunting metabolites through alternative energy-generating pathways to sustain longevity. PMID:24555535

Blocking Glycolytic Metabolism Increases Memory T Cells and Antitumor Function | Center for Cancer Research

Cancer.gov

CD8+ T cells are a major component of the cellular immune response, which is necessary to control a variety of bacterial and viral infections. CD8+ T cells also play a major role in the cell-mediated antitumor immune response. After encountering antigen, naïve CD8+ T cells undergo an extensive period of proliferation and expansion, and differentiate into effector cells and distinct memory T cell subsets. Preclinical studies using adoptive transfer of purified CD8+ T cells have shown that the ability of T cells to proliferate and survive for a long time after transfer is associated with effective antitumor and antiviral responses. Understanding how the formation of long-lived memory T cell subsets is controlled may enable development of more potent immunotherapies against cancer and infectious diseases.

Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

PubMed

Chen, Z R; Somogyi, A A; Reynolds, G; Bochner, F

1991-04-01

1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in the seven extensive metabolisers and 8 ml min-1 in the poor metaboliser; to norcodeine the values were 103 +/- 33 ml min-1 and 90 ml min-1; to codeine-6-glucuronide the values were 914 +/- 129 ml min-1 and 971 ml min-1; and intrinsic clearance was 1568 +/- 103 ml min-1 and 1450 ml min-1. These values were not significantly (P greater than 0.05) altered by chronic administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry

PubMed Central

Knittel, Jessica L.; Holler, Justin M.; Chmiel, Jeffrey D.; Vorce, Shawn P.; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z.

2016-01-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography–mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1–10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. PMID:26792810

Clinical Pharmacology in Adult and Pediatric Inflammatory Bowel Disease.

PubMed

Hemperly, Amy; Sandborn, William J; Vande Casteele, Niels

2018-05-17

This review describes the clinical pharmacology of the major drugs used for the treatment of patients with inflammatory bowel disease (IBD). Pharmacokinetics, drug metabolism, mechanism of action, efficacy, and safety profile are discussed. Some small molecules were developed to act systemically (eg, ozanimod) or locally (eg, aminosalicylates) and thus have disparate pharmacokinetic properties. In addition, locally acting compounds have been optimized to mitigate systemic exposure-eg, budesonide, which undergoes extensive first-pass metabolism-thereby reducing systemic bioavailability and side effects. Other small molecules such as thiopurines are precursors of their active metabolites and differences in genotype or phenotype of metabolizing enzymes may affect efficacy and safety, requiring therapeutic drug monitoring (TDM). Monoclonal antibodies (MAs) are large molecules administered parenterally, and their pharmacokinetics may be influenced not only by the general immunoglobulin (Ig) G metabolism and recycling pathways but also by antigen properties such as antigen distribution and antigen concentration. In addition, antibody structure, host factors, concurrent medications, and immunogenicity may contribute to the substantial inter- and intrapatient variability in drug exposure and response observed for MAs. Current guidelines recommend reactive TDM of tumor necrosis factor antagonists at the time of loss of response. Evidence for proactive TDM and for the role of TDM for biologics with a different mechanism of action is emerging. Although small molecules offer potential benefits over biologics with oral administration and lack of immunogenicity, there may be risk for more systemic side effects due to off-target binding. Understanding drug metabolism, pharmacokinetic characteristics, and mechanism of action are important in selecting the right drug at the right time at the right dose for patients with IBD.10.1093/ibd/izy189_video1izy189.video15786062223001.

Dynamic Adaptation of Liver Mitochondria to Chronic Alcohol Feeding in Mice

PubMed Central

Han, Derick; Ybanez, Maria D.; Johnson, Heather S.; McDonald, Jeniece N.; Mesropyan, Lusine; Sancheti, Harsh; Martin, Gary; Martin, Alanna; Lim, Atalie M; Dara, Lily; Cadenas, Enrique; Tsukamoto, Hidekazu; Kaplowitz, Neil

2012-01-01

Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD+ and NADH levels (∼2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD+, the rate-limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver. PMID:23086958

METABOLISM AND GENOTOXICITY OF 1-NITROPYRENE

EPA Science Inventory

1-Nitropyrene (NP), a nitrated polycyclic aromatic hydrocarbon and a potent bacterial mutagen, has been identified in combustion emissions and may contribute to the burden of genotoxicity associated with air pollution. NP undergoes rapid metabolism by rat hepatic subcellular frac...

LC-MS Proteomics Analysis of the Insulin/IGF-1 Deficient Caenorhabditis elegans daf-2(e1370) Mutant Reveals Extensive Restructuring of Intermediary Metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Depuydt, Geert G.; Xie, Fang; Petyuk, Vladislav A.

2014-02-20

The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity and metabolism in C. elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass-spectrometry (LC-MS) based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2); daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the up-regulation of many core intermediarymore » metabolic pathways. These include, glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid β-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complex I, II, III and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative for spatio-temporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. This restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves, possibly also shunting metabolites through alternative energy-generating pathways, in order to sustain longevity.« less

LC–MS Proteomics Analysis of the Insulin/IGF-1-Deficient Caenorhabditis elegans daf-2(e1370) Mutant Reveals Extensive Restructuring of Intermediary Metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Depuydt, Geert; Xie, Fang; Petyuk, Vladislav A.

2014-04-04

The insulin/IGF-1 receptor is a major known determinant of dauer formation, stress resistance, longevity, and metabolism in Caenorhabditis elegans. In the past, whole-genome transcript profiling was used extensively to study differential gene expression in response to reduced insulin/IGF-1 signaling, including the expression levels of metabolism-associated genes. Taking advantage of the recent developments in quantitative liquid chromatography mass spectrometry (LC–MS)-based proteomics, we profiled the proteomic changes that occur in response to activation of the DAF-16 transcription factor in the germline-less glp-4(bn2);daf-2(e1370) receptor mutant. Strikingly, the daf-2 profile suggests extensive reorganization of intermediary metabolism, characterized by the upregulation of many core intermediarymore » metabolic pathways. These include glycolysis/gluconeogenesis, glycogenesis, pentose phosphate cycle, citric acid cycle, glyoxylate shunt, fatty acid β-oxidation, one-carbon metabolism, propionate and tyrosine catabolism, and complexes I, II, III, and V of the electron transport chain. Interestingly, we found simultaneous activation of reciprocally regulated metabolic pathways, which is indicative of spatiotemporal coordination of energy metabolism and/or extensive post-translational regulation of these enzymes. Finally, this restructuring of daf-2 metabolism is reminiscent to that of hypometabolic dauers, allowing the efficient and economical utilization of internal nutrient reserves and possibly also shunting metabolites through alternative energy-generating pathways to sustain longevity.« less

Influence of Power Delivery Timing on the Energetics and Biomechanics of Humans Wearing a Hip Exoskeleton

PubMed Central

Young, Aaron J.; Foss, Jessica; Gannon, Hannah; Ferris, Daniel P.

2017-01-01

A broad goal in the field of powered lower limb exoskeletons is to reduce the metabolic cost of walking. Ankle exoskeletons have successfully achieved this goal by correctly timing a plantarflexor torque during late stance phase. Hip exoskeletons have the potential to assist with both flexion and extension during walking gait, but the optimal timing for maximally reducing metabolic cost is unknown. The focus of our study was to determine the best assistance timing for applying hip assistance through a pneumatic exoskeleton on human subjects. Ten non-impaired subjects walked with a powered hip exoskeleton, and both hip flexion and extension assistance were separately provided at different actuation timings using a simple burst controller. The largest average across-subject reduction in metabolic cost for hip extension was at 90% of the gait cycle (just prior to heel contact) and for hip flexion was at 50% of the gait cycle; this resulted in an 8.4 and 6.1% metabolic reduction, respectively, compared to walking with the unpowered exoskeleton. However, the ideal timing for both flexion and extension assistance varied across subjects. When selecting the assistance timing that maximally reduced metabolic cost for each subject, average metabolic cost for hip extension was 10.3% lower and hip flexion was 9.7% lower than the unpowered condition. When taking into account user preference, we found that subject preference did not correlate with metabolic cost. This indicated that user feedback was a poor method of determining the most metabolically efficient assistance power timing. The findings of this study are relevant to developers of exoskeletons that have a powered hip component to assist during human walking gait. PMID:28337434

Influence of Power Delivery Timing on the Energetics and Biomechanics of Humans Wearing a Hip Exoskeleton.

PubMed

Young, Aaron J; Foss, Jessica; Gannon, Hannah; Ferris, Daniel P

2017-01-01

A broad goal in the field of powered lower limb exoskeletons is to reduce the metabolic cost of walking. Ankle exoskeletons have successfully achieved this goal by correctly timing a plantarflexor torque during late stance phase. Hip exoskeletons have the potential to assist with both flexion and extension during walking gait, but the optimal timing for maximally reducing metabolic cost is unknown. The focus of our study was to determine the best assistance timing for applying hip assistance through a pneumatic exoskeleton on human subjects. Ten non-impaired subjects walked with a powered hip exoskeleton, and both hip flexion and extension assistance were separately provided at different actuation timings using a simple burst controller. The largest average across-subject reduction in metabolic cost for hip extension was at 90% of the gait cycle (just prior to heel contact) and for hip flexion was at 50% of the gait cycle; this resulted in an 8.4 and 6.1% metabolic reduction, respectively, compared to walking with the unpowered exoskeleton. However, the ideal timing for both flexion and extension assistance varied across subjects. When selecting the assistance timing that maximally reduced metabolic cost for each subject, average metabolic cost for hip extension was 10.3% lower and hip flexion was 9.7% lower than the unpowered condition. When taking into account user preference, we found that subject preference did not correlate with metabolic cost. This indicated that user feedback was a poor method of determining the most metabolically efficient assistance power timing. The findings of this study are relevant to developers of exoskeletons that have a powered hip component to assist during human walking gait.

Short-term effects of air temperature on plasma metabolite concentrations in patients undergoing cardiac catheterization

EPA Science Inventory

BACKGROUND: Epidemiological studies have shown associations between air temperature and cardiovascular health outcomes. Metabolic dysregulation might also play a role in the development of cardiovascular disease.OBJECTIVES: To investigate short-term temperature effects on metabol...

Gender and Species Differences in Triadimefon Metabolism by Rodent Hepatic Microsomes

EPA Science Inventory

Understanding the potential differences in metabolic capacity and kinetics between various common laboratory species as well as between genders is an important facet of chemical risk assessment that is often overlooked, particularly for chemicals which undergo non-cytochrome P450...

Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

ClinicalTrials.gov

2016-08-01

Lipid Metabolism, Inborn Errors; Hypercholesterolemia, Autosomal Dominant; Hyperlipidemias; Metabolic Diseases; Hyperlipoproteinemia Type II; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Metabolic Disorder; Congenital Abnormalities; Hypercholesterolemia; Hyperlipoproteinemias; Dyslipidemias; Lipid Metabolism Disorders

Even 'safe' medications need to be administered with care.

PubMed

Lutwak, Nancy; Howland, Mary Ann; Gambetta, Rosemarie; Dill, Curt

2013-01-02

A 60-year-old man with a history of hepatic cirrhosis and cardiomyopathy underwent transoesophageal echocardiogram. He received mild sedation and topical lidocaine. During the recovery period the patient developed ataxia and diplopia for about 30 mins, a result of lidocaine toxicity. The patient was administered a commonly used local anaesthetic, a combination of 2% viscous lidocaine, 4% lidocaine gargle and 5% lidocaine ointment topically to the oropharnyx. The total dose was at least 280 mg. Oral lidocaine undergoes extensive first pass metabolism and its clearance is quite dependent on rates of liver blood flow as well as other factors. The patient's central nervous system symptoms were mild and transient but remind us that to avoid adverse side effects, orally administered drugs with fairly high hepatic extraction ratio given to patients with chronic liver disease need to be given in reduced dosages. Even 'Safe' medications need to be carefully administered.

Even ‘safe’ medications need to be administered with care

PubMed Central

Lutwak, Nancy; Howland, Mary Ann; Gambetta, Rosemarie; Dill, Curt

2013-01-01

A 60-year-old man with a history of hepatic cirrhosis and cardiomyopathy underwent transoesophageal echocardiogram. He received mild sedation and topical lidocaine. During the recovery period the patient developed ataxia and diplopia for about 30 mins, a result of lidocaine toxicity. The patient was administered a commonly used local anaesthetic, a combination of 2% viscous lidocaine, 4% lidocaine gargle and 5% lidocaine ointment topically to the oropharnyx. The total dose was at least 280 mg. Oral lidocaine undergoes extensive first pass metabolism and its clearance is quite dependent on rates of liver blood flow as well as other factors. The patient's central nervous system symptoms were mild and transient but remind us that to avoid adverse side effects, orally administered drugs with fairly high hepatic extraction ratio given to patients with chronic liver disease need to be given in reduced dosages. Even ‘Safe’ medications need to be carefully administered. PMID:23283606

A kinetic study on the chemical cleavage of nucleoside diphosphate sugars.

PubMed

Huhta, Eija; Parjanen, Atte; Mikkola, Satu

2010-03-30

Nucleoside diphosphate sugars serve in essential roles in metabolic processes. They have, therefore, been used in mechanistic studies on glycosylation reactions, and their analogues have been synthesised as enzyme and receptor inhibitors. Despite extensive biochemical research, little is known about their chemical reactions. In the present work the chemical cleavage of two different types of nucleoside diphosphate sugars has been studied. UDP-Glc is phosphorylated at the anomeric carbon, whereas in ADP-Rib C-1 is unsubstituted, allowing hence the equilibrium between cyclic hemiacetal and acyclic carbonyl forms. Due to the structural difference, these substrates react via different pathways under slightly alkaline conditions: while UDP-Glc reacts exclusively by a nucleophilic attack of a glucose hydroxyl group on the diphosphate moiety, ADP-Rib undergoes a complex reaction sequence that involves isomerisation processes of the acyclic ribose sugar and results in a release of ADP. Copyright 2009 Elsevier Ltd. All rights reserved.

daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.

PubMed

Lin, K; Dorman, J B; Rodan, A; Kenyon, C

1997-11-14

The wild-type Caenorhabditis elegans nematode ages rapidly, undergoing development, senescence, and death in less than 3 weeks. In contrast, mutants with reduced activity of the gene daf-2, a homolog of the insulin and insulin-like growth factor receptors, age more slowly than normal and live more than twice as long. These mutants are active and fully fertile and have normal metabolic rates. The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators. In humans, insulin down-regulates the expression of certain genes by antagonizing the activity of HNF-3, raising the possibility that aspects of this regulatory system have been conserved.

Mucoadhesive drug delivery systems

PubMed Central

Shaikh, Rahamatullah; Raj Singh, Thakur Raghu; Garland, Martin James; Woolfson, A David; Donnelly, Ryan F.

2011-01-01

Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Over the past few decades, mucosal drug delivery has received a great deal of attention. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. Application of dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The mucoadhesive ability of a dosage form is dependent upon a variety of factors, including the nature of the mucosal tissue and the physicochemical properties of the polymeric formulation. This review article aims to provide an overview of the various aspects of mucoadhesion, mucoadhesive materials, factors affecting mucoadhesion, evaluating methods, and finally various mucoadhesive drug delivery systems (buccal, nasal, ocular, gastro, vaginal, and rectal). PMID:21430958

A compendium of geochemical information from the Saanich Inlet water column

NASA Astrophysics Data System (ADS)

Torres-Beltrán, Mónica; Hawley, Alyse K.; Capelle, David; Zaikova, Elena; Walsh, David A.; Mueller, Andreas; Scofield, Melanie; Payne, Chris; Pakhomova, Larysa; Kheirandish, Sam; Finke, Jan; Bhatia, Maya; Shevchuk, Olena; Gies, Esther A.; Fairley, Diane; Michiels, Céline; Suttle, Curtis A.; Whitney, Frank; Crowe, Sean A.; Tortell, Philippe D.; Hallam, Steven J.

2017-10-01

Extensive and expanding oxygen minimum zones (OMZs) exist at variable depths in coastal and open ocean waters. As oxygen levels decline, nutrients and energy are increasingly diverted away from higher trophic levels into microbial community metabolism, resulting in fixed nitrogen loss and production of climate active trace gases including nitrous oxide and methane. While ocean deoxygenation has been reported on a global scale, our understanding of OMZ biology and geochemistry is limited by a lack of time-resolved data sets. Here, we present a historical dataset of oxygen concentrations spanning fifty years and nine years of monthly geochemical time series observations in Saanich Inlet, a seasonally anoxic fjord on the coast of Vancouver Island, British Columbia, Canada that undergoes recurring changes in water column oxygenation status. This compendium provides a unique geochemical framework for evaluating long-term trends in biogeochemical cycling in OMZ waters.

Redox-linked Conformational Dynamics in Apoptosis Inducing Factor

PubMed Central

Sevrioukova, Irina F.

2009-01-01

Apoptosis inducing factor (AIF) is a bifunctional mitochondrial flavoprotein critical for energy metabolism and induction of caspase-independent apoptosis, whose exact role in normal mitochondria remains unknown. Upon reduction with NADH, AIF undergoes dimerization and forms tight, long-lived FADH2-NAD charge-transfer complexes (CTC) proposed to be functionally important. To get a deeper insight into structure/function relations and redox mechanism of this vitally important protein, we determined the x-ray structures of oxidized and NADH-reduced forms of naturally folded recombinant murine AIF. Our structures reveal that CTC with the pyridine nucleotide is stabilized by (i) π-stacking interactions between coplanar nicotinamide, isoalloxazine and Phe309 rings, (ii) rearrangement of multiple aromatic residues in the C-terminal domain, likely serving as an electron delocalization site, and (iii) an extensive hydrogen-bonding network involving His453, a key residue undergoing a conformational switch to directly interact and orient the nicotinamide in position optimal for charge transfer. Via the His453-containing peptide, redox changes in the active site are transmitted to the surface, promoting AIF dimerization and restricting access to a primary nuclear localization signal through which the apoptogenic form is transported to the nucleus. Structural findings agree with the biochemical data and support the hypothesis that both normal and apoptogenic functions of AIF are controlled by NADH. PMID:19447115

Moderate hyperventilation during intravenous anesthesia increases net cerebral lactate efflux.

PubMed

Grüne, Frank; Kazmaier, Stephan; Sonntag, Hans; Stolker, Robert Jan; Weyland, Andreas

2014-02-01

Hyperventilation is known to decrease cerebral blood flow (CBF) and to impair cerebral metabolism, but the threshold in patients undergoing intravenous anesthesia is unknown. The authors hypothesized that reduced CBF associated with moderate hyperventilation might impair cerebral aerobic metabolism in patients undergoing intravenous anesthesia. Thirty male patients scheduled for coronary surgery were included in a prospective, controlled crossover trial. Measurements were performed under fentanyl-midazolam anesthesia in a randomized sequence aiming at partial pressures of carbon dioxide of 30 and 50 mmHg. Endpoints were CBF, blood flow velocity in the middle cerebral artery, and cerebral metabolic rates for oxygen, glucose, and lactate. Global CBF was measured using a modified Kety-Schmidt technique with argon as inert gas tracer. CBF velocity of the middle cerebral artery was recorded by transcranial Doppler sonography. Data were presented as mean (SD). Two-sided paired t tests and one-way ANOVA for repeated measures were used for statistical analysis. Moderate hyperventilation significantly decreased CBF by 60%, blood flow velocity by 41%, cerebral oxygen delivery by 58%, and partial pressure of oxygen of the jugular venous bulb by 45%. Cerebral metabolic rates for oxygen and glucose remained unchanged; however, net cerebral lactate efflux significantly increased from -0.38 (2.18) to -2.41(2.43) µmol min 100 g. Moderate hyperventilation, when compared with moderate hypoventilation, in patients with cardiovascular disease undergoing intravenous anesthesia increased net cerebral lactate efflux and markedly reduced CBF and partial pressure of oxygen of the jugular venous bulb, suggesting partial impairment of cerebral aerobic metabolism at clinically relevant levels of hypocapnia.

Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat.

PubMed

Qaiser, M Zeeshan; Dolman, Diana E M; Begley, David J; Abbott, N Joan; Cazacu-Davidescu, Mihaela; Corol, Delia I; Fry, Jonathan P

2017-09-01

Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found 3 H-PregS to enter more rapidly than 3 H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of 3 H-DHEAS and 3 H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the 3 H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory. © 2017 International Society for Neurochemistry.

Analysis of Parent Synthetic Cannabinoids in Blood and Urinary Metabolites by Liquid Chromatography Tandem Mass Spectrometry.

PubMed

Knittel, Jessica L; Holler, Justin M; Chmiel, Jeffrey D; Vorce, Shawn P; Magluilo, Joseph; Levine, Barry; Ramos, Gerardo; Bosy, Thomas Z

2016-04-01

Synthetic cannabinoids emerged on the designer drug market in recent years due to their ability to produce cannabis-like effects without the risk of detection by traditional drug testing techniques such as immunoassay and gas chromatography-mass spectrometry. As government agencies work to schedule existing synthetic cannabinoids, new, unregulated and structurally diverse compounds continue to be developed and sold. Synthetic cannabinoids undergo extensive metabolic conversion. Consequently, both blood and urine specimens may play an important role in the forensic analysis of synthetic cannabinoids. It has been observed that structurally similar synthetic cannabinoids follow common metabolic pathways, which often produce metabolites with similar metabolic transformations. Presented are two validated quantitative methods for extracting and identifying 15 parent synthetic cannabinoids in blood, 17 synthetic cannabinoid metabolites in urine and the qualitative identification of 2 additional parent compounds. The linear range for most synthetic cannabinoid compounds monitored was 0.1-10 ng/mL with the limit of detection between 0.01 and 0.5 ng/mL. Selectivity, specificity, accuracy, precision, recovery and matrix effect were also examined and determined to be acceptable for each compound. The validated methods were used to analyze a compilation of synthetic cannabinoid investigative cases where both blood and urine specimens were submitted. The study suggests a strong correlation between the metabolites detected in urine and the parent compounds found in blood. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The Laboratory’s Role in Opioid Pain Medication Monitoring

PubMed Central

2012-01-01

Opioid analgesics are the most potent pain medications therefore they are often used for the treatment of chronic malignant and non-malignant pain. Their strong addictive potential requires close monitoring of patients on opioid therapy for possible non-compliance with prescriptions, for drug diversion, and for proof of avoidance of non-prescribed or illicit opioids. Monitoring can be performed by urine drug screens or qualitative or quantitative drug confirmation assays. Natural, semi-synthetic and synthetic opioids have dissimilar chemical structures and they undergo extensive metabolism. Phase one metabolic reactions of opioids can produce other opioids with similar structures to other, non-prescribed medications. Only detailed and concurrent analysis of parent drugs and metabolites can provide accurate clinical information regarding patient compliance. Traditional immunoassays, often used for urine drug screening, react with only a small number of opioids or only with a single medication and they exhibit variable cross reactivity with their phase two metabolites. Additionally the limit of detection of these immunoassays may not be sufficient for medical purposes, therefore clinical interpretation of immunoassay test results can be challenging. Recently liquid chromatography, mass spectrometry (LCMSMS) based assays have been adapted by many clinical laboratories. These LCMSMS tests can provide information about the presence of several opioids and their metabolites in a single sample at clinically meaningful detection limits, allowing accurate assessment of patient compliance. This review article will investigate in details the various opioids, their metabolism and the challenges the testing laboratories and ordering clinicians face. PMID:27683413

Rasagiline – a novel MAO B inhibitor in Parkinson’s disease therapy

PubMed Central

Lecht, Shimon; Haroutiunian, Simon; Hoffman, Amnon; Lazarovici, Philip

2007-01-01

Parkinson’s disease (PD) is a progressive neurodegenerative, dopamine deficiency disorder. The main therapeutic strategies for PD treatment relies on dopamine precursors (levodopa), inhibition of dopamine metabolism (monoamine oxidase [MAO] B and catechol-O-methyl transferase inhibitors), and dopamine receptor agonists. Recently, a novel selective and irreversible MAO B propargylamine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect®) was approved for PD therapy. In contrast to selegiline, the prototype of MAO B inhibitors, rasagiline is not metabolized to potentially toxic amphetamine metabolites. The oral bioavailability of rasagiline is 35%, it reaches Tmax after 0.5–1 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5–1 mg once-daily as adjunctive to levodopa in advanced PD patients. Rasagiline treatment was not associated with “cheese effect” and up to 20 mg per day was well tolerated. In PD patients with hepatic impairment, rasagiline dosage should be carefully adjusted. Rasagiline should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. Although further clinical evidence is needed on the neuroprotective effects of rasagiline in PD patients, this drug provides an additional tool for PD therapy. PMID:18488080

Metformin impacts cecal bile acid profiles in mice.

PubMed

Sillner, Nina; Walker, Alesia; Koch, Wendelin; Witting, Michael; Schmitt-Kopplin, Philippe

2018-04-15

Bile acids (BAs) are major components of bile synthesized from cholesterol and take part in the digestion of dietary lipids, as well as having signaling functions. They undergo extensive microbial metabolism inside the gastrointestinal tract. Here, we present a method of ultra-high pressure liquid chromatography coupled to ion trap mass spectrometry for quantification of 45 BAs in mouse cecum. The system was validated in regard to sensitivity with limits of detection and quantification (0.6-24.9 nM), interday accuracy (102.4%), interday precision (15.2%), recovery rate (74.7%), matrix effect (98.2%) and carry-over effect (<1.1%). Afterwards, we applied our method to investigate the effect of metformin on BA profiles. Diabetic mice were treated with metformin for 1 day or 14 days. One day of treatment resulted in a significant increase of total BA concentration (2.7-fold increase; db/db metformin 5.32 μmol/g, db/db control mice 1.95 μmol/g), most notable in levels of 7-oxodeoxycholic, 3-dehydrocholic and cholic acid. We observed only minor impact on BA metabolism after 14 days of metformin treatment, compared to the single treatment. Furthermore, healthy wild type mice had elevated concentrations of allocholic and ω-muricholic acid compared to diabetic mice. Our method proved the applicability of profiling BAs in cecum to investigate intestinal BA metabolism in diabetes and pharmacological applications. Copyright © 2018 Elsevier B.V. All rights reserved.

Oxygen and Temperature Effects on Vertically Migrating Animals in Oxygen Minimum Zones

NASA Astrophysics Data System (ADS)

Seibel, B.

2016-02-01

Large populations of oceanic nekton and zooplankton undergo daily migrations from shallow water at night to depths greater than 200 m during the daytime. In some regions, these migrations cross extreme gradients of temperature, oxygen and carbon dioxide. Oxygen minimum zones (OMZs) are extensive and characterized by deep-water (100-800 m) oxygen partial pressures that would be lethal to most marine organisms, yet are tolerated by vertical migrators. Climate change is predicted to further deplete oxygen, and measurable reductions in oxygen have already been documented in some regions. Increases in shallow water temperature and carbon dioxide are occurring simultaneously. Oxygen levels and temperature are important drivers of biodiversity and distribution, and documented changes in community structure and function are reportedly associated with OMZ expansion and warming. Here I answer fundamental questions concerning zooplankton distributions, adaptations, and functions in oxygen minimum zones. In particular I report that metabolic suppression is a common strategy that facilitates diel occupancy of extreme hypoxia in many oceanic taxa. Anaerobic metabolic pathways play a minimal role in compensating for reduced aerobic ATP production. Numerous epigenetic mechanisms lead to reductions in energetically costly cellular processes, such as transcription and translation. Total metabolism is reduced by 50% or more during exposure to levels of hypoxia that characterize the daytime habitat for most vertically-migrating zooplankton. I further show that many migrators approach their upper thermal maximum in shallow water at night. Thus expanding OMZs and global warming may together compress the habitable depth range for many species.

Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate.

PubMed

Ogungbenro, Kayode; Aarons, Leon

2014-04-01

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.

Obesity paradox in patients undergoing coronary intervention: A review

PubMed Central

Patel, Nirav; Elsaid, Ossama; Shenoy, Abhishek; Sharma, Abhishek; McFarlane, Samy I

2017-01-01

There is strong relationship exist between obesity and cardiovascular disease including coronary artery disease (CAD). However, better outcomes noted in obese patients undergoing percutaneous cardiovascular interventions for CAD, a phenomenon known as the obesity paradox. In this review, we performed extensive search for obesity paradox in obese patients undergoing percutaneous coronary intervention and discussed possible mechanism and disparities in different race and sex. PMID:29081905

ARISTOLOCHIC ACID I METABOLISM IN THE ISOLATED PERFUSED RAT KIDNEY

PubMed Central

Priestap, Horacio A.; Torres, M. Cecilia; Rieger, Robert A.; Dickman, Kathleen G.; Freshwater, Tomoko; Taft, David R.; Barbieri, Manuel A.; Iden, Charles R.

2012-01-01

Aristolochic acids are natural nitro-compounds found globally in the plant genus Aristolochia that have been implicated in the severe illness in humans termed aristolochic acid nephropathy (AAN). Aristolochic acids undergo nitroreduction, among other metabolic reactions, and active intermediates arise that are carcinogenic. Previous experiments with rats showed that aristolochic acid I (AA-I), after oral administration or injection, is subjected to detoxication reactions to give aristolochic acid Ia, aristolactam Ia, aristolactam I and their glucuronide and sulfate conjugates that can be found in urine and faeces. Results obtained with whole rats do not clearly define the role of liver and kidney in such metabolic transformation. In this study, in order to determine the specific role of the kidney on the renal disposition of AA-I and to study the biotransformations suffered by AA-I in this organ, isolated kidneys of rats were perfused with AA-I. AA-I and metabolite concentrations were determined in perfusates and urines using HPLC procedures. The isolated perfused rat kidney model showed that AA-I distributes rapidly and extensively in kidney tissues by uptake from the peritubular capillaries and the tubules. It was also established that the kidney is able to metabolize AA-I into aristolochic acid Ia, aristolochic acid Ia O-sulfate, aristolactam Ia, aristolactam I and aristolactam Ia O-glucuronide. Rapid demethylation and sulfation of AA-I in the kidney generate aristolochic acid Ia and its sulfate conjugate that are voided to the urine. Reduction reactions to give the aristolactam metabolites occur to a slower rate. Renal clearances showed that filtered AA-I is reabsorbed at the tubules whereas the metabolites are secreted. The unconjugated metabolites produced in the renal tissues are transported to both urine and perfusate whereas the conjugated metabolites are almost exclusively secreted to the urine. PMID:22118289

Metabolism of the Synthetic Progestogen Norethynodrel by Human Ketosteroid Reductases of the Aldo-Keto Reductase Superfamily

PubMed Central

Jin, Yi; Duan, Ling; Chen, Mo; Penning, Trevor M; Kloosterboer, Helenius J.

2012-01-01

Human ketosteroid reductases of the aldo-keto reductase (AKR) superfamily, i.e. AKR1C1-4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxy metabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ4-isomer of NOR and the most commonly used synthetic progestin, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB. PMID:22210085

Altered xanthine oxidase and N-acetyltransferase activity in obese children.

PubMed

Chiney, Manoj S; Schwarzenberg, Sarah J; Johnson, L'aurelle A

2011-07-01

It is well established that oxidative and conjugative enzyme activity differs between obese and healthy-weight adults. However, the effect of obesity on drug metabolism in children has not been studied extensively. This study examined whether obese and healthy-weight children vary with respect to oxidative enzyme activity of CYP1A2, xanthine oxidase (XO) and conjugative enzyme activity of N-acetyltransferase 2 (NAT2). In vivo CYP1A2, XO and NAT2 activity was assessed in obese (n= 9) and lean (n= 16) children between the ages of 6-10 years using caffeine (118.3 ml Coca Cola®) as probe. Urine samples were collected in 2-h increments over 8 h. Caffeine and metabolites were measured using LC/MS, and urinary metabolic ratios were determined based on reported methods. Sixteen healthy-weight and nine obese children were evaluated. XO activity was elevated in paediatric obese volunteers compared with non-obese paediatric volunteers (XO metabolic ratio of 0.7 ± 0.06 vs. 0.6 ± 0.06, respectively, 95% CI 0.046, 0.154, P < 0.001). NAT2 activity was fivefold higher in the obese (1 ± 0.4) as compared with non-obese children (0.2 ± 0.1), 95% CI 0.26, 1.34, P < 0.05. However, no difference was observed in CYP1A2 activity between the groups (95% CI -2.72, 0.12, P > 0.05). This study provides evidence that obese children have elevated XO and NAT2 enzyme activity when compared with healthy-weight controls. Further studies are needed to determine how this may impact the efficacy of therapeutic agents that may undergo metabolism by these enzymes. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long-chain acyl-CoA dehydrogenase-deficient mice.

PubMed

Tucci, Sara; Mingirulli, Nadja; Wehbe, Zeinab; Dumit, Verónica I; Kirschner, Janbernd; Spiekerkoetter, Ute

2018-01-01

The white skeletal muscle of very long-chain acyl-CoA-dehydrogenase-deficient (VLCAD -/- ) mice undergoes metabolic modification to compensate for defective β-oxidation in a progressive and time-dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD -/- mice with different medium-chain triglycerides over 1 year revealed that odd-chain species has no effect on muscle fiber switch, whereas even-chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process. © 2017 Federation of European Biochemical Societies.

Biochemistry of proinflammatory macrophage activation.

PubMed

Nonnenmacher, Yannic; Hiller, Karsten

2018-06-01

In the last decade, metabolism has been recognized as a major determinant of immunological processes. During an inflammatory response, macrophages undergo striking changes in their metabolism. This metabolic reprogramming is governed by a complex interplay between metabolic enzymes and metabolites of different pathways and represents the basis for proper macrophage function. It is now evident that these changes go far beyond the well-known Warburg effect and the perturbation of metabolic targets is being investigated as a means to treat infections and auto-immune diseases. In the present review, we will aim to provide an overview of the metabolic responses during proinflammatory macrophage activation and show how these changes modulate the immune response.

Metabolic Syndrome Prevalence and Associations in a Bariatric Surgery Cohort from the Longitudinal Assessment of Bariatric Surgery-2 Study

PubMed Central

Selzer, Faith; Smith, Mark D.; Berk, Paul D.; Courcoulas, Anita P.; Inabnet, William B.; King, Wendy C.; Pender, John; Pomp, Alfons; Raum, William J.; Schrope, Beth; Steffen, Kristine J.; Wolfe, Bruce M.; Patterson, Emma J.

2014-01-01

Abstract Background: Metabolic syndrome is associated with higher risk for cardiovascular disease, sleep apnea, and nonalcoholic steatohepatitis, all common conditions in patients referred for bariatric surgery, and it may predict early postoperative complications. The objective of this study was to determine the prevalence of metabolic syndrome, defined using updated National Cholesterol Education Program criteria, in adults undergoing bariatric surgery and compare the prevalence of baseline co-morbid conditions and select operative and 30-day postoperative outcomes by metabolic syndrome status. Methods: Complete metabolic syndrome data were available for 2275 of 2458 participants enrolled in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2), an observational cohort study designed to evaluate long-term safety and efficacy of bariatric surgery in obese adults. Results: The prevalence of metabolic syndrome was 79.9%. Compared to those without metabolic syndrome, those with metabolic syndrome were significantly more likely to be men, to have a higher prevalence of diabetes and prior cardiac events, to have enlarged livers and higher median levels of liver enzymes, a history of sleep apnea, and a longer length of stay after surgery following laparoscopic Roux-en-Y gastric bypass (RYGB) and gastric sleeves but not open RYGB or laparoscopic adjustable gastric banding. Metabolic syndrome status was not significantly related to duration of surgery or rates of composite end points of intraoperative events and 30-day major adverse surgical outcomes. Conclusions: Nearly four in five participants undergoing bariatric surgery presented with metabolic syndrome. Establishing a diagnosis of metabolic syndrome in bariatric surgery patients may identify a high-risk patient profile, but does not in itself confer a higher risk for short-term adverse postsurgery outcomes. PMID:24380645

Metabolic syndrome prevalence and associations in a bariatric surgery cohort from the Longitudinal Assessment of Bariatric Surgery-2 study.

PubMed

Purnell, Jonathan Q; Selzer, Faith; Smith, Mark D; Berk, Paul D; Courcoulas, Anita P; Inabnet, William B; King, Wendy C; Pender, John; Pomp, Alfons; Raum, William J; Schrope, Beth; Steffen, Kristine J; Wolfe, Bruce M; Patterson, Emma J

2014-03-01

Metabolic syndrome is associated with higher risk for cardiovascular disease, sleep apnea, and nonalcoholic steatohepatitis, all common conditions in patients referred for bariatric surgery, and it may predict early postoperative complications. The objective of this study was to determine the prevalence of metabolic syndrome, defined using updated National Cholesterol Education Program criteria, in adults undergoing bariatric surgery and compare the prevalence of baseline co-morbid conditions and select operative and 30-day postoperative outcomes by metabolic syndrome status. Complete metabolic syndrome data were available for 2275 of 2458 participants enrolled in the Longitudinal Assessment of Bariatric Surgery-2 (LABS-2), an observational cohort study designed to evaluate long-term safety and efficacy of bariatric surgery in obese adults. The prevalence of metabolic syndrome was 79.9%. Compared to those without metabolic syndrome, those with metabolic syndrome were significantly more likely to be men, to have a higher prevalence of diabetes and prior cardiac events, to have enlarged livers and higher median levels of liver enzymes, a history of sleep apnea, and a longer length of stay after surgery following laparoscopic Roux-en-Y gastric bypass (RYGB) and gastric sleeves but not open RYGB or laparoscopic adjustable gastric banding. Metabolic syndrome status was not significantly related to duration of surgery or rates of composite end points of intraoperative events and 30-day major adverse surgical outcomes. Nearly four in five participants undergoing bariatric surgery presented with metabolic syndrome. Establishing a diagnosis of metabolic syndrome in bariatric surgery patients may identify a high-risk patient profile, but does not in itself confer a higher risk for short-term adverse postsurgery outcomes.

CRISPR/Cas9 System as a Valuable Genome Editing Tool for Wine Yeasts with Application to Decrease Urea Production

PubMed Central

Vigentini, Ileana; Gebbia, Marinella; Belotti, Alessandra; Foschino, Roberto; Roth, Frederick P.

2017-01-01

An extensive repertoire of molecular tools is available for genetic analysis in laboratory strains of S. cerevisiae. Although this has widely contributed to the interpretation of gene functionality within haploid laboratory isolates, the genetics of metabolism in commercially-relevant polyploid yeast strains is still poorly understood. Genetic engineering in industrial yeasts is undergoing major changes due to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) engineering approaches. Here we apply the CRISPR/Cas9 system to two commercial “starter” strains of S. cerevisiae (EC1118, AWRI796), eliminating the CAN1 arginine permease pathway to generate strains with reduced urea production (18.5 and 35.5% for EC1118 and AWRI796, respectively). In a wine-model environment based on two grape musts obtained from Chardonnay and Cabernet Sauvignon cultivars, both S. cerevisiae starter strains and CAN1 mutants completed the must fermentation in 8–12 days. However, recombinant strains carrying the can1 mutation failed to produce urea, suggesting that the genetic modification successfully impaired the arginine metabolism. In conclusion, the reduction of urea production in a wine-model environment confirms that the CRISPR/Cas9 system has been successfully established in S. cerevisiae wine yeasts. PMID:29163459

Influence of atorvastatin on the pharmacodynamic and pharmacokinetic activity of repaglinide in rats and rabbits.

PubMed

Sekhar, Makula Chandra; Reddy, P Jaya Chandra

2012-05-01

Dyslipidemia is common in patients with type 2 diabetes. Statins are used as the first choice in treatment of diabetic dyslipidemia. Atorvastatin represents a first-line treatment option, alongside other hydroxyl methylglutaryl coenzyme A reductase inhibitors. Repaglinide is a short-acting, oral, insulin secretagogue that is used in the treatment of type 2 diabetes mellitus. Both the category of drugs undergo extensive metabolism with cytochrome enzyme system. This may lead to drug-drug interaction problems with altered repaglinide activity which is cautious. Repaglinide/atorvastatin/atorvastatin + repaglinide were administered orally to normal, diabetic rats, and to normal rabbits. Blood samples were collected at different time intervals and were analyzed for blood glucose by GOD-POD method using commercial glucose kits and repaglinide estimation in plasma by HPLC method. Diabetes was induced by alloxan 100 mg/kg body weight administered by I.P route. In the presence of atorvastatin, repaglinide activity was increased and maintained for longer period in diabetic rats compared with repaglinide matching control. The present study concludes co-administration of atorvastatin was found to improve repaglinide responses significantly in diabetic rats and improved glucose metabolism of atorvastatin played an important role and increased repaglinide levels by competitive CYP 3A4 enzyme inhibition by atorvastatin could be added advantage for anti hyperglycemic activity.

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

PubMed Central

WILCOX, CHRISTOPHER S.; PEARLMAN, ADAM

2009-01-01

Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension. PMID:19112152

Potential additional effect of omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in grade III obese patients undergoing laparoscopic Roux-en-Y gastric bypass: a randomized trial.

PubMed

Herrera, Miguel F; Pantoja, Juan Pablo; Velázquez-Fernández, David; Cabiedes, Javier; Aguilar-Salinas, Carlos; García-García, Eduardo; Rivas, Alfredo; Villeda, Christian; Hernández-Ramírez, Diego F; Dávila, Andrea; Zaraín, Aarón

2010-07-01

To assess the additional effect of sudden visceral fat reduction by omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in patients with grade III obesity (G-III O) undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB). Twenty-two patients were randomized into two groups, LRYGB alone or with omentectomy. Levels of interleukin-6, C-reactive protein, tumor necrosis factor-alpha, leptin, adiponectin, glucose, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, as well as clinical characteristics, were evaluated before surgery and at 1, 3, 6, and 12 months after surgery. Results were compared between groups. Baseline characteristics were comparable in both groups. Mean operative time was significantly higher in the group of patients who underwent omentectomy (P < 0.001). Median weight of the omentum was 795 +/- 341 g. In one patient, a duodenal perforation occurred at the time of omentectomy. BMI, blood pressure, glucose, total cholesterol, LDL, and triglycerides significantly improved in both groups at 1, 3, 6, and 12 months of follow-up when compared with basal values. However, there were no consistent statistically significant differences among the groups in terms of metabolic syndrome components, acute-phase reactants, and inflammatory mediators. Omentectomy does not have an ancillary short-term significant impact on the components of metabolic syndrome and does not induce important changes in the inflammatory mediators in patients undergoing LRYGB. Operative time is more prolonged when omentectomy is performed.

Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

USDA-ARS?s Scientific Manuscript database

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia

ClinicalTrials.gov

2016-08-01

Lipid Metabolism, Inborn Errors; Hypercholesterolemia, Autosomal Dominant; Hyperlipidemias; Metabolic Diseases; Hyperlipoproteinemia Type II; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Metabolic Disorder; Congenital Abnormalities; Hypercholesterolemia; Hyperlipoproteinemias; Dyslipidemias; Lipid Metabolism Disorders

Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery.

PubMed

Senanayake, Eshan L; Howell, Neil J; Ranasinghe, Aaron M; Drury, Nigel E; Freemantle, Nick; Frenneaux, Michael; Oelofse, Tessa; Green, David; Wilson, Ian C; Rooney, Stephen J; Mascaro, Jorge; Graham, Timothy R; Bhudia, Sunil; Lewis, Michael; Pagano, Domenico

2015-09-01

Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR). In a multicentre double-blind randomized controlled trial of patients with AS undergoing AVR ± coronary artery bypass graft surgery, patients were randomized to preoperative oral therapy with either perhexiline or placebo. The primary end point was incidence of inotrope use to improve haemodynamic performance due to a low cardiac output state during the first 6 h of reperfusion, judged by a blinded end points committee. Secondary outcome measures included haemodynamic measurements, electrocardiographic and biochemical markers of new myocardial injury and clinical safety outcome measures. The trial was halted early on the advice of the Data Safety and Monitoring Board. Sixty-two patients were randomized to perhexiline and 65 to placebo. Of these, 112 (54 perhexiline and 48 placebo) patients received the intervention, remained in the trial at the time of the operation and were analysed. Of 110 patients who achieved the primary end point, 30 patients (16 perhexiline and 14 placebo) had inotropes started appropriately; there was no difference in the incidence of inotrope usage OR of 1.65 [confidence interval (CI): 0.67-4.06] P = 0.28. There was no difference in myocardial injury as evidenced by electrocardiogram odds ratio (OR) of 0.36 (CI: 0.07-1.97) P = 0.24 or postoperative troponin release. Gross secondary outcome measures were comparable between the groups. Perhexiline as a metabolic modulator to enhance standard myocardial protection does not provide an additional benefit in haemodynamic performance or attenuate myocardial injury in the hypertrophied heart secondary to AS. The role of perhexiline in cardiac surgery is limited. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics

PubMed Central

Vuong, Chau; Xie, Lisa H.; Potter, Brittney M. J.; Zhang, Jing; Zhang, Ping; Duan, Dehui; Nolan, Christina K.; Sciotti, Richard J.; Zottig, Victor E.; Nanayakkara, N. P. Dhammika; Tekwani, Babu L.; Walker, Larry A.; Smith, Philip L.; Paris, Robert M.; Read, Lisa T.; Li, Qigui; Pybus, Brandon S.; Sousa, Jason C.; Reichard, Gregory A.; Smith, Bryan

2015-01-01

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations. PMID:25870069

The association between nitroglycerin use and adverse outcomes in women undergoing cesarean delivery in the second stage of labor.

PubMed

Isquick, Sarah; Henry, Dana; Nakagawa, Sanae; Moghadassi, Michelle; Thiet, Mari-Paule; Norton, Mary; Lucero, Jennifer

2017-06-01

To identify predictors of hysterotomy extension in women undergoing cesarean delivery (CD) in the second stage of labor, and whether use of nitroglycerin (NTG) during CD has a protective effect. We conducted a retrospective cohort study of women undergoing CD in the second stage of labor from 2012 to 2015. Some women received NTG at the obstetrician's request. Logistic regression was used to examine the relationship between second stage duration and NTG administration on maternal and neonatal outcomes. Of the 391 women in the sample, 27% had an extension and 12% received NTG. Second stage ≥4 h was associated with a 2.14-fold higher risk of extension (95% CI 1.22-3.75), a 2.00-fold higher risk of hemorrhage (95% CI: 1.20-3.33) and 2.42-fold higher risk of blood transfusion during delivery hospitalization (95% CI: 0.99-5.91). Intravenous (IV) and sublingual-spray (SL-spray) NTG administration were not associated with an increased risk of hemorrhage or extension. SL-NTG was associated with 4.68-fold increased odds of 5-min Apgar <7 (95% CI 1.42-15.41) and 3.36-fold greater odds of NICU admission (95% CI 1.20-9.41). We found no evidence that NTG protects against extension, and SL-NTG use was associated with adverse neonatal outcomes. Clinical trials should be conducted to evaluate risk and benefits of NTG use.

Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome P450 2C9 and variants.

PubMed

Patton, Amy L; Seely, Kathryn A; Yarbrough, Azure L; Fantegrossi, William; James, Laura P; McCain, Keith R; Fujiwara, Ryoichi; Prather, Paul L; Moran, Jeffery H; Radominska-Pandya, Anna

2018-04-06

Synthetic cannabinoids (SCBs), synonymous with 'K2', 'Spice' or 'synthetic marijuana', are psychoactive drugs of abuse that frequently result in clinical effects and toxicity more severe than those classically associated with Δ 9 -tetrahydrocannabinol such as extreme agitation, hallucinations, supraventricular tachycardia, syncope, and seizures. JWH-018 is one of the earliest compounds identified in various SCB products, and our laboratory previously demonstrated that JWH-018 undergoes extensive metabolism by cytochromes P450 (P450), binds to, and activates cannabinoid receptors (CBRs). The major enzyme involved in the metabolism of JWH-018 is CYP2C9, a highly polymorphic enzyme found largely in the intestines and liver, with *1 being designated as the wild type, and *2 and *3 as the two most common variants. Three different major products have been identified in human urine and plasma: JWH-018 (ω)-OH, JWH-018 (ω-1)-OH(R), and JWH-018 (ω-1)-OH(S). The (ω-1)-OH metabolite of JWH-018 is a chiral molecule, and is thus designated as either (ω-1)-OH(R) or (ω-1)-OH(S). Here, in vitro enzyme kinetic assays performed with human recombinant CYP2C9 variants (*1, *2, and *3) revealed that oxidative metabolism by CYP2C9*3 resulted in significantly less formation of (ω)-OH and (ω-1)-OH metabolites. Surprisingly, CYP2C9*2 was roughly 3.6-fold more efficient as the CYP2C9*1 enzyme based on V max /K m , increasing the rate of JWH-018 metabolism and allowed for a much more rapid elimination. These results suggest that genetic polymorphisms of P450 enzymes result in the production of varying levels of biologically active JWH-018 metabolites in some individuals, offering a mechanistic explanation for the diverse clinical toxicity often observed following JWH-018 abuse. Copyright © 2018 Elsevier Inc. All rights reserved.

77 FR 20654 - Proposed Extension of Existing Collection; Comment Request; Correction

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

...) and the Longshore and Harbor Workers' Compensation Act (LHWCA). These acts provide vocational... may pay an individual undergoing vocational rehabilitation a maintenance allowance, not to exceed $200 a month. 33 U.S.C. 908(g) of the LHWCA provides that person(s) undergoing such vocational...

Adaptation to walking with an exoskeleton that assists ankle extension.

PubMed

Galle, S; Malcolm, P; Derave, W; De Clercq, D

2013-07-01

The goal of this study was to investigate adaptation to walking with bilateral ankle-foot exoskeletons with kinematic control that assisted ankle extension during push-off. We hypothesized that subjects would show a neuromotor and metabolic adaptation during a 24min walking trial with a powered exoskeleton. Nine female subjects walked on a treadmill at 1.36±0.04ms(-1) during 24min with a powered exoskeleton and 4min with an unpowered exoskeleton. Subjects showed a metabolic adaptation after 18.5±5.0min, followed by an adapted period. Metabolic cost, electromyography and kinematics were compared between the unpowered condition, the beginning of the adaptation and the adapted period. In the beginning of the adaptation (4min), a reduction in metabolic cost of 9% was found compared to the unpowered condition. This reduction was accompanied by reduced muscular activity in the plantarflexor muscles, as the powered exoskeleton delivered part of the necessary ankle extension moment. During the adaptation this metabolic reduction further increased to 16%, notwithstanding a constant exoskeleton assistance. This increased reduction is the result of a neuromotor adaptation in which subjects adapt to walking with the exoskeleton, thereby reducing muscular activity in all leg muscles. Because of the fast adaptation and the significant reductions in metabolic cost we want to highlight the potential of an ankle-foot exoskeleton with kinematic control that assists ankle extension during push-off. Copyright © 2013 Elsevier B.V. All rights reserved.

Nutritional and metabolic status of breast cancer women.

PubMed

Bering, Tatiana; Maurício, Sílvia Fernandes; Silva, Jacqueline Braga da; Correia, Maria Isabel Toulson Davisson

2014-09-28

The nutritional and metabolic status have been related to cancer risk factors as well as to cancer treatment morbimortality. Thus, its assessment is important for developing strategies for the promotion, maintenance and / or recovery of nutritional status and cancer outcome. Several different methods for nutritional assessment in breast cancer patients undergoing adjuvant therapy were used, including subjective global assessment (SGA), body mass index (BMI), triceps skinfold (TSF), mid-arm circumference (MAC), adductor pollicis muscle thickness (APMT), hand grip strength (HGS) and bioelectrical impedance analysis (BIA). The presence of metabolic syndrome (MetS) was also evaluated. The occurrence of complications during cancer treatment versus the nutritional status was assessed. We followed 78 women with a mean age of 53.2 } 11.6 years. Most patients were considered well nourished (80.8%). Excessive body fat mass by BIA and MetS were found in 80,8 % and 41.9% of the patients respectively. There were significant differences in BMI, TSF, WC (waist circumference) and % fat mass between patients with and without MetS. Most patients experienced complications during cancer treatment, but there was no association with nutritional or metabolic status. In breast cancer women undergoing adjuvant therapy, the prevalence of metabolic syndrome was high and, on the contrary, undernutrition was low. There were no short-term effects of metabolic syndrome or undernutrition on clinical outcomes. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

META-ANALYSIS OF CYP2D6 METABOLIZER PHENOTYPE AND METOPROLOL PHARMACOKINETICS

PubMed Central

Blake, CM; Kharasch, ED; Schwab, M; Nagele, P

2013-01-01

Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate release metoprolol was performed. Pooled analysis (n= 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13-, 2.6-, and 15-fold between ultra-rapid and poor metabolizers (all p<0.001). Enantiomer-specific analysis revealed genotype-dependent enantio-selective metabolism, with nearly 40% greater R- vs S-metoprolol metabolism in ultra-rapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer specific metabolism of metoprolol. PMID:23665868

Autologous Islet Transplantation in Patients Requiring Pancreatectomy: A Broader Spectrum of Indications Beyond Chronic Pancreatitis.

PubMed

Balzano, G; Maffi, P; Nano, R; Mercalli, A; Melzi, R; Aleotti, F; Zerbi, A; De Cobelli, F; Gavazzi, F; Magistretti, P; Scavini, M; Peccatori, J; Secchi, A; Ciceri, F; Del Maschio, A; Falconi, M; Piemonti, L

2016-06-01

Islet autotransplantation (IAT) is usually performed in patients undergoing pancreatic surgery for chronic pancreatitis. In the present series, IAT was offered also to patients undergoing pancreatic surgery for both nonmalignant and malignant diseases, having either completion pancreatectomy as treatment for severe pancreatic fistulas (n = 21) or extensive distal pancreatectomy for neoplasms of the pancreatic neck (n = 19) or pancreatoduodenectomy because of the high risk of pancreatic fistula (n = 32). Fifty-eight of 72 patients who were eligible to this broader spectrum of indication actually received IAT. There was no evidence of a higher-than-expected rate of major complications for pancreatectomy. Forty-five patients receiving IAT were still alive at the time of the last scheduled follow-up (1375 ± 365 days). Eighteen (95%) of 19 and 11 (28%) of 39 patients reached insulin independence after partial or total pancreatectomy, respectively. The metabolic results were dependent on the transplanted islet mass. Thirty-one of 58 patients had malignant diseases of the pancreas or periampullary region, and only three patients developed ex novo liver metastases after IAT (median follow-up 914 ± 382 days). Our data demonstrate the feasibility, efficacy, and safety of IAT for a broader spectrum of clinical indications beyond chronic pancreatitis. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

The rate of lactate production from glucose in hearts is not altered by per-deuteration of glucose

NASA Astrophysics Data System (ADS)

Funk, Alexander M.; Anderson, Brian L.; Wen, Xiaodong; Hever, Thomas; Khemtong, Chalermchai; Kovacs, Zoltan; Sherry, A. Dean; Malloy, Craig R.

2017-11-01

This study was designed to determine whether perdeuterated glucose experiences a kinetic isotope effect (KIE) as glucose passes through glycolysis and is further oxidized in the tricarboxylic acid (TCA) cycle. Metabolism of deuterated glucose was investigated in two groups of perfused rat hearts. The control group was supplied with a 1:1 mixture of [U-13C6]glucose and [1,6-13C2]glucose, while the experimental group received [U-13C6,U-2H7]glucose and [1,6-13C2]glucose. Tissue extracts were analyzed by 1H, 2H and proton-decoupled 13C NMR spectroscopy. Extensive 2H-13C scalar coupling plus chemical shift isotope effects were observed in the proton-decoupled 13C NMR spectra of lactate, alanine and glutamate. A small but measureable (∼8%) difference in the rate of conversion of [U-13C6]glucose vs. [1,6-13C2]glucose to lactate, likely reflecting rates of Csbnd C bond breakage in the aldolase reaction, but conversion of [U-13C6]glucose versus [U-13C6,U-2H7]glucose to lactate did not differ. This shows that the presence of deuterium in glucose does not alter glycolytic flux. However, there were two distinct effects of deuteration on metabolism of glucose to alanine and oxidation of glucose in the TCA. First, alanine undergoes extensive exchange of methyl deuterons with solvent protons in the alanine amino transferase reaction. Second, there is a substantial kinetic isotope effect in metabolism of [U-13C6,U-2H7]glucose to alanine and glutamate. In the presence of [U-13C6,U-2H7]glucose, alanine and lactate are not in rapid exchange with the same pool of pyruvate. These studies indicate that the appearance of hyperpolarized 13C-lactate from hyperpolarized [U-13C6,U-2H7]glucose is not substantially influenced by a deuterium kinetic isotope effect.

Differential cytochrome P450 2D metabolism alters tafenoquine pharmacokinetics.

PubMed

Vuong, Chau; Xie, Lisa H; Potter, Brittney M J; Zhang, Jing; Zhang, Ping; Duan, Dehui; Nolan, Christina K; Sciotti, Richard J; Zottig, Victor E; Nanayakkara, N P Dhammika; Tekwani, Babu L; Walker, Larry A; Smith, Philip L; Paris, Robert M; Read, Lisa T; Li, Qigui; Pybus, Brandon S; Sousa, Jason C; Reichard, Gregory A; Smith, Bryan; Marcsisin, Sean R

2015-07-01

Cytochrome P450 (CYP) 2D metabolism is required for the liver-stage antimalarial efficacy of the 8-aminoquinoline molecule tafenoquine in mice. This could be problematic for Plasmodium vivax radical cure, as the human CYP 2D ortholog (2D6) is highly polymorphic. Diminished CYP 2D6 enzyme activity, as in the poor-metabolizer phenotype, could compromise radical curative efficacy in humans. Despite the importance of CYP 2D metabolism for tafenoquine liver-stage efficacy, the exact role that CYP 2D metabolism plays in the metabolism and pharmacokinetics of tafenoquine and other 8-aminoquinoline molecules has not been extensively studied. In this study, a series of tafenoquine pharmacokinetic experiments were conducted in mice with different CYP 2D metabolism statuses, including wild-type (WT) (reflecting extensive metabolizers for CYP 2D6 substrates) and CYPmouse 2D knockout (KO) (reflecting poor metabolizers for CYP 2D6 substrates) mice. Plasma and liver pharmacokinetic profiles from a single 20-mg/kg of body weight dose of tafenoquine differed between the strains; however, the differences were less striking than previous results obtained for primaquine in the same model. Additionally, the presence of a 5,6-ortho-quinone tafenoquine metabolite was examined in both mouse strains. The 5,6-ortho-quinone species of tafenoquine was observed, and concentrations of the metabolite were highest in the WT extensive-metabolizer phenotype. Altogether, this study indicates that CYP 2D metabolism in mice affects tafenoquine pharmacokinetics and could have implications for human tafenoquine pharmacokinetics in polymorphic CYP 2D6 human populations. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

PubMed

Targher, Giovanni; Rossini, Maurizio; Lonardo, Amedeo

2016-02-01

Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.

Bile acid metabolism and signaling in cholestasis, inflammation and cancer

PubMed Central

Apte, Udayan

2015-01-01

Bile acids are synthesized from cholesterol in the liver. Some cytochrome P450 (CYP) enzymes play key roles in bile acid synthesis. Bile acids are physiological detergent molecules, so are highly cytotoxic. They undergo enterohepatic circulation and play important roles in generating bile flow and facilitating biliary secretion of endogenous metabolites and xenobiotics and intestinal absorption of dietary fats and lipid soluble vitamins. Bile acid synthesis, transport and pool size are therefore tightly regulated under physiological conditions. In cholestasis, impaired bile flow leads to accumulation of bile acids in the liver, causing hepatocyte and biliary injury and inflammation. Chronic cholestasis is associated with fibrosis, cirrhosis and eventually liver failure. Chronic cholestasis also increases the risk of developing hepatocellular or cholangiocellular carcinomas. Extensive research in the last two decades has shown that bile acids act as signaling molecules that regulate various cellular processes. The bile acid-activated nuclear receptors are ligand-activated transcriptional factors that play critical roles in the regulation of bile acid, drug and xenobiotic metabolism. In cholestasis, these bile acid-activated receptors regulate a network of genes involved in bile acid synthesis, conjugation, transport and metabolism to alleviate bile acid-induced inflammation and injury. Additionally, bile acids are known to regulate cell growth and proliferation, and altered bile acid levels in diseased conditions have been implicated in liver injury/regeneration and tumorigenesis. We will cover the mechanisms that regulate bile acid homeostasis and detoxification during cholestasis, and the roles of bile acids in the initiation and regulation of hepatic inflammation, regeneration and carcinogenesis. PMID:26233910

Verification of propofol sulfate as a further human propofol metabolite using LC-ESI-QQQ-MS and LC-ESI-QTOF-MS analysis.

PubMed

Maas, Alexandra; Maier, Christoph; Michel-Lauter, Beate; Broecker, Sebastian; Madea, Burkhard; Hess, Cornelius

2017-03-01

Propofol (2,6-diisopropylphenol) is a water-insoluble, intravenous anesthetic that is widely used for the induction and maintenance of anesthesia as well as for endoscopic and pediatric sedation. After admission, propofol undergoes extensive hepatic and extrahepatic metabolism, including direct conjugation to propofol glucuronide and hydroxylation to 2,6-diisopropyl-1,4-quinol. The latter substance subsequently undergoes phase II metabolism, resulting in the formation of further metabolites (1quinolglucuronide, 4quinolglucuronide and 4quinol-sulfate). Further minor phase I propofol metabolites (2-(ω-propanol)-6-isopropylphenol and 2-(ω-propanol)-6-isopropyl-1,4-quinol)) are also described. Due to its chemical structure with the phenolic hydroxyl group, propofol is also an appropriate substrate for sulfation by sulfotransferases. The existence of propofol sulfate was investigated by liquid chromatography electrospray ionization triple quadrupole mass spectrometry (LCESIQQQ-MS) and liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LCESI-QTOF-MS). A propofol sulfate reference standard was used for identification and method development, yielding a precursor at m/z 257 (deprotonated propofol sulfate) and product ions at m/z 177 (deprotonated propofol) and m/z 80 ([SO3]-). Propofol sulfate - a further phase II metabolite of propofol - was verified in urine samples by LC-ESI-QQQ-MS and LC-ESI-QTOF-MS. Analyses of urine samples from five volunteers collected before and after propofol-induced sedation verified the presence of propofol sulfate in urine following propofol administration, whereas ascertained concentrations of this metabolite were significantly lower compared with detected propofol glucuronide concentrations. The existence of propofol sulfate as a further phase II propofol metabolite in humans could be verified by two different detection techniques (LCESIQQQ-MS and LC-ESI-QTOFMS) on the basis of a propofol sulfate reference standard. Evaluation of the quantitative analyses of propofol sulfate imply that propofol sulfate represents a minor metabolite of propofol and is only slightly involved in human propofol clearance.

Estrogen Signaling in Metabolic Inflammation

PubMed Central

Monteiro, Rosário; Teixeira, Diana; Calhau, Conceição

2014-01-01

There is extensive evidence supporting the interference of inflammatory activation with metabolism. Obesity, mainly visceral obesity, is associated with a low-grade inflammatory state, triggered by metabolic surplus where specialized metabolic cells such as adipocytes activate cellular stress initiating and sustaining the inflammatory program. The increasing prevalence of obesity, resulting in increased cardiometabolic risk and precipitating illness such as cardiovascular disease, type 2 diabetes, fatty liver, cirrhosis, and certain types of cancer, constitutes a good example of this association. The metabolic actions of estrogens have been studied extensively and there is also accumulating evidence that estrogens influence immune processes. However, the connection between these two fields of estrogen actions has been underacknowledged since little attention has been drawn towards the possible action of estrogens on the modulation of metabolism through their anti-inflammatory properties. In the present paper, we summarize knowledge on the modification inflammatory processes by estrogens with impact on metabolism and highlight major research questions on the field. Understanding the regulation of metabolic inflammation by estrogens may provide the basis for the development of therapeutic strategies to the management of metabolic dysfunctions. PMID:25400333

77 FR 55478 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-10

... Examination Survey (NHANES)-- (0920-0237, Expiration 11/30/2012)--Extension--National Center for Health... health of the population of the United States. The National Health and Nutrition Examination Survey... of the survey. This extension requests generic clearance for all activities needed to successfully...

Evolution of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome after bariatric surgery: a comparative study between gastric bypass and sleeve gastrectomy.

PubMed

Iannelli, A; Anty, R; Schneck, A S; Tran, A; Hébuterne, X; Gugenheim, J

2013-09-01

Laparoscopic sleeve gastrectomy (LSG) for morbid obesity is gaining in popularity as it offers several advantages over laparoscopic Roux-en-Y gastric bypass (LRYGBP), but comparative data between these two procedures have rarely been reported. This case control study compared the incidence of low-grade systemic inflammation, insulin resistance, anthropometrics, resting energy expenditure and metabolic syndrome in 30 patients undergoing LRYGBP and 30 patients undergoing LSG, matched for age, sex, body mass index (BMI), and glycosylated hemoglobin (HbA1c). At 1-year after surgery, the percent of excess weight loss was 67.8 ± 20.9 for LRYGBP and 61.6 ± 19.4 for LSG. Patients undergoing LRYGBP showed significantly lower plasma levels of C-reactive protein (3.3 ± 2.7 mg/dL vs. 5.3 ± 3.9 mg/dL; P < 0.05), waist circumference (97.4 ± 16.0 vs. 105.5 ± 14.7 cm; P < 0.05), total cholesterol (4.6 ± 1.0 vs. 5.7 ± 0.9 mmol/L; P < 0.01) and LDL cholesterol (2.6 ± 0.8 vs. 3.6 ± 0.8 mmol/L; P < 0.01). Insulin resistance (HOMA index 1.6 ± 1.0 after LRYGBP vs. 2.3 ± 2.4 after LSG), resting energy expenditure (1666.7 ± 320.5 after LRYGBP vs. 1600.4 ± 427.3 Kcal after LSG) and remission of metabolic syndrome (92.9% after LRYGBP vs. 80% after LSG) were not different between the two groups. In this study, patients undergoing LRYGBP demonstrated significantly improved lipid profiles, decreased systemic low-grade inflammation compared with those undergoing LSG at 1-year follow-up. Copyright © 2013. Published by Elsevier Masson SAS.

Development of whole sporozoite malaria vaccines.

PubMed

Hollingdale, Michael R; Sedegah, Martha

2017-01-01

Despite recent advances, malaria remains a major health threat both to populations in endemic areas as well travelers, including military personnel, to these areas. Subunit vaccines have not yet achieved sufficient efficacy needed for use in any of these at risk populations. Areas covered: This review discusses the current status of various whole sporozoite vaccine approaches and is mainly focused on current clinical trials. Expert commentary: Nearly 100% efficacy was achieved by administering multiple bites of radiation-attenuated sporozoite (RAS) Plasmodium falciparum-infected mosquitoes; this is impractical for widespread use. Now, this high level efficacy has been reproduced using purified, metabolically active RAS (PfSPZ Sanaria® Vaccine), which is undergoing extensive clinical testing. Alternative whole sporozoite vaccines include immunization with fully infectious sporozoites under chloroquine prophylaxis (CPS) or as genetically-attenuated parasites (GAP). By also manufacturing purified infectious sporozoites, it is now possible to combine these with CPS and GAP, as well as perform challenge studies using controlled doses of sporozoites.

Taxonomy, Physiology, and Natural Products of Actinobacteria.

PubMed

Barka, Essaid Ait; Vatsa, Parul; Sanchez, Lisa; Gaveau-Vaillant, Nathalie; Jacquard, Cedric; Meier-Kolthoff, Jan P; Klenk, Hans-Peter; Clément, Christophe; Ouhdouch, Yder; van Wezel, Gilles P

2016-03-01

Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Taxonomy, Physiology, and Natural Products of Actinobacteria

PubMed Central

Vatsa, Parul; Sanchez, Lisa; Gaveau-Vaillant, Nathalie; Jacquard, Cedric; Klenk, Hans-Peter; Clément, Christophe; Ouhdouch, Yder

2015-01-01

SUMMARY Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum. PMID:26609051

Metabolic syndrome, diet and exercise.

PubMed

De Sousa, Sunita M C; Norman, Robert J

2016-11-01

Polycystic ovary syndrome (PCOS) is associated with a range of metabolic complications including insulin resistance (IR), obesity, dyslipidaemia, hypertension, obstructive sleep apnoea (OSA) and non-alcoholic fatty liver disease. These compound risks result in a high prevalence of metabolic syndrome and possibly increased cardiovascular (CV) disease. As the cardiometabolic risk of PCOS is shared amongst the different diagnostic systems, all women with PCOS should undergo metabolic surveillance though the precise approach differs between guidelines. Lifestyle interventions consisting of increased physical activity and caloric restriction have been shown to improve both metabolic and reproductive outcomes. Pharmacotherapy and bariatric surgery may be considered in resistant metabolic disease. Issues requiring further research include the natural history of PCOS-associated metabolic disease, absolute CV risk and comparative efficacy of lifestyle interventions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Introduction to the molecular basis of cancer metabolism and the Warburg effect.

PubMed

Ngo, Darleen C; Ververis, Katherine; Tortorella, Stephanie M; Karagiannis, Tom C

2015-04-01

In differentiated normal cells, the conventional route of glucose metabolism involves glycolysis, followed by the citric acid cycle and electron transport chain to generate usable energy in the form of adenosine triphosphate (ATP). This occurs in the presence of oxygen. In hypoxic conditions, normal cells undergo anaerobic glycolysis to yield significantly less energy producing lactate as a product. As first highlighted in the 1920s by Otto Warburg, the metabolism exhibited by tumor cells involves an increased rate of aerobic glycolysis, known as the Warburg effect. In aerobic glycolysis, pyruvate molecules yielded from glycolysis are converted into fewer molecules of ATP even in the presence of oxygen. Evidence indicates that the reasons as to why tumor cells undergo aerobic glycolysis include: (1) the shift in priority to accumulate biomass rather than energy production, (2) the evasion of apoptosis as fewer reactive oxygen species are released by the mitochondria and (3) the production of lactate to further fuel growth of tumors. In this mini-review we discuss emerging molecular aspects of cancer metabolism and the Warburg effect. Aspects of the Warburg effect are analyzed in the context of the established hallmarks of cancer including the role of oncogenes and tumor suppressor genes.

Extension Procedures for Confirmatory Factor Analysis

ERIC Educational Resources Information Center

Nagy, Gabriel; Brunner, Martin; Lüdtke, Oliver; Greiff, Samuel

2017-01-01

We present factor extension procedures for confirmatory factor analysis that provide estimates of the relations of common and unique factors with external variables that do not undergo factor analysis. We present identification strategies that build upon restrictions of the pattern of correlations between unique factors and external variables. The…

Metabolic Bone Diseases and Total Hip Arthroplasty: Preventing Complications.

PubMed

Moya-Angeler, Joaquin; Lane, Joseph M; Rodriguez, Jose A

2017-11-01

Metabolic bone diseases are a diverse group of conditions characterized by abnormalities in calcium metabolism and/or bone cell physiology. These unbalanced processes can eventually lead to bony deformities and altered joint biomechanics, resulting in degenerative joint disease. Not infrequently, patients with metabolic bone diseases have restricting hip joint pain that ultimately necessitates hip arthroplasty. To minimize complications, the surgeon must consider the particular characteristics of these patients. The surgical and medical management of patients with metabolic bone diseases undergoing hip arthroplasty requires appropriate preoperative diagnosis, careful attention to the technical challenges of surgery, and strategies to maximize the long-term results of the surgical intervention, such as the use of bone anabolic and anticatabolic agents.

Complete metabolic remission with Gefitinib in a hemodialysis patient with bone metastases from non-small cell lung cancer.

PubMed

Del Conte, Alessandro; Minatel, Emilio; Schinella, Domenico; Baresic, Tanja; Basso, Stefano M M; Lumachi, Franco

2014-01-01

Gefitinib is highly active in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growth factor receptor (EGFR) gene. The feasibility and the degree of response to treatment with gefitinib in patients with chronic renal failure (CRF) undergoing hemodialysis has not yet been fully described in literature. We describe the case of a 70-year-old man with CRF undergoing hemodialysis three times-a-week who developed vertebral and rib bone metastasis three years after lobectomy. The bone biopsy confirmed the pulmonary origin and pyrosequencing analysis revealed deletion in E746-E750 of exon 19. We started daily administration of 250 mg gefitinib with no changes in the hemodialysis schedule. Gefitinib was well-tolerated without any adverse event. After three months, the (18)F-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG PET/CT) showed complete metabolic remission of bone lesions. The patient is still under treatment and maintains response (30 months to date). To our knowledge, this is the first description of complete metabolic remission in this type of patient. In conclusion, gefitinib has been safely administered to a patient with NSCLC with EGFR-activating mutation undergoing chronic hemodialysis and its use has achieved an excellent and prolonged response on bone metastases.

Floral reversion mechanism in longan (Dimocarpus longan Lour.) revealed by proteomic and anatomic analyses.

PubMed

You, Xiangrong; Wang, Lingxia; Liang, Wenyu; Gai, Yonghong; Wang, Xiaoyan; Chen, Wei

2012-02-02

Two-dimensional gel electrophoresis (2-DE) was used to analyze the proteins related to floral reversion in Dimocarpus longan Lour. Proteins were extracted from buds undergoing the normal process of flowering and from those undergoing floral reversion in three developing stages in D. longan. Differentially expressed proteins were identified from the gels after 2-DE analysis, which were confirmed using matrix-assisted laser desorption/ionization-time of flying-mass spectroscopy and protein database search. A total of 39 proteins, including 18 up-regulated and 21 down-regulated proteins, were classified into different categories, such as energy and substance metabolism, protein translation, secondary metabolism, phytohormone, cytoskeleton structure, regulation, and stress tolerance. Among these, the largest functional class was associated with primary metabolism. Down-regulated proteins were involved in photosynthesis, transcription, and translation, whereas up-regulated proteins were involved in respiration. Decreased flavonoid synthesis and up-regulated GA20ox might be involved in the floral reversion process. Up-regulated 14-3-3 proteins played a role in the regulation of floral reversion in D. longan by responding to abiotic stress. Observations via transmission electron microscopy revealed the ultrastructure changes in shedding buds undergoing floral reversion. Overall, the results provided insights into the molecular basis for the floral reversion mechanism in D. longan. Copyright © 2011 Elsevier B.V. All rights reserved.

Metabolic syndrome in hemodialysis patients as a risk factor for new-onset diabetes mellitus after renal transplant: a prospective observational study

PubMed Central

Bonet, Josep; Martinez-Castelao, Albert; Bayés, Beatriz

2013-01-01

Purpose Metabolic syndrome is a cluster of biochemical abnormalities including cardiovascular and diabetes risk factors. The development of diabetes mellitus after renal transplant represents a major posttransplant complication that may adversely affect graft/patient survival. The aim of this study was to assess the role of metabolic syndrome in patients on hemodialysis as a risk factor for the incidence of new-onset diabetes mellitus after renal transplant. Patients and methods This was a prospective observational epidemiologic study carried out in adult nondiabetic patients undergoing chronic hemodialysis and on the renal transplant waiting list between November 2008 and April 2009. Patients were followed up from Visit 1 (baseline) to 6 months after the renal transplant. The analysis of the role of metabolic syndrome in hemodialysis patients as a risk factor for the incidence of new-onset diabetes mellitus after renal transplant included the estimation of relative risk and its 95% confidence interval (CI). Results A total of 383 evaluable patients were entered into the study (mean age, 52.7 years; male, 57.7%; Caucasian, 90.1%). The prevalence of metabolic syndrome on hemodialysis was 30.4% (95% CI, 25.8%–35.4%). Hypertension was the most prevalent criterion for metabolic syndrome (65.0%), followed by low levels of high-density lipoprotein cholesterol (52.7%), abdominal obesity (36.2%), hypertriglyceridemia (32.4%), and impaired glucose (8.9%). After the renal transplant, the prevalence of metabolic syndrome was still 25.8%. During the posttransplant period, the incidence of new-onset diabetes mellitus reached 13.0% (95% CI, 7.8%–20.6%) and patients with pretransplant metabolic syndrome were 2.6 times (95% CI, 1.043–6.608) more likely to develop new-onset diabetes mellitus after the renal transplant than those without metabolic syndrome. Conclusion The presence of metabolic syndrome in patients undergoing hemodialysis represents an independent risk factor for the incidence of new-onset diabetes mellitus after renal transplant. PMID:24082792

A rapid method for direct detection of metabolic conversion and magnetization exchange with application to hyperpolarized substrates

NASA Astrophysics Data System (ADS)

Larson, Peder E. Z.; Kerr, Adam B.; Leon Swisher, Christine; Pauly, John M.; Vigneron, Daniel B.

2012-12-01

In this work, we present a new MR spectroscopy approach for directly observing nuclear spins that undergo exchange, metabolic conversion, or, generally, any frequency shift during a mixing time. Unlike conventional approaches to observe these processes, such as exchange spectroscopy (EXSY), this rapid approach requires only a single encoding step and thus is readily applicable to hyperpolarized MR in which the magnetization is not replenished after T1 decay and RF excitations. This method is based on stimulated-echoes and uses phase-sensitive detection in conjunction with precisely chosen echo times in order to separate spins generated during the mixing time from those present prior to mixing. We are calling the method Metabolic Activity Decomposition Stimulated-echo Acquisition Mode or MAD-STEAM. We have validated this approach as well as applied it in vivo to normal mice and a transgenic prostate cancer mouse model for observing pyruvate-lactate conversion, which has been shown to be elevated in numerous tumor types. In this application, it provides an improved measure of cellular metabolism by separating [1-13C]-lactate produced in tissue by metabolic conversion from [1-13C]-lactate that has flowed into the tissue or is in the blood. Generally, MAD-STEAM can be applied to any system in which spins undergo a frequency shift.

A rapid method for direct detection of metabolic conversion and magnetization exchange with application to hyperpolarized substrates.

PubMed

Larson, Peder E Z; Kerr, Adam B; Swisher, Christine Leon; Pauly, John M; Vigneron, Daniel B

2012-12-01

In this work, we present a new MR spectroscopy approach for directly observing nuclear spins that undergo exchange, metabolic conversion, or, generally, any frequency shift during a mixing time. Unlike conventional approaches to observe these processes, such as exchange spectroscopy (EXSY), this rapid approach requires only a single encoding step and thus is readily applicable to hyperpolarized MR in which the magnetization is not replenished after T(1) decay and RF excitations. This method is based on stimulated-echoes and uses phase-sensitive detection in conjunction with precisely chosen echo times in order to separate spins generated during the mixing time from those present prior to mixing. We are calling the method Metabolic Activity Decomposition Stimulated-echo Acquisition Mode or MAD-STEAM. We have validated this approach as well as applied it in vivo to normal mice and a transgenic prostate cancer mouse model for observing pyruvate-lactate conversion, which has been shown to be elevated in numerous tumor types. In this application, it provides an improved measure of cellular metabolism by separating [1-(13)C]-lactate produced in tissue by metabolic conversion from [1-(13)C]-lactate that has flowed into the tissue or is in the blood. Generally, MAD-STEAM can be applied to any system in which spins undergo a frequency shift. Copyright © 2012 Elsevier Inc. All rights reserved.

Metabolic Reprogramming in Thyroid Carcinoma

PubMed Central

Coelho, Raquel Guimaraes; Fortunato, Rodrigo S.; Carvalho, Denise P.

2018-01-01

Among all the adaptations of cancer cells, their ability to change metabolism from the oxidative to the glycolytic phenotype is a hallmark called the Warburg effect. Studies on tumor metabolism show that improved glycolysis and glutaminolysis are necessary to maintain rapid cell proliferation, tumor progression, and resistance to cell death. Thyroid neoplasms are common endocrine tumors that are more prevalent in women and elderly individuals. The incidence of thyroid cancer has increased in the Past decades, and recent findings describing the metabolic profiles of thyroid tumors have emerged. Currently, several drugs are in development or clinical trials that target the altered metabolic pathways of tumors are undergoing. We present a review of the metabolic reprogramming in cancerous thyroid tissues with a focus on the factors that promote enhanced glycolysis and the possible identification of promising metabolic targets in thyroid cancer. PMID:29629339

In vivo testing of chemicals that undergo substantial biotransformation: An opportunity to advance in vitro-in vivo metabolism extrapolation procedures for fish

EPA Science Inventory

This is one of several keynote presentations given at the beginning of a one-day workshop on in vivo testing with fish. The purpose of this talk is to describe recent progress on using in vitro data to predict metabolism impacts on chemical accumulation by fish. The focus of th...

Metabolic bone diseases during long-term total parenteral nutrition.

PubMed

Acca, M; Ragno, A; Francucci, C M; D'Erasmo, E

2007-01-01

Long-term total parenteral nutrition (TPN) is a procedure commonly applied to patients with advanced forms of intestinal malabsorption. Among TPN complications, bone metabolic diseases, such as osteoporosis and osteomalacia, are a common finding. Initially considered to be a manifestation of aluminium toxicity which followed massive contamination with the element of the solutions used in TPN, metabolic osteopathy during TPN is currently considered a multiform syndrome, with a multifactorial pathogenesis, which may manifest itself with vague or clear clinical pictures. In this review, we analyse clinical, pathogenetic, and therapeutic aspects of the most common bone metabolic diseases in patients undergoing long-term TPN.

Vitamin Deficiency Anemia

MedlinePlus

... are unique to specific vitamin deficiencies. Folate-deficiency anemia risk factors include: Undergoing hemodialysis for kidney failure. ... the metabolism of folate. Vitamin B-12 deficiency anemia risk factors include: Lack of intrinsic factor. Most ...

[Amalgam. IV. Metabolism of mercury].

PubMed

Gladys, S; van Meerbeek, B; Vanherle, G; Lambrechts, P

1993-04-01

After absorption in the body by four ways, each type of mercury undergoes a specific metabolism. Elementary mercury as mercury vapour becomes rapidly oxidized to Hg2+ and, afterwards, is metabolized as an inorganic mercurial compound. From the blood circulation mercury reaches target organs like the kidneys, the central nervous system, the liver and the hypophysis, in which mercury accumulates. The retention time varies by organ and is longest in the brain. Mercury is mainly eliminated with urine and faeces, to a lesser degree with transpiration and mother's milk and sometimes by respiration.

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

PubMed Central

Schild, Tanya; Low, Vivien; Blenis, John; Gomes, Ana P.

2018-01-01

Summary Metastases arising from tumors have the proclivity to colonize specific organs, suggesting that they must rewire their biology to meet the demands of the organ colonized, thus altering their primary properties. Each metastatic site presents distinct metabolic challenges to a colonizing cancer cell, ranging from fuel and oxygen availability to oxidative stress. Here, we discuss the organ-specific metabolic adaptations cancer cells must undergo, which provide the ability to overcome the unique barriers to colonization in foreign tissues and establish the metastatic tissue tropism phenotype. PMID:29533780

Complex systems in metabolic engineering.

PubMed

Winkler, James D; Erickson, Keesha; Choudhury, Alaksh; Halweg-Edwards, Andrea L; Gill, Ryan T

2015-12-01

Metabolic engineers manipulate intricate biological networks to build efficient biological machines. The inherent complexity of this task, derived from the extensive and often unknown interconnectivity between and within these networks, often prevents researchers from achieving desired performance. Other fields have developed methods to tackle the issue of complexity for their unique subset of engineering problems, but to date, there has not been extensive and comprehensive examination of how metabolic engineers use existing tools to ameliorate this effect on their own research projects. In this review, we examine how complexity affects engineering at the protein, pathway, and genome levels within an organism, and the tools for handling these issues to achieve high-performing strain designs. Quantitative complexity metrics and their applications to metabolic engineering versus traditional engineering fields are also discussed. We conclude by predicting how metabolic engineering practices may advance in light of an explicit consideration of design complexity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prospective Evaluation of Changes in Tumor Size and Tumor Metabolism in Patients with Advanced Gastric Cancer Undergoing Chemotherapy: Association and Clinical Implication.

PubMed

Park, Seongyeol; Ha, Seunggyun; Kwon, Hyun Woo; Kim, Woo Hyoung; Kim, Tae-Yong; Oh, Do-Youn; Cheon, Gi Jeong; Bang, Yung-Jue

2017-06-01

A change in tumor size is a well-validated and commonly used value for evaluating response to chemotherapy in cancer. Metabolic changes induced by chemotherapy are related to prognosis in several tumor types. However, the clinical implication of metabolic changes in patients with advanced gastric cancer (AGC) undergoing chemotherapy remains unclear. We aimed to evaluate response of tumor size and metabolism in AGC during chemotherapy and to reveal the relationship between them in view of their impact on patient survival. Methods: We prospectively enrolled patients with AGC before the initiation of first-line palliative chemotherapy. Using baseline and follow-up contrast-enhanced CT and 18 F-FDG PET, we assessed the tumor diameter, SUV max , and total lesion glycolysis in each lesion and their changes during chemotherapy at the same time. We included all lesions with the maximal longest diameters over 1 cm on CT, and each lesion was evaluated by matched 18 F-FDG PET. We analyzed the association between changes in tumor metabolism and tumor size and performed outcome analysis on overall survival (OS) and progression-free survival (PFS). Results: Seventy-four patients were enrolled, and the number of all lesions included in this study was 620. Compared with adenocarcinomas, poorly cohesive carcinomas demonstrated lower SUV max irrespective of tumor size ( P < 0.001). Human epidermal growth factor receptor 2 (HER2)-positive tumors showed higher SUV max than HER2-negative tumors ( P = 0.002). The changes in SUV max due to chemotherapy had a linear correlation with the changes in tumor size of each lesion, and a 30% tumor size reduction was associated with a 50% SUV max reduction ( P < 0.001). Total lesion glycolysis changes also correlated with tumor size changes ( P < 0.001). Better OS and PFS were obtained in patients with both tumor size and SUV max reduction than in patients with either size or SUV max reduction only (OS, P = 0.003; PFS, P = 0.038). Conclusion: Changes in tumor metabolism induced by chemotherapy correlated with changes in tumor size in AGC. Considering both changes in metabolism and size could help predict a more accurate prognosis for AGC patients undergoing chemotherapy. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

A new picture of cell wall protein dynamics in elongating cells of Arabidopsis thaliana: Confirmed actors and newcomers

PubMed Central

Irshad, Muhammad; Canut, Hervé; Borderies, Gisèle; Pont-Lezica, Rafael; Jamet, Elisabeth

2008-01-01

Background Cell elongation in plants requires addition and re-arrangements of cell wall components. Even if some protein families have been shown to play roles in these events, a global picture of proteins present in cell walls of elongating cells is still missing. A proteomic study was performed on etiolated hypocotyls of Arabidopsis used as model of cells undergoing elongation followed by growth arrest within a short time. Results Two developmental stages (active growth and after growth arrest) were compared. A new strategy consisting of high performance cation exchange chromatography and mono-dimensional electrophoresis was established for separation of cell wall proteins. This work allowed identification of 137 predicted secreted proteins, among which 51 had not been identified previously. Apart from expected proteins known to be involved in cell wall extension such as xyloglucan endotransglucosylase-hydrolases, expansins, polygalacturonases, pectin methylesterases and peroxidases, new proteins were identified such as proteases, proteins related to lipid metabolism and proteins of unknown function. Conclusion This work highlights the CWP dynamics that takes place between the two developmental stages. The presence of proteins known to be related to cell wall extension after growth arrest showed that these proteins may play other roles in cell walls. Finally, putative regulatory mechanisms of protein biological activity are discussed from this global view of cell wall proteins. PMID:18796151

Endoscopic analysis of gastric ulcer after one week's treatment with omeprazole and rabeprazole in relation to CYP2C19 genotype.

PubMed

Ando, Takashi; Ishikawa, Takeshi; Kokura, Satoshi; Naito, Yuji; Yoshida, Norimasa; Yoshikawa, Toshikazu

2008-04-01

In Japanese healthy CYP2C19 extensive metabolizers, rabeprazole 10 mg shows a faster onset of action and stronger inhibition of acid secretion than does omeprazole 20 mg on the first 3 days of administration. We evaluated gastric ulcer improvement after 1 week's treatment with rabeprazole or omeprazole in relation to CYP2C19 polymorphism. A 6-mm rubber disc was placed temporarily at the side of the ulcer for measurement of the ulcer area. The improvement ratios of ulcer area in homozygous extensive metabolizers (homoEMs), heterozygous extensive metabolizers (heteroEMs) and poor metabolizers (PMs) treated with rabeprazole 10 mg were 60.8, 65.0 and 55.3%, respectively, and these values are not significantly different. Corresponding values with omeprazole 20 mg were 46.3, 61.7 and 63.2%, respectively, and the value of homoEMs was significantly smaller than that of heteroEMs. The improvement ratios with rabeprazole in homoEMs and heteroEMs were significantly greater than that with omeprazole in homoEMs.

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway

PubMed Central

Terelius, Ylva; Abedi-Valugerdi, Manuchehr; Naughton, Seán; Saghafian, Maryam; Moshfegh, Ali; Mattsson, Jonas; Potácová, Zuzana; Hassan, Moustapha

2017-01-01

Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood. In the present study, we performed in vitro and in vivo investigations to elucidate the involvement of flavin-containing monooxygenase-3 (FMO3) and cytochrome P450 enzymes (CYPs) in Bu metabolic pathway. Rapid clearance of THT was observed when incubated with human liver microsomes. Furthermore, among different recombinant microsomal enzymes, the highest intrinsic clearance for THT was obtained via FMO3 followed by several CYPs including 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4. In Bu- or THT-treated mice, inhibition of FMO3 by phenylthiourea significantly suppressed the clearance of both Bu and THT. Moreover, the simultaneous administration of a high dose of THT (200μmol/kg) to Bu-treated mice reduced the clearance of Bu. Consistently, in patients undergoing HSCT, repeated administration of Bu resulted in a significant up-regulation of FMO3 and glutathione-S-transfrase -1 (GSTA1) genes. Finally, in a Bu-treated patient, additional treatment with voriconazole (an antimycotic drug known as an FMO3-substrate) significantly altered the Bu clearance. In conclusion, we demonstrate for the first time that FMO3 along with CYPs contribute a major part in busulphan metabolic pathway and certainly can affect its kinetics. The present results have high clinical impact. Furthermore, these findings might be important for reducing the treatment-related toxicity of Bu, through avoiding interaction with other concomitant used drugs during conditioning and hence improving the clinical outcomes of HSCT. PMID:29121650

Flavin-containing monooxygenase 3 (FMO3) role in busulphan metabolic pathway.

PubMed

El-Serafi, Ibrahim; Terelius, Ylva; Abedi-Valugerdi, Manuchehr; Naughton, Seán; Saghafian, Maryam; Moshfegh, Ali; Mattsson, Jonas; Potácová, Zuzana; Hassan, Moustapha

2017-01-01

Busulphan (Bu) is an alkylating agent used in the conditioning regimen prior to hematopoietic stem cell transplantation (HSCT). Bu is extensively metabolized in the liver via conjugations with glutathione to form the intermediate metabolite (sulfonium ion) which subsequently is degraded to tetrahydrothiophene (THT). THT was reported to be oxidized forming THT-1-oxide that is further oxidized to sulfolane and finally 3-hydroxysulfolane. However, the underlying mechanisms for the formation of these metabolites remain poorly understood. In the present study, we performed in vitro and in vivo investigations to elucidate the involvement of flavin-containing monooxygenase-3 (FMO3) and cytochrome P450 enzymes (CYPs) in Bu metabolic pathway. Rapid clearance of THT was observed when incubated with human liver microsomes. Furthermore, among different recombinant microsomal enzymes, the highest intrinsic clearance for THT was obtained via FMO3 followed by several CYPs including 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4. In Bu- or THT-treated mice, inhibition of FMO3 by phenylthiourea significantly suppressed the clearance of both Bu and THT. Moreover, the simultaneous administration of a high dose of THT (200μmol/kg) to Bu-treated mice reduced the clearance of Bu. Consistently, in patients undergoing HSCT, repeated administration of Bu resulted in a significant up-regulation of FMO3 and glutathione-S-transfrase -1 (GSTA1) genes. Finally, in a Bu-treated patient, additional treatment with voriconazole (an antimycotic drug known as an FMO3-substrate) significantly altered the Bu clearance. In conclusion, we demonstrate for the first time that FMO3 along with CYPs contribute a major part in busulphan metabolic pathway and certainly can affect its kinetics. The present results have high clinical impact. Furthermore, these findings might be important for reducing the treatment-related toxicity of Bu, through avoiding interaction with other concomitant used drugs during conditioning and hence improving the clinical outcomes of HSCT.

GeoChip-based analysis of metabolic diversity of microbial communities at the Juan de Fuca Ridge hydrothermal vent

PubMed Central

Wang, Fengping; Zhou, Huaiyang; Meng, Jun; Peng, Xiaotong; Jiang, Lijing; Sun, Ping; Zhang, Chuanlun; Van Nostrand, Joy D.; Deng, Ye; He, Zhili; Wu, Liyou; Zhou, Jizhong; Xiao, Xiang

2009-01-01

Deep-sea hydrothermal vents are one of the most unique and fascinating ecosystems on Earth. Although phylogenetic diversity of vent communities has been extensively examined, their physiological diversity is poorly understood. In this study, a GeoChip-based, high-throughput metagenomics technology revealed dramatic differences in microbial metabolic functions in a newly grown protochimney (inner section, Proto-I; outer section, Proto-O) and the outer section of a mature chimney (4143-1) at the Juan de Fuca Ridge. Very limited numbers of functional genes were detected in Proto-I (113 genes), whereas much higher numbers of genes were detected in Proto-O (504 genes) and 4143-1 (5,414 genes). Microbial functional genes/populations in Proto-O and Proto-I were substantially different (around 1% common genes), suggesting a rapid change in the microbial community composition during the growth of the chimney. Previously retrieved cbbL and cbbM genes involved in the Calvin Benson Bassham (CBB) cycle from deep-sea hydrothermal vents were predominant in Proto-O and 4143-1, whereas photosynthetic green-like cbbL genes were the major components in Proto-I. In addition, genes involved in methanogenesis, aerobic and anaerobic methane oxidation (e.g., ANME1 and ANME2), nitrification, denitrification, sulfate reduction, degradation of complex carbon substrates, and metal resistance were also detected. Clone libraries supported the GeoChip results but were less effective than the microarray in delineating microbial populations of low biomass. Overall, these results suggest that the hydrothermal microbial communities are metabolically and physiologically highly diverse, and the communities appear to be undergoing rapid dynamic succession and adaptation in response to the steep temperature and chemical gradients across the chimney. PMID:19273854

Metabolite identification of triptolide by data-dependent accurate mass spectrometric analysis in combination with online hydrogen/deuterium exchange and multiple data-mining techniques.

PubMed

Du, Fuying; Liu, Ting; Liu, Tian; Wang, Yongwei; Wan, Yakun; Xing, Jie

2011-10-30

Triptolide (TP), the primary active component of the herbal medicine Tripterygium wilfordii Hook F, has shown promising antileukemic and anti-inflammatory activity. The pharmacokinetic profile of TP indicates an extensive metabolic elimination in vivo; however, its metabolic data is rarely available partly because of the difficulty in identifying it due to the absence of appropriate ultraviolet chromophores in the structure and the presence of endogenous interferences in biological samples. In the present study, the biotransformation of TP was investigated by improved data-dependent accurate mass spectrometric analysis, using an LTQ/Orbitrap hybrid mass spectrometer in conjunction with the online hydrogen (H)/deuterium (D) exchange technique for rapid structural characterization. Accurate full-scan MS and MS/MS data were processed with multiple post-acquisition data-mining techniques, which were complementary and effective in detecting both common and uncommon metabolites from biological matrices. As a result, 38 phase I, 9 phase II and 8 N-acetylcysteine (NAC) metabolites of TP were found in rat urine. Accurate MS/MS data were used to support assignments of metabolite structures, and online H/D exchange experiments provided additional evidence for exchangeable hydrogen atoms in the structure. The results showed the main phase I metabolic pathways of TP are hydroxylation, hydrolysis and desaturation, and the resulting metabolites subsequently undergo phase II processes. The presence of NAC conjugates indicated the capability of TP to form reactive intermediate species. This study also demonstrated the effectiveness of LC/HR-MS(n) in combination with multiple post-acquisition data-mining methods and the online H/D exchange technique for the rapid identification of drug metabolites. Copyright © 2011 John Wiley & Sons, Ltd.

Comparative ultrastructure of fruit plastids in three genetically diverse genotypes of apple (Malus × domestica Borkh.) during development.

PubMed

Schaeffer, Scott M; Christian, Ryan; Castro-Velasquez, Nohely; Hyden, Brennan; Lynch-Holm, Valerie; Dhingra, Amit

2017-10-01

Comparative ultrastructural developmental time-course analysis has identified discrete stages at which the fruit plastids undergo structural and consequently functional transitions to facilitate subsequent development-guided understanding of the complex plastid biology. Plastids are the defining organelle for a plant cell and are critical for myriad metabolic functions. The role of leaf plastid, chloroplast, is extensively documented; however, fruit plastids-chromoplasts-are poorly understood, especially in the context of the diverse metabolic processes operating in these diverse plant organs. Recently, in a comparative study of the predicted plastid-targeted proteomes across seven plant species, we reported that each plant species is predicted to harbor a unique set of plastid-targeted proteins. However, the temporal and developmental context of these processes remains unknown. In this study, an ultrastructural analysis approach was used to characterize fruit plastids in the epidermal and collenchymal cell layers at 11 developmental timepoints in three genotypes of apple (Malus × domestica Borkh.): chlorophyll-predominant 'Granny Smith', carotenoid-predominant 'Golden Delicious', and anthocyanin-predominant 'Top Red Delicious'. Plastids transitioned from a proplastid-like plastid to a chromoplast-like plastid in epidermis cells, while in the collenchyma cells, they transitioned from a chloroplast-like plastid to a chloro-chromo-amyloplast plastid. Plastids in the collenchyma cells of the three genotypes demonstrated a diverse array of structures and features. This study enabled the identification of discrete developmental stages during which specific functions are most likely being performed by the plastids as indicated by accumulation of plastoglobuli, starch granules, and other sub-organeller structures. Information regarding the metabolically active developmental stages is expected to facilitate biologically relevant omics studies to unravel the complex biochemistry of plastids in perennial non-model systems.

Comprehensive Evaluation of Altered Systemic Metabolism and Pancreatic Cancer Risk

DTIC Science & Technology

2016-10-01

To explore altered metabolism is patients with pancreatic cancer, we are conducting studies in participants from four large prospective cohorts, where...participants from four large prospective cohorts, where individuals provide extensive data on metabolic phenotypes, such as obesity and diabetes, and...Pancreatic cancer; Metabolism; Early detection ACCOMPLISHMENTS: What were the major goals of the project? Four major tasks were described

Changes in cerebral metabolic activity in men undergoing androgen deprivation therapy for non-metastatic prostate cancer.

PubMed

Cherrier, M M; Cross, D J; Higano, C S; Minoshima, S

2018-04-27

Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT. Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET ( 18 F-FDGPET) at baseline (before treatment) and again after 9 months of ADT. Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem. These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms.

[Detection and identification of a new metabolite of fenethylline].

PubMed

Goenechea, S; Brzezinka, H

1984-01-01

Fenetylline is metabolized in humans on two pathways. In addition to previously described degradation to amphetamine and 7-oxyethyltheophylline fenetylline undergoes moreover oxydative N-dealkylation to yield 7-aminoethyltheophylline and phenylacetone.

The Warburg effect: molecular aspects and therapeutic possibilities.

PubMed

Ngo, Hanh; Tortorella, Stephanie M; Ververis, Katherine; Karagiannis, Tom C

2015-04-01

It has been about nine decades since the proposal of Otto Warburg on the metabolism of cancer cells. Unlike normal cells which undergo glycolysis and oxidative phosphorylation in the presence of oxygen, proliferating and cancer cells exhibit an increased uptake of glucose and increased rate of glycolysis and predominantly undergo lactic acid fermentation. Whether this phenomenon is the consequence of genetic dysregulation in cancer or is the cause of cancer still remains unknown. However, there is certainly a strong link between the genetic factors, epigenetic modulation, cancer immunosurveillance and the Warburg effect, which will be discussed in this review. Dichloroacetate and 3-bromopyruvate are among the substances that have been studied as potential cancer therapies. With our expanding knowledge of cellular metabolism, therapies targeting the Warburg effect appear very promising. This review discusses different aspects of these emerging therapies.

Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine-buprenorphine combination in standing horses.

PubMed

van Dijk, P; Lankveld, D P K; Rijkenhuizen, A B M; Jonker, F H

2003-04-01

To assess the hormonal, metabolic and physiological effects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Prospective study. Eight healthy adult Dutch Warmblood horses and five healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. The sedative effect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesterified fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the effects of detomidine were antagonized using atipamezole. The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses which, with the exception of NEFA values, were not significantly different from changes found in the control group. While atipamezole did not produce detectable adverse effects, it is possible that anatagonism may not be essential. The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the effects of detomidine may not be necessary in all cases.

Metabolic syndrome in patients with prostate cancer undergoing androgen suppression.

PubMed

Morote, J; Ropero, J; Planas, J; Celma, A; Placer, J; Ferrer, R; de Torres, I

2014-06-01

Cardiovascular mortality is the leading cause of death in patients with prostate cancer (PC), metabolic syndrome (MS) being related to it. The main objective of this study was to determine the prevalence of MS in patients with CP undergoing androgen suppression (AS). We performed a retrospective study of cases and controls that included 159 patients. The study group was made up of 53 patients with PC undergoing SA for a period exceeding 12 months. The control group was formed by 53 patients with PC at the time of diagnosis and 53 patients with negative prostate biopsy. All patients were evaluated for presence of MS according to NCEP-ATPIII criteria. Prevalence of MS in patients without PC was 32.1% and in those with non-treated PC 35.8%, P = .324. In patients with PC undergoing AS, prevalence of MS was 50.9%, P < .001. When AS duration was less than 36 months, prevalence of MS was 44.0% and when greater than 36 months 57.1%, P < .001. Waist circumference and hyperglycemia were the two MS components that significantly increased. AS and its duration were independent predictors factors for the development of MS. Continuous AS therapy increases the prevalence of MS and especially waist circumference and hyperglycemia. Development of MS increases according to AS duration. Copyright © 2013 AEU. Published by Elsevier Espana. All rights reserved.

Preoperative oral supplementation with carbohydrate and branched-chain amino acid-enriched nutrient improves insulin resistance in patients undergoing a hepatectomy: a randomized clinical trial using an artificial pancreas.

PubMed

Okabayashi, Takehiro; Nishimori, Isao; Yamashita, Koichi; Sugimoto, Takeki; Namikawa, Tsutomu; Maeda, Hiromichi; Yatabe, Tomoaki; Hanazaki, Kazuhiro

2010-03-01

Glucose metabolism is adversely affected in patients following major surgery. Patients may develop hyperglycemia due to a combination of surgical stress and postoperative insulin resistance. A randomized trial was conducted to elucidate the effect of preoperative supplementation with carbohydrates and branched-chain amino acids on postoperative insulin resistance in patients undergoing hepatic resection. A total of 26 patients undergoing a hepatectomy for the treatment of a hepatic neoplasm were randomly assigned to receive a preoperative supplement of carbohydrate and branched-chain amino acid-enriched nutrient mixture or not. The postoperative blood glucose level and the total insulin requirement for normoglycemic control during the 16 h following hepatic resection were determined using the artificial pancreas STG-22. Postoperative insulin requirements for normoglycemic control in the group with preoperative nutritional support was significantly lower than that in the control group (P = 0.039). There was no incidence of hypoglycemia (<40 mg/dL) observed in patients, including those with diabetes mellitus, when the STG-22 was used to control blood glucose levels. STG-22 is a safe and reliable tool to control postoperative glucose metabolism and evaluate insulin resistance. The preoperative oral administration of carbohydrate and branched-chain amino acid-enriched nutrient is of clinical benefit and reduces postoperative insulin resistance in patients undergoing hepatic resection.

Perspectives on Systems Modeling of Human Peripheral Blood Mononuclear Cells

PubMed Central

Sen, Partho; Kemppainen, Esko; Orešič, Matej

2018-01-01

Human peripheral blood mononuclear cells (PBMCs) are the key drivers of the immune responses. These cells undergo activation, proliferation and differentiation into various subsets. During these processes they initiate metabolic reprogramming, which is coordinated by specific gene and protein activities. PBMCs as a model system have been widely used to study metabolic and autoimmune diseases. Herein we review various omics and systems-based approaches such as transcriptomics, epigenomics, proteomics, and metabolomics as applied to PBMCs, particularly T helper subsets, that unveiled disease markers and the underlying mechanisms. We also discuss and emphasize several aspects of T cell metabolic modeling in healthy and disease states using genome-scale metabolic models. PMID:29376056

Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism.

PubMed

Brackett, Julienne; Schafer, Eric S; Leung, Daniel H; Bernhardt, M Brooke

2014-06-01

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL. © 2013 Wiley Periodicals, Inc.

Intake of Hydrolyzed Casein is Associated with Reduced Body Fat Accretion and Enhanced Phase II Metabolism in Obesity Prone C57BL/6J Mice

PubMed Central

Clausen, Morten Rahr; Zhang, Xumin; Yde, Christian C.; Ditlev, Ditte B.; Lillefosse, Haldis H.; Madsen, Lise; Kristiansen, Karsten; Liaset, Bjørn; Bertram, Hanne C.

2015-01-01

The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets. PMID:25738501

Mood state and cerebral metabolism in persons with age-associated memory impairment.

PubMed

Cherrier, M M; Small, G W; Komo, S; La Rue, A

1997-12-30

People undergoing medical procedures sometimes experience feelings that may influence the results. In this study, we explore the relationship between changes in mood state self-ratings and cerebral glucose metabolism during positron emission tomography (PET) in persons with age-associated memory impairment (mean age 59.4 +/- 9.8 years). Brain regions of interest involved in both mood and memory were examined. Mood ratings of increased boredom correlated significantly with mesial temporal and parietal asymmetry and decreased parietal metabolism. Mood ratings of increased fatigue correlated with basal ganglia asymmetry and the right basal ganglia and left mesial temporal metabolism. These findings suggest that subjective mood state changes during PET may influence metabolism in brain regions implicated in emotion and memory function in people with age-related memory complaints.

The metabolic basis of cognitive insight in psychosis: A positron emission tomography study

PubMed Central

Paoli, Riccardo A.; Cigliobianco, Michela; Prunas, Cecilia; Zugno, Elisa; Bottinelli, Francesca; Brambilla, Paolo; Altamura, A. Carlo

2017-01-01

The purpose of this study was to investigate the relationship between cognitive insight and cerebral metabolism in patients suffering from psychosis. The Beck Cognitive Insight Scale (BCIS) was administered to 63 patients with psychosis undergoing Positron Emission Tomography investigation. The sample was divided into two groups considering the BCIS score. Data were analyzed using Statistical Parametric Mapping. Results: patients with low insight, compared to those with high insight, showed decreased metabolism in the right fusiform gyrus, left precuneus, superior temporal gyrus and insula bilaterally, as well as increased metabolism in the left orbito-frontal gyrus (all p<0.005). Our results suggest that reduced posterior (occipito-temporo-insulo-parietal) and increased anterior (orbitofrontal) cerebral metabolism may sustain low cognitive insight in psychosis. PMID:28414766

Human reductive halothane metabolism in vitro is catalyzed by cytochrome P450 2A6 and 3A4.

PubMed

Spracklin, D K; Thummel, K E; Kharasch, E D

1996-09-01

The anesthetic halothane undergoes extensive oxidative and reductive biotransformation, resulting in metabolites that cause hepatotoxicity. Halothane is reduced anaerobically by cytochrome P450 (P450) to the volatile metabolites 2-chloro-1,1-difluoroethene (CDE) and 2-chloro-1,1,1-trifluoroethane (CTE). The purpose of this investigation was to identify the human P450 isoform(s) responsible for reductive halothane metabolism. CDE and CTE formation from halothane metabolism by human liver microsomes was determined by GC/MS analysis. Halothane metabolism to CDE and CTE under reductive conditions was completely inhibited by carbon monoxide, which implicates exclusively P450 in this reaction. Eadie-Hofstee plots of both CDE and CTE formation were nonlinear, suggesting multiple P450 isoform involvement. Microsomal CDE and CTE formation were each inhibited 40-50% by P450 2A6-selective inhibitors (coumarin and 8-methoxypsoralen) and 55-60% by P450 3A4-selective inhibitors (ketoconazole and troleandomycin). P450 1A-, 2B6-, 2C9/10-, and 2D6-selective inhibitors (7,8-benzoflavone, furafylline, orphenadrine, sulfaphenazole, and quinidine) had no significant effect on reductive halothane metabolism. Measurement of product formation catalyzed by a panel of cDNA-expressed P450 isoforms revealed that maximal rates of CDE formation occurred with P450 2A6, followed by P450 3A4. P450 3A4 was the most effective catalyst of CTE formation. Among a panel of 11 different human livers, there were significant linear correlations between the rate of CDE formation and both 2A6 activity (r = 0.64, p < 0.04) and 3A4 activity (r = 0.64, p < 0.03). Similarly, there were significant linear correlations between CTE formation and both 2A6 activity (r = 0.55, p < 0.08) and 3A4 activity (r = 0.77, p < 0.005). The P450 2E1 inhibitors 4-methylpyrazole and diethyldithiocarbamate inhibited CDE and CTE formation by 20-45% and 40-50%, respectively; however, cDNA-expressed P450 2E1 did not catalyze significant amounts of CDE or CTE production, and microsomal metabolite formation was not correlated with P450 2E1 activity. This investigation demonstrated that human liver microsomal reductive halothane metabolism is catalyzed predominantly by P450 2A6 and 3A4. This isoform selectivity for anaerobic halothane metabolism contrasts with that for oxidative human halothane metabolism, which is catalyzed predominantly by P450 2E1.

Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis.

PubMed

Bu, Pengcheng; Chen, Kai-Yuan; Xiang, Kun; Johnson, Christelle; Crown, Scott B; Rakhilin, Nikolai; Ai, Yiwei; Wang, Lihua; Xi, Rui; Astapova, Inna; Han, Yan; Li, Jiahe; Barth, Bradley B; Lu, Min; Gao, Ziyang; Mines, Robert; Zhang, Liwen; Herman, Mark; Hsu, David; Zhang, Guo-Fang; Shen, Xiling

2018-06-05

Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth. Copyright © 2018 Elsevier Inc. All rights reserved.

Classic histamine H1 receptor antagonists: a critical review of their metabolic and pharmacokinetic fate from a bird's eye view.

PubMed

Sharma, A; Hamelin, B A

2003-04-01

The so-called "classic" histamine H(1) receptor antagonists are highly lipophilic compounds associated with significant biotransformation and tissue distribution. They are categorized according to their chemical structure into ethanolamines, alkylamines, ethylenediamines, piperazines, phenothiazines and piperidines, all of which have characteristic metabolic fates. The former four categories undergo primarily cytochrome P450-mediated oxidative N-desalkylations and deamination whereas the aromatic rings of the latter two undergo P450-mediated oxidative hydroxylation and/or epoxide formation. The common tertiary amino group is susceptible to oxidative metabolism by flavin containing monooxygenases forming N-oxides, and the alicyclic tertiary amines produce small amounts (up to 7%) of N-glucuronides in humans. Species, sex and racial differences in the metabolism and pharmacokinetics of antihistamines are known. Specific P450-isozymes implicated in the metabolism were identified in a few cases, such as CYP2D6 that contributes to the metabolism of promethazine, diphenhydramine and chlorpheniramine. Low circulating plasma concentrations of antihistamines are in part explained by significant first-pass effect and tissue distribution. Antihistaminic effects last up to 6 hours though some compounds exhibit a longer duration of action due to circulating active metabolites. Importantly, diphenhydramine inhibited CYP2D6 leading to a clinically significant drug-drug interaction with metoprolol. Other classic antihistamines were shown to be potent in vitro inhibitors of CYP2D6 and CYP3A4. The prescription-free access to most classic antihistamines can easily lead to their co-administration with other drugs metabolized by the same enzyme system thereby leading to drug accumulation and adverse effects. In depth knowledge of the metabolic pathways of classic antihistamines and the enzymes involved is crucial to prevent the high incidence of drug interactions in humans, which are predictable based on pre-clinical data but unexpected when such data is unavailable.

Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol.

PubMed

Morselli, Eugenia; Galluzzi, Lorenzo; Kepp, Oliver; Criollo, Alfredo; Maiuri, Maria Chiara; Tavernarakis, Nektarios; Madeo, Frank; Kroemer, Guido

2009-12-23

Although autophagy has widely been conceived as a self-destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies. Similarly, resveratrol can trigger autophagy in cells from different organisms, extend lifespan in nematodes, and ameliorate the fitness of human cells undergoing metabolic stress. These beneficial effects are lost when essential autophagy modulators are genetically or pharmacologically inactivated, indicating that autophagy is required for the cytoprotective and/or anti-aging effects of spermidine and resveratrol. Genetic and functional studies indicate that spermidine inhibits histone acetylases, while resveratrol activates the histone deacetylase Sirtuin 1 to confer cytoprotection/longevity. Although it remains elusive whether the same histones (or perhaps other nuclear or cytoplasmic proteins) act as the downstream targets of spermidine and resveratrol, these results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity.

Enterodiol is Actively Transported by Rat Liver Cell Membranes.

PubMed

de Athayde Moncorvo Collado, Alejandro; Salazar, Paula B; Minahk, Carlos

2018-05-04

The interaction of enterodiol and the well-described polyphenol epigallocatechin gallate (EGCG) with hepatic membranes has been matter of interest in the last few years. On one hand, EGCG is only able to bind to the phospholipid polar head groups, as it has been already described in synthetic lipid bilayers and erythrocyte membranes but cannot get inserted into the hydrophobic core or be transported into the lumen of membrane vesicles. On the other, enterodiol has no interaction with non-energized membranes either, but it is able to interact and even be transported upon addition of ATP. In fact, the ATPase activity undergoes a twofold increase in the presence of enterodiol but not in the presence of EGCG. This is the first report on the transport of enterodiol by liver membranes, and it may help explain the rather high blood concentrations of this estrogenic enterolignan compared to EGCG, which is extensively metabolized by the intestine and the liver. The present results suggest that a fraction of enterodiol may escape the liver inactivation by being pumped out from the hepatocytes to the bloodstream.

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

PubMed

Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

2016-01-01

Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Early effects of Lansoprazole orally disintegrating tablets on intragastric pH in CYP2C19 extensive metabolizers

PubMed Central

Yamagishi, Hatsushi; Koike, Tomoyuki; Ohara, Shuichi; Horii, Toru; Kikuchi, Ryousuke; Kobayashi, Shigeyuki; Abe, Yasuhiko; Iijima, Katsunori; Imatani, Akira; Suzuki, Kaori; Hishinuma, Takanori; Goto, Junichi; Shimosegawa, Tooru

2008-01-01

AIM: To compare rabeprazole (RPZ; 10 mg) with Lansoprazole orally disintegrating tablets (LPZ; 30 mg OD) in terms of antisecretory activity and blood drug concentration after a single dose. METHODS: Eight H pylori-negative cytochrome P450 (CYP) 2C19 extensive metabolizers were assigned to receive a single oral dose of RPZ 10 mg or LPZ 30 mg OD. Twelve hour intragastric pH monitoring was performed on the day of treatment. Blood samples were also collected after the administration of each drug. RESULTS: LPZ 30 mg OD induced a significantly earlier rise in blood drug concentration than RPZ 10 mg; consequently, LPZ 30 mg OD induced a significantly earlier rise in median pH in the third and fourth hours of the study. CONCLUSION: In H pylori-negative CYP2C19 extensive metabolizers, LPZ 30 mg OD induced a significantly faster inhibition of gastric acid secretion than RPZ 10 mg. PMID:18395905

Differential Consequences of Tramadol in Overdosing: Dilemma of a Polymorphic Cytochrome P450 2D6-Mediated Substrate.

PubMed

Srinivas, Nuggehally R

2015-09-01

Tramadol is a centrally acting opioid analgesic that is prone to polymorphic metabolism via cytochrome P450 (CYP) 2D6. The generation of the active metabolite, O-desmethyltramadol, which occurs through the CYP 2D6 pathway, significantly contributes to the drug's activity. However, dosage adjustments of tramadol are typically not practiced in the clinic when treating patients who are homozygous extensive metabolizers, heterozygous extensive metabolizers, or poor metabolizers. In the event of a tramadol overdose, the consequences may be influenced importantly by the genotype or phenotype status of the subject. Depending on the individual subject's CYP 2D6 status, one may see excessive miotic-related toxicity driven by the excessive availability of O-desmethyltramadol or one may manifest mydriatic-related toxicity driven by the excessive availability of tramadol. This report provides pharmacokinetic perspectives in situations of tramadol overdosing.

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids1

PubMed Central

Cassidy, Aedín; Minihane, Anne-Marie

2017-01-01

At a population level, there is growing evidence of the beneficial effects of dietary flavonoids on health. However, there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes. In addition, food composition and flavonoid source are likely to affect bioavailability, and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main subclasses of flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones, for which there is growing evidence from prospective studies of beneficial effects on health. The identification of key factors that govern metabolism and an understanding of how the differential capacity to metabolize these bioactive compounds affect health outcomes will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas that need to be addressed to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base that is required to move toward the development of dietary guidelines and recommendations for flavonoids and flavonoid-rich foods. PMID:27881391

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids.

PubMed

Cassidy, Aedín; Minihane, Anne-Marie

2017-01-01

At a population level, there is growing evidence of the beneficial effects of dietary flavonoids on health. However, there is extensive heterogeneity in the response to increased intake, which is likely mediated via wide interindividual variability in flavonoid absorption and metabolism. Flavonoids are extensively metabolized by phase I and phase II metabolism (which occur predominantly in the gastrointestinal tract and liver) and colonic microbial metabolism. A number of factors, including age, sex, and genotype, may affect these metabolic processes. In addition, food composition and flavonoid source are likely to affect bioavailability, and emerging data suggest a critical role for the microbiome. This review will focus on the current knowledge for the main subclasses of flavonoids, including anthocyanins, flavonols, flavan-3-ols, and flavanones, for which there is growing evidence from prospective studies of beneficial effects on health. The identification of key factors that govern metabolism and an understanding of how the differential capacity to metabolize these bioactive compounds affect health outcomes will help establish how to optimize intakes of flavonoids for health benefits and in specific subgroups. We identify research areas that need to be addressed to further understand important determinants of flavonoid bioavailability and metabolism and to advance the knowledge base that is required to move toward the development of dietary guidelines and recommendations for flavonoids and flavonoid-rich foods.

Metabolic remodeling triggered by salivation and diabetes in major salivary glands.

PubMed

Nogueira, Fernando N; Carvalho, Rui A

2017-02-01

The metabolic profile of major salivary glands was evaluated by 13 C nuclear magnetic resonance isotopomer analysis ( 13 C NMR-IA) following the infusion of [U- 13 C]glucose in order to define the true metabolic character of submandibular (SM) and parotid (PA) glands at rest and during salivary stimulation, and to determine the metabolic remodeling driven by diabetes. In healthy conditions, the SM gland is characterized at rest by a glycolytic metabolic profile and extensive pyruvate cycling. On the contrary, the PA gland, although also dominated by glycolysis, also possesses significant Krebs' cycle activity and does not sustain extensive pyruvate cycling. Under stimulation, both glands increase their glycolytic and Krebs' cycle fluxes, but the metabolic coupling between the two pathways is further compromised to account for the much increased biosynthetic anaplerotic fluxes. In diabetes, the responsiveness of the PA gland to a salivary stimulus is seriously hindered, mostly as a result of the incapacity to burst glycolytic activity and also an inability to improve the Krebs' cycle flux to compensate. The Krebs' cycle activity in the SM gland is also consistently compromised, but the glycolytic flux in this gland is more resilient. This diabetes-induced metabolic remodeling in SM and PA salivary glands illustrates the metabolic need to sustain adequate saliva production, and identifies glycolytic and oxidative pathways as key players in the metabolic dynamism of salivary glands. Copyright © 2016 John Wiley & Sons, Ltd.

The complex interplay between mitochondrial dynamics and cardiac metabolism

PubMed Central

Parra, Valentina; Verdejo, Hugo; del Campo, Andrea; Pennanen, Christian; Kuzmicic, Jovan; Iglewski, Myriam; Hill, Joseph A.; Rothermel, Beverly A.

2012-01-01

Mitochondria are highly dynamic organelles, capable of undergoing constant fission and fusion events, forming networks. These dynamic events allow the transmission of chemical and physical messengers and the exchange of metabolites within the cell. In this article we review the signaling mechanisms controlling mitochondrial fission and fusion, and its relationship with cell bioenergetics, especially in the heart. Furthermore we also discuss how defects in mitochondrial dynamics might be involved in the pathogenesis of metabolic cardiac diseases. PMID:21258852

Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine-buprenorphine combination in standing horses.

PubMed

Van Dijk, P; Lankveld, Dpk; Rijkenhuizen, Abm; Jonker, F H

2003-04-01

To assess the hormonal, metabolic and physiological effects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Prospective study. Eight healthy adult Dutch Warmblood horses and five healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. The sedative effect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesterified fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the effects of detomidine were antagonized using atipamezole. The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses which, with the exception of NEFA values, were not significantly different from changes found in the control group. While atipamezole did not produce detectable adverse effects, it is possible that anatagonism may not be essential. The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the effects of detomidine may not be necessary in all cases. Copyright © 2003 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Knee Pain in a Renal Transplant Patient

DTIC Science & Technology

2017-04-26

chronic kidney disease. They often develop soft tissue rheumatic syndromes, crystalline arthropathy, and metabolic bone disease. We describe a...hemodialysis. Furthermore, patients who undergo kidney transplant report improvement of symptoms. Disclaimer: The views expressed are those of the author(s

Organ Specific Proteomic Dissection of Selaginella bryopteris Undergoing Dehydration and Rehydration

PubMed Central

Deeba, Farah; Pandey, Ashutosh K.; Pandey, Vivek

2016-01-01

To explore molecular mechanisms underlying the physiological response of Selaginella bryopteris, a comprehensive proteome analysis was carried out in roots and fronds undergoing dehydration and rehydration. Plants were dehydrated for 7 days followed by 2 and 24 h of rehydration. In roots out of 59 identified spots, 58 protein spots were found to be up-regulated during dehydration stress. The identified proteins were related to signaling, stress and defense, protein and nucleotide metabolism, carbohydrate and energy metabolism, storage and epigenetic control. Most of these proteins remained up-regulated on first rehydration, suggesting their role in recovery phase also. Among the 90 identified proteins in fronds, about 49% proteins were up-regulated during dehydration stress. Large number of ROS scavenging proteins was enhanced on dehydration. Many other proteins involved in energy, protein turnover and nucleotide metabolism, epigenetic control were also highly upregulated. Many photosynthesis related proteins were upregulated during stress. This would have helped plant to recover rapidly on rehydration. This study provides a comprehensive picture of different cellular responses elucidated by the proteome changes during dehydration and rehydration in roots and fronds as expected from a well-choreographed response from a resurrection plant. PMID:27092152

Early carbon mobilization and radicle protrusion in maize germination.

PubMed

Sánchez-Linares, Luis; Gavilanes-Ruíz, Marina; Díaz-Pontones, David; Guzmán-Chávez, Fernando; Calzada-Alejo, Viridiana; Zurita-Villegas, Viridiana; Luna-Loaiza, Viridiana; Moreno-Sánchez, Rafael; Bernal-Lugo, Irma; Sánchez-Nieto, Sobeida

2012-07-01

Considerable amounts of information is available on the complex carbohydrates that are mobilized and utilized by the seed to support early seedling development. These events occur after radicle has protruded from the seed. However, scarce information is available on the role of the endogenous soluble carbohydrates from the embryo in the first hours of germination. The present work analysed how the soluble carbohydrate reserves in isolated maize embryos are mobilized during 6-24 h of water imbibition, an interval that exclusively embraces the first two phases of the germination process. It was found that sucrose constitutes a very significant reserve in the scutellum and that it is efficiently consumed during the time in which the adjacent embryo axis is engaged in an active metabolism. Sucrose transporter was immunolocalized in the scutellum and in vascular elements. In parallel, a cell-wall invertase activity, which hydrolyses sucrose, developed in the embryo axis, which favoured higher glucose uptake. Sucrose and hexose transporters were active in the embryo tissues, together with the plasma membrane H(+)-ATPase, which was localized in all embryo regions involved in both nutrient transport and active cell elongation to support radicle extension. It is proposed that, during the initial maize germination phases, a net flow of sucrose takes place from the scutellum towards the embryo axis and regions that undergo elongation. During radicle extension, sucrose and hexose transporters, as well as H(+)-ATPase, become the fundamental proteins that orchestrate the transport of nutrients required for successful germination.

Does preoperative oral carbohydrate treatment reduce the postoperative surgical stress response in lumbar disc surgery?

PubMed

Dilmen, Ozlem Korkmaz; Yentur, Ercument; Tunali, Yusuf; Balci, Huriye; Bahar, Mois

2017-02-01

Surgical trauma produces metabolic and hormonal responses, which are characterized by insulin resistance. Due to extension of the preoperative fasting period, which increases the magnitude of postoperative insulin resistance, preoperative oral carbohydrates (POC) have been developed. This prospective, randomized, controlled study was performed on 43 ASA I-II patients undergoing elective microsurgical lumbar discectomy. The intervention group received oral carbohydrate solution 800mL the night before and 400mL 2h prior to operation. The other group fasted for 8h prior to operation. Blood samples were obtained the day before the operation, before induction of anesthesia, after skin incision, 1h, 2h, 6h and 24h following skin incision. Blood glucose, plasma insulin, cortisol and interleukin-6 (IL-6) levels were determined. The primary endpoint was to assess the effect of POC treatment on insulin resistance and surgical stress response following lumbar disc surgery. The secondary endpoint was to assess POC's effects on postoperative nausea and vomiting. The serum insulin levels were higher before induction of anesthesia in the study group and returned to fasted group levels by 2h after skin incision. The plasma IL-6 levels were higher in the intervention group at 6h after the skin incision. There were no differences between the two groups with respect to blood glucose, plasma cortisol levels and the incidence of nausea and vomiting. This study suggests that use of POC treatment does not attenuate development of insulin resistance in patients undergoing lumbar disc surgery. Copyright © 2016. Published by Elsevier B.V.

Endocrine response to realimentation in young northern elephant seals (Mirounga angustirostris): Indications for development of fasting adaptation.

PubMed

Dailey, Rachael E; Fontaine, Christine M; Avery, Julie P

2016-09-01

Most organisms undergo changes in their environment, both predictably and unpredictably, which require them to alter priorities in nutrient allocation with regards to food availability. Species that more predictably encounter extended periods of limited food resources or intake while mitigating the negative effects of starvation are considered to be fasting adapted. Northern elephant seals (NES) are one such species and routinely undergo extended periods of fasting for breeding, molting, as well as a post-weaning fast at 6-8weeks of age. However, during unusual times of nutritional deprivation, animals may enter stage III fasting. While fasting and foraging in this species has been extensively studied, realimentation following fasting beyond normal life history parameters has not been investigated. In this study, changes in ghrelin, growth hormone (GH), and insulin-like growth factor (IGF)-I were compared across 8weeks of realimentation following emaciation in three age classes: neonates, post-molt pups, and yearlings. Longitudinal changes in hormone profiles indicate that neonate and post-molt pups are slow to recover mass and positive energy balance despite an energy dense diet fed at 10% body mass. In addition, ghrelin and GH concentrations remained elevated in post-molt pups compared to other age classes. Changes in hormone concentrations early in realimentation indicate that yearling animals recover more rapidly from periods of nutritional deprivation than do younger animals. Overall, this suggests that the ability to regulate metabolic homeostasis with regards to nutrient allocation may develop over time, even in a species that is considered to be fasting adapted. Copyright © 2016 Elsevier Inc. All rights reserved.

Modular Ligation Extension of Guide RNA Operons (LEGO) for Multiplexed dCas9 Regulation of Metabolic Pathways in Saccharomyces cerevisiae.

PubMed

Deaner, Matthew; Holzman, Allison; Alper, Hal S

2018-04-16

Metabolic engineering typically utilizes a suboptimal step-wise gene target optimization approach to parse a highly connected and regulated cellular metabolism. While the endonuclease-null CRISPR/Cas system has enabled gene expression perturbations without genetic modification, it has been mostly limited to small sets of gene targets in eukaryotes due to inefficient methods to assemble and express large sgRNA operons. In this work, we develop a TEF1p-tRNA expression system and demonstrate that the use of tRNAs as splicing elements flanking sgRNAs provides higher efficiency than both Pol III and ribozyme-based expression across a variety of single sgRNA and multiplexed contexts. Next, we devise and validate a scheme to allow modular construction of tRNA-sgRNA (TST) operons using an iterative Type IIs digestion/ligation extension approach, termed CRISPR-Ligation Extension of sgRNA Operons (LEGO). This approach enables facile construction of large TST operons. We demonstrate this utility by constructing a metabolic rewiring prototype for 2,3-butanediol production in 2 distinct yeast strain backgrounds. These results demonstrate that our approach can act as a surrogate for traditional genetic modification on a much shorter design-cycle timescale. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Assimilation of Endogenous Nicotinamide Riboside Is Essential for Calorie Restriction-mediated Life Span Extension in Saccharomyces cerevisiae*

PubMed Central

Lu, Shu-Ping; Kato, Michiko; Lin, Su-Ju

2009-01-01

NAD+ (nicotinamide adenine dinucleotide) is an essential cofactor involved in various biological processes including calorie restriction-mediated life span extension. Administration of nicotinamide riboside (NmR) has been shown to ameliorate deficiencies related to aberrant NAD+ metabolism in both yeast and mammalian cells. However, the biological role of endogenous NmR remains unclear. Here we demonstrate that salvaging endogenous NmR is an integral part of NAD+ metabolism. A balanced NmR salvage cycle is essential for calorie restriction-induced life span extension and stress resistance in yeast. Our results also suggest that partitioning of the pyridine nucleotide flux between the classical salvage cycle and the NmR salvage branch might be modulated by the NAD+-dependent Sir2 deacetylase. Furthermore, two novel deamidation steps leading to nicotinic acid mononucleotide and nicotinic acid riboside production are also uncovered that further underscore the complexity and flexibility of NAD+ metabolism. In addition, utilization of extracellular nicotinamide mononucleotide requires prior conversion to NmR mediated by a periplasmic phosphatase Pho5. Conversion to NmR may thus represent a strategy for the transport and assimilation of large nonpermeable NAD+ precursors. Together, our studies provide a molecular basis for how NAD+ homeostasis factors confer metabolic flexibility. PMID:19416965

Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae.

PubMed

Lu, Shu-Ping; Kato, Michiko; Lin, Su-Ju

2009-06-19

NAD(+) (nicotinamide adenine dinucleotide) is an essential cofactor involved in various biological processes including calorie restriction-mediated life span extension. Administration of nicotinamide riboside (NmR) has been shown to ameliorate deficiencies related to aberrant NAD(+) metabolism in both yeast and mammalian cells. However, the biological role of endogenous NmR remains unclear. Here we demonstrate that salvaging endogenous NmR is an integral part of NAD(+) metabolism. A balanced NmR salvage cycle is essential for calorie restriction-induced life span extension and stress resistance in yeast. Our results also suggest that partitioning of the pyridine nucleotide flux between the classical salvage cycle and the NmR salvage branch might be modulated by the NAD(+)-dependent Sir2 deacetylase. Furthermore, two novel deamidation steps leading to nicotinic acid mononucleotide and nicotinic acid riboside production are also uncovered that further underscore the complexity and flexibility of NAD(+) metabolism. In addition, utilization of extracellular nicotinamide mononucleotide requires prior conversion to NmR mediated by a periplasmic phosphatase Pho5. Conversion to NmR may thus represent a strategy for the transport and assimilation of large nonpermeable NAD(+) precursors. Together, our studies provide a molecular basis for how NAD(+) homeostasis factors confer metabolic flexibility.

Sirtuins and the metabolic hurdles in cancer

PubMed Central

German, Natalie J.; Haigis, Marcia C.

2017-01-01

The metabolic demands of cancer cannot be met by normal cell metabolism. Cancer cells undergo dramatic alteration of metabolic pathways in a process called reprogramming, characterized by increased nutrient uptake and re-purposing of these fuels for biosynthetic, bioenergetic or signaling pathways. Partitioning carbon sources toward growth and away from ATP production necessitates other means of generating energy for biosynthetic reactions. Additionally, cancer cell adaptations frequently leads to increased production of reactive oxygen species and lactic acid- metabolites which can be beneficial to cancer growth but also are potentially toxic and must be appropriately cleared. Sirtuins are a family of deacylases and ADP-ribosyltransferases with clear links to the regulation of cancer metabolism. Through their unique ability to integrate cellular stress and nutrient status with coordination of metabolic outputs, sirtuins are well poised to play pivotal roles in tumor metabolism. Here, we review the multi-faceted duties of sirtuins in tackling the metabolic hurdles in cancer. We focus on both beneficial and adverse effects of sirtuins in the regulation of energetic, biosynthetic and toxicity barriers faced by cancer cells. PMID:26126285

LaRC-RP41: A Tough, High-Performance Composite Matrix

NASA Technical Reports Server (NTRS)

Pater, Ruth H.; Johnston, Norman J.; Smith, Ricky E.; Snoha, John J.; Gautreaux, Carol R.; Reddy, Rakasi M.

1991-01-01

New polymer exhibits increased toughness and resistance to microcracking. Cross-linking PMR-15 and linear LaRC-TPI combined to provide sequential semi-2-IPN designated as LaRC-RP41. Synthesized from PMR-15 imide prepolymer undergoing cross-linking in immediate presence of LaRC-TPI polyamic acid, also undergoing simultaneous imidization and linear chain extension. Potentially high-temperature matrix resin, adhesive, and molding resin. Applications include automobiles, electronics, aircraft, and aerospace structures.

Metabolic pathways for lipid synthesis under nitrogen stress in Chlamydomonas and Nannochloropsis.

PubMed

Banerjee, Avik; Maiti, Subodh K; Guria, Chandan; Banerjee, Chiranjib

2017-01-01

Microalgae are currently being considered as a clean, sustainable and renewable energy source. Enzymes that catalyse the metabolic pathways for biofuel production are specific and require strict regulation and co-ordination. Thorough knowledge of these key enzymes along with their regulatory molecules is essential to enable rational metabolic engineering, to drive the metabolic flux towards the desired metabolites of importance. This paper reviews two key enzymes that play their role in production of bio-oil: DGAT (acyl-CoA:diacylglycerol acyltransferase) and PDAT (phospholipid:diacylglycerol acyltransferase). It also deals with the transcription factors that control the enzymes while cell undergoes a metabolic shift under stress. The paper also discusses the association of other enzymes and pathways that provide substrates and precursors for oil accumulation. Finally a futuristic solution has been proposed about a synthetic algal cell platform that would be committed towards biofuel synthesis.

Metabolic Dysregulation in Amyotrophic Lateral Sclerosis: Challenges and Opportunities

PubMed Central

Joardar, Archi; Manzo, Ernesto

2017-01-01

Purpose of Review Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which there is no cure and treatments are at best palliative. Several genes have been linked to ALS, which highlight defects in multiple cellular processes including RNA processing, proteostasis and metabolism. Clinical observations have identified glucose intolerance and dyslipidemia as key features of ALS however the causes of these metabolic alterations remain elusive. Recent Findings Recent studies reveal that motor neurons and muscle cells may undergo cell type specific metabolic changes that lead to utilization of alternate fuels. For example, ALS patients’ muscles exhibit reduced glycolysis and increased reliance on fatty acids. In contrast, ALS motor neurons contain damaged mitochondria and exhibit impaired lipid beta oxidation, potentially leading to increased glycolysis as a compensatory mechanism. Summary These findings highlight the complexities of metabolic alterations in ALS and provide new opportunities for designing therapeutic strategies based on restoring cellular energetics. PMID:29057168

Metabolic Dysregulation in Amyotrophic Lateral Sclerosis: Challenges and Opportunities.

PubMed

Joardar, Archi; Manzo, Ernesto; Zarnescu, Daniela C

2017-06-01

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which there is no cure and treatments are at best palliative. Several genes have been linked to ALS, which highlight defects in multiple cellular processes including RNA processing, proteostasis and metabolism. Clinical observations have identified glucose intolerance and dyslipidemia as key features of ALS however the causes of these metabolic alterations remain elusive. Recent studies reveal that motor neurons and muscle cells may undergo cell type specific metabolic changes that lead to utilization of alternate fuels. For example, ALS patients' muscles exhibit reduced glycolysis and increased reliance on fatty acids. In contrast, ALS motor neurons contain damaged mitochondria and exhibit impaired lipid beta oxidation, potentially leading to increased glycolysis as a compensatory mechanism. These findings highlight the complexities of metabolic alterations in ALS and provide new opportunities for designing therapeutic strategies based on restoring cellular energetics.

Patients with glycogen storage diseases undergoing anesthesia: a case series.

PubMed

Gurrieri, Carmelina; Sprung, Juraj; Weingarten, Toby N; Warner, Mary E

2017-10-06

Glycogen storage diseases are rare genetic disorders of glycogen synthesis, degradation, or metabolism regulation. When these patients are subjected to anesthesia, perioperative complications can develop, including hypoglycemia, rhabdomyolysis, myoglobinuria, acute renal failure, and postoperative fatigue. The objective of this study was to describe the perioperative course of a cohort of patients with glycogen storage diseases. This is a retrospective review of patients with glycogen storage diseases undergoing anesthetic care at our institution from January 1, 1990, through June 30, 2015 to assess perioperative management and outcomes. We identified 30 patients with a glycogen storage disease who underwent 41 procedures under anesthesia management. Intraoperative lactic acidosis developed during 4 major surgeries (3 liver transplants, 1 myectomy), and in all cases resolved within 24 postoperative hours. Lactated Ringer solution was used frequently. Preoperative and intraoperative hypoglycemia was noted in some patients with glycogen storage disease type I, all of which responded to administration of dextrose-containing solutions. No serious postoperative complications occurred. Patients with glycogen storage disease, despite substantial comorbid conditions, tolerates the anesthetic management without major complications. Several patients who experienced self-limited metabolic acidosis were undergoing major surgical procedures, during which acidosis could be anticipated. Close monitoring and management of blood glucose levels of patients with glycogen storage disease type I is prudent.

76 FR 39878 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-07

.... Proposed Project Pulmonary Function Testing Course Approval Program, 29 CFR 1910.1043--Extension--(OMB No... Occupational Safety and Health Administration's Cotton Dust Standard, 29 CFR 1920.1043, for approving courses...

76 FR 29243 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-20

.... Proposed Project Pulmonary Function Testing Course Approval Program, 29 CFR 1910.1043--Extension--(OMB No... Occupational Safety and Health Administration's Cotton Dust Standard, 29 CFR 1920.1043, for approving courses...

A Pilot Study of Metabolic Effects of Omentectomy

ClinicalTrials.gov

2015-11-18

Patients Who Consented to Undergo Laparoscopic Gastric Banding Surgery for Weight Loss and Consent to Participate in This studyBMI ≥35 kg/m2; Confirmed Type 2 Diabetes Treated With Oral Agents and/or Only Diet Therapy; Age 18-64 Years

Identifying Cytochrome P450 Functional Networks and Their Allosteric Regulatory Elements

DTIC Science & Technology

2013-12-03

drug alters the metabolism of another drug, potentially altering the pharmacological properties of either drug and leading to adverse toxic effects ...Despite extensive efforts in past decades to understand the mechanism behind these effects , drug metabolism and drug-drug interactions remain...important isoforms that is responsible for >50% of all drug metabolism, exhibits atypical kinetics due to allosteric effects [6]. Recently, Woods et al

The consequences of pediatric renal transplantation on bone metabolism and growth.

PubMed

Bacchetta, Justine; Ranchin, Bruno; Demède, Delphine; Allard, Lise

2013-10-01

During childhood, growth retardation, decreased final height and renal osteodystrophy are common complications of chronic kidney disease (CKD). These problems remain present in patients undergoing renal transplantation, even though steroid-sparing strategies are more widely used. In this context, achieving normal height and growth in children after transplantation is a crucial issue for both quality of life and self-esteem. The aim of this review is to provide an overview of pathophysiology of CKD-mineral bone disorder (MBD) in children undergoing renal transplantation and to propose keypoints for its daily management. In adults, calcimimetics are effective for posttransplant hyperparathyroidism, but data are missing in the pediatric population. Fibroblast growth factor 23 levels are associated with increased risk of rejection, but the underlying mechanisms remain unclear. A recent meta-analysis also demonstrated the effectiveness of rhGH therapy in short transplanted children. In 2013, the daily clinical management of CKD-MBD in transplanted children should still focus on simple objectives: to optimize renal function, to develop and promote steroid-sparing strategies, to provide optimal nutritional support to maximize final height and avoid bone deformations, to equilibrate calcium/phosphate metabolism so as to provide acceptable bone quality and cardiovascular status, to correct all metabolic and clinical abnormalities that can worsen both bone and growth (mainly metabolic acidosis, anemia and malnutrition), promote good lifestyle habits (adequate calcium intake, regular physical activity, no sodas consumption, no tobacco exposure) and eventually to correct native vitamin D deficiency (target of 25-vitamin D >75 nmol/l).

Genome-scale modelling of microbial metabolism with temporal and spatial resolution.

PubMed

Henson, Michael A

2015-12-01

Most natural microbial systems have evolved to function in environments with temporal and spatial variations. A major limitation to understanding such complex systems is the lack of mathematical modelling frameworks that connect the genomes of individual species and temporal and spatial variations in the environment to system behaviour. The goal of this review is to introduce the emerging field of spatiotemporal metabolic modelling based on genome-scale reconstructions of microbial metabolism. The extension of flux balance analysis (FBA) to account for both temporal and spatial variations in the environment is termed spatiotemporal FBA (SFBA). Following a brief overview of FBA and its established dynamic extension, the SFBA problem is introduced and recent progress is described. Three case studies are reviewed to illustrate the current state-of-the-art and possible future research directions are outlined. The author posits that SFBA is the next frontier for microbial metabolic modelling and a rapid increase in methods development and system applications is anticipated. © 2015 Authors; published by Portland Press Limited.

[Effect of rat intestinal flora on in vitro metabolic transformation of pumiloside].

PubMed

Fang, Hui; Li, Meng-Xuan; Li, Hai-Bo; Liu, Wen-Jun; Meng, Zhao-Qing; Huang, Wen-Zhe; Wang, Zhen-Zhong; Xiao, Wei

2016-05-01

To study the metabolic transformation of pumiloside by rat intestinal flora in vitro and identify its metabolites. Pumiloside was incubated in the rat intestinal flora in vitro. HPLC was used to monitor the metabolic process, and HPLC-Q-TOF-MS was used to identify the structures of biotransformation products. In vitro, pumiloside was easily metabolized by rat intestinal flora, and with the prolongation of metabolic time, pumiloside was transformed into several metabolites. Three metabolites were initially identified in this experiment. The study indicated that pumiloside could be extensively metabolized in the rat intestinal flora in vitro. Copyright© by the Chinese Pharmaceutical Association.

Three good reasons for heart surgeons to understand cardiac metabolism.

PubMed

Doenst, Torsten; Bugger, Heiko; Schwarzer, Michael; Faerber, Gloria; Borger, Michael A; Mohr, Friedrich W

2008-05-01

It is the principal goal of cardiac surgeons to improve or reinstate contractile function with, through or after a surgical procedure on the heart. Uninterrupted contractile function of the heart is irrevocably linked to the uninterrupted supply of energy in the form of ATP. Thus, it would appear natural that clinicians interested in myocardial contractile function are interested in the way the heart generates ATP, i.e. the processes generally referred to as energy metabolism. Yet, it may appear that the relevance of energy metabolism in cardiac surgery is limited to the area of cardioplegia, which is a declining research interest. It is the goal of this review to change this trend and to illustrate the role and the therapeutic potential of metabolism and metabolic interventions for management. We present three compelling reasons why cardiac metabolism is of direct, practical interest to the cardiac surgeon and why a better understanding of energy metabolism might indeed result in improved surgical outcomes: (1) To understand cardioplegic arrest, ischemia and reperfusion, one needs a working knowledge of metabolism; (2) hyperglycemia is an underestimated and modifiable risk factor; (3) acute metabolic interventions can be effective in patients undergoing cardiac surgery.

Dysregulated metabolism contributes to oncogenesis

PubMed Central

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

2015-01-01

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

Preoperative oral carbohydrate therapy.

PubMed

Nygren, Jonas; Thorell, Anders; Ljungqvist, Olle

2015-06-01

Management of the postoperative response to surgical stress is an important issue in major surgery. Avoiding preoperative fasting using preoperative oral carbohydrates (POC) has been suggested as a measure to prevent and reduce the extent to which such derangements occur. This review summarizes the current evidence and rationale for this treatment. A recent review from the Cochrane Collaboration reports enhanced gastrointestinal recovery and shorter hospital stay with the use of POC with no effect on postoperative complication rates. Multiple randomized controlled trials demonstrate improved postoperative metabolic response after POC administration, including reduced insulin resistance, protein sparing, improved muscle function and preserved immune response. Cohort studies in patients undergoing major abdominal surgery have shown that the use of POC as part of an enhanced recovery after surgery protocol is a significant predictor for improved clinical outcomes. Avoiding preoperative fasting with POC is associated with attenuated postoperative insulin resistance, improved metabolic response, enhanced perioperative well-being, and better clinical outcomes. The impact is greatest for patients undergoing major surgeries.

Free Radical Metabolism of Methyleugenol and Related Compounds

PubMed Central

2015-01-01

Methyleugenol, the methyl ether of eugenol, both of which are flavorant constituents of spices, has been listed by the National Toxicology Program’s Report on Carcinogens as reasonably anticipated to be a human carcinogen. This finding is based on the observation of increased incidence of malignant tumors at multiple tissue sites in experimental animals of different species. By contrast, eugenol is not listed. In this study, we show that both methyleugenol and eugenol readily undergo peroxidative metabolism in vitro to form free radicals with large hyperfine interactions of the methylene allylic hydrogen atoms. These large hyperfine splittings indicate large electron densities adjacent to those hydrogen atoms. Methyleugenol undergoes autoxidation such that the commercial product contains 10–30 mg/L hydroperoxide and is capable of activating peroxidases without the presence of added hydrogen peroxide. Additionally, the hydroperoxide is not a good substrate for catalase, which demonstrates that these antioxidant defenses will not be effective in protecting against methyleugenol exposure. PMID:24564854

The metabolic response of Candida albicans to farnesol under hyphae-inducing conditions.

PubMed

Han, Ting-Li; Cannon, Richard D; Villas-Bôas, Silas G

2012-12-01

Farnesol is a quorum-sensing molecule (QSM) produced, and sensed, by the polymorphic fungus, Candida albicans. This cell-to-cell communication molecule is known to suppress the hyphal formation of C. albicans at high cell density. Despite many studies investigating the signalling mechanisms by which QSMs influence the morphogenesis of C. albicans, the downstream metabolic effect of these signalling pathways in response to farnesol-mediated morphogenesis remains obscure. Here, we have used metabolomics to investigate the metabolic response of C. albicans upon exposure to farnesol under hyphae-inducing conditions. We have found a general up-regulation of central carbon metabolic pathways when hyphal formation was suppressed by farnesol evidenced by a considerably larger number of central carbon metabolic intermediates detected under this condition at an overall lower intracellular level. By combining the metabolic profiles from farnesol-exposed cells with previous metabolomics data for C. albicans undergoing morphogenesis, we have identified several metabolic pathways that are likely to be associated with the morphogenetic process of C. albicans, as well as metabolic pathways such as those involved in lipid metabolism that appeared to be specifically affected by farnesol. Therefore, our results provide important new insights into the metabolic role of farnesol in C. albicans metabolism. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Secretagogue stimulation of neurosecretory cells elicits filopodial extensions uncovering new functional release sites.

PubMed

Papadopulos, Andreas; Martin, Sally; Tomatis, Vanesa M; Gormal, Rachel S; Meunier, Frederic A

2013-12-04

Regulated exocytosis in neurosecretory cells relies on the timely fusion of secretory granules (SGs) with the plasma membrane. Secretagogue stimulation leads to an enlargement of the cell footprint (surface area in contact with the coverslip), an effect previously attributed to exocytic fusion of SGs with the plasma membrane. Using total internal reflection fluorescence microscopy, we reveal the formation of filopodia-like structures in bovine chromaffin and PC12 cells driving the footprint expansion, suggesting the involvement of cortical actin network remodeling in this process. Using exocytosis-incompetent PC12 cells, we demonstrate that footprint enlargement is largely independent of SG fusion, suggesting that vesicular exocytic fusion plays a relatively minor role in filopodial expansion. The footprint periphery, including filopodia, undergoes extensive F-actin remodeling, an effect abolished by the actomyosin inhibitors cytochalasin D and blebbistatin. Imaging of both Lifeact-GFP and the SG marker protein neuropeptide Y-mCherry reveals that SGs actively translocate along newly forming actin tracks before undergoing fusion. Together, these data demonstrate that neurosecretory cells regulate the number of SGs undergoing exocytosis during sustained stimulation by controlling vesicular mobilization and translocation to the plasma membrane through actin remodeling. Such remodeling facilitates the de novo formation of fusion sites.

Molecular monitoring of epithelial-to-mesenchymal transition in breast cancer cells by means of Raman spectroscopy.

PubMed

Marro, M; Nieva, C; Sanz-Pamplona, R; Sierra, A

2014-09-01

In breast cancer the presence of cells undergoing the epithelial-to-mesenchymal transition is indicative of metastasis progression. Since metabolic features of breast tumour cells are critical in cancer progression and drug resistance, we hypothesized that the lipid content of malignant cells might be a useful indirect measure of cancer progression. In this study Multivariate Curve Resolution was applied to cellular Raman spectra to assess the metabolic composition of breast cancer cells undergoing the epithelial to mesenchymal transition. Multivariate Curve Resolution analysis led to the conclusion that this transition affects the lipid profile of cells, increasing tryptophan but maintaining a low fatty acid content in comparison with highly metastatic cells. Supporting those results, a Partial Least Square-Discriminant analysis was performed to test the ability of Raman spectroscopy to discriminate the initial steps of epithelial to mesenchymal transition in breast cancer cells. We achieved a high level of sensitivity and specificity, 94% and 100%, respectively. In conclusion, Raman microspectroscopy coupled with Multivariate Curve Resolution enables deconvolution and tracking of the molecular content of cancer cells during a biochemical process, being a powerful, rapid, reagent-free and non-invasive tool for identifying metabolic features of breast cancer cell aggressiveness at first stages of malignancy. Copyright © 2014 Elsevier B.V. All rights reserved.

A Data Repository and Visualization Toolbox for Metabolic Pathways and PBPK parameter prediction

EPA Science Inventory

NHANES is an extensive, well-structured collection of data about hundreds chemicals products of human metabolism and their concentration in human biomarkers, which includes parent to product mapping where known. Together, these data can be used to test the efficacy of application...

Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

PubMed Central

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C.; Cacabelos, Pablo; Teijido, Óscar

2018-01-01

Alzheimer’s disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders. PMID:29301387

Pharmacogenetics of Vascular Risk Factors in Alzheimer's Disease.

PubMed

Cacabelos, Ramón; Meyyazhagan, Arun; Carril, Juan C; Cacabelos, Pablo; Teijido, Óscar

2018-01-03

Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. Among 111 pentagenic ( APOE-APOB-APOC3-CETP-LPL ) haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC) exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC) are severely hypercholesterolemic. Furthermore, APOE , NOS3 , ACE , AGT , and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.

Template Directed Replication Supports the Maintenance of the Metabolically Coupled Replicator System

NASA Astrophysics Data System (ADS)

Könnyű, Balázs; Czárán, Tamás

2015-06-01

The RNA World scenario of prebiotic chemical evolution is among the most plausible conceptual framework available today for modelling the origin of life. RNA offers genetic and catalytic (metabolic) functionality embodied in a single chemical entity, and a metabolically cooperating community of RNA molecules would constitute a viable infrabiological subsystem with a potential to evolve into proto-cellular life. Our Metabolically Coupled Replicator System (MCRS) model is a spatially explicit computer simulation implementation of the RNA-World scenario, in which replicable ribozymes cooperate in supplying each other with monomers for their own replication. MCRS has been repeatedly demonstrated to be viable and evolvable, with different versions of the model improved in depth (chemical detail of metabolism) or in extension (additional functions of RNA molecules). One of the dynamically relevant extensions of the MCRS approach to prebiotic RNA evolution is the explicit inclusion of template replication into its assumptions, which we have studied in the present version. We found that this modification has not changed the behaviour of the system in the qualitative sense, just the range of the parameter space which is optimal for the coexistence of metabolically cooperating replicators has shifted in terms of metabolite mobility. The system also remains resistant and tolerant to parasitic replicators.

Influence of metabolic inhibitors on mitochondrial permeability transition and glutathione status.

PubMed

Reed, D J; Savage, M K

1995-05-24

Treatment of isolated mitochondria with Ca2+ and inorganic phosphate (Pi) induces an inner membrane permeability that appears to be mediated through a cyclosporin A (CsA)-inhibitable Ca(2+)-dependent pore. Isolated mitochondria during inner membrane permeability undergo rapid efflux of matrix solutes such as glutathione as GSH and Ca2+, loss of coupled functions, and large amplitude swelling. Permeability transition without large amplitude swelling, a parameter often used to assess inner membrane permeability, has been observed. The addition of either oligomycin, antimycin, or sulfide to incubation buffer containing Ca2+ and Pi abolished large amplitude swelling of mitochondria. The GSH status during a Ca(2+)- and Pi-dependent mechanism of mitochondrial GSH release in isolated mitochondria was influenced significantly by metabolic inhibitors of the respiratory chain but did not prevent inner membrane permeability as demonstrated by the release of mitochondrial GSH and Ca2+. The release of GSH was inhibited by the addition of CsA, a potent inhibitor of permeability transition. Under these conditions we did not find GSSG; however, rapid oxidation of pyridine nucleotides and depletion of ATP and ADP with conversion to AMP occurred. The addition of CsA, prevented the oxidation of pyridine nucleotides and depletion of ATP and ADP. Since NADH and NADPH were extensively oxidized, protection against oxidative stress is reflected in maintenance of GSH and not observable lipid peroxidation. Evidence from transmission electron microscopy analysis, combined with the GSH release data, indicate that permeability transition can be observed in the absence of large amplitude swelling.

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin.

PubMed

Xin, Hong; Xia, Yang-Liu; Hou, Jie; Wang, Ping; He, Wei; Yang, Ling; Ge, Guang-Bo; Xu, Wei

2015-12-01

This study aimed to characterize the glucuronidation pathway of arctigenin (AR) in human liver microsomes (HLM) and human intestine microsomes (HIM). HLM and HIM incubation systems were employed to catalyse the formation of AR glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards AR was screened. A combination of chemical inhibition assay and kinetic analysis was used to determine the UGT isoforms involved in the glucuronidation of AR in HLM and HIM. AR could be extensively metabolized to one mono-glucuronide in HLM and HIM. The mono-glucuronide was biosynthesized and characterized as 4'-O-glucuronide. UGT1A1, 1A3, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7 and 2B17 participated in the formation of 4'-O-G, while UGT2B17 demonstrated the highest catalytic activity in this biotransformation. Both kinetic analysis and chemical inhibition assays demonstrated that UGT1A9, UGT2B7 and UGT2B17 played important roles in AR-4'-O-glucuronidation in HLM. Furthermore, HIM demonstrated moderate efficiency for AR-4'-O-glucuronidation, implying that AR may undergo a first-pass metabolism during the absorption process. UGT1A9, UGT2B7 and UGT2B17 were the major isoforms responsible for the 4'-O-glucuronidation of AR in HLM, while UGT2B7 and UGT2B17 were the major contributors to this biotransformation in HIM. © 2015 Royal Pharmaceutical Society.

Metabolic Engineering of Saccharomyces cerevisiae

PubMed Central

Ostergaard, Simon; Olsson, Lisbeth; Nielsen, Jens

2000-01-01

Comprehensive knowledge regarding Saccharomyces cerevisiae has accumulated over time, and today S. cerevisiae serves as a widley used biotechnological production organism as well as a eukaryotic model system. The high transformation efficiency, in addition to the availability of the complete yeast genome sequence, has facilitated genetic manipulation of this microorganism, and new approaches are constantly being taken to metabolicially engineer this organism in order to suit specific needs. In this paper, strategies and concepts for metabolic engineering are discussed and several examples based upon selected studies involving S. cerevisiae are reviewed. The many different studies of metabolic engineering using this organism illustrate all the categories of this multidisciplinary field: extension of substrate range, improvements of producitivity and yield, elimination of byproduct formation, improvement of process performance, improvements of cellular properties, and extension of product range including heterologous protein production. PMID:10704473

Metabolism and Biomarkers of Heterocyclic Aromatic Amines in Molecular Epidemiology Studies: Lessons Learned from Aromatic Amines

PubMed Central

2011-01-01

Aromatic amines and heterocyclic aromatic amines (HAAs) are structurally related classes of carcinogens that are formed during the combustion of tobacco or during the high-temperature cooking of meats. Both classes of procarcinogens undergo metabolic activation by N-hydroxylation of the exocyclic amine group, to produce a common proposed intermediate, the arylnitrenium ion, which is the critical metabolite implicated in toxicity and DNA damage. However, the biochemistry and chemical properties of these compounds are distinct and different biomarkers of aromatic amines and HAAs have been developed for human biomonitoring studies. Hemoglobin adducts have been extensively used as biomarkers to monitor occupational and environmental exposures to a number of aromatic amines; however, HAAs do not form hemoglobin adducts at appreciable levels and other biomarkers have been sought. A number of epidemiologic studies that have investigated dietary consumption of well-done meat in relation to various tumor sites reported a positive association between cancer risk and well-done meat consumption, although some studies have shown no associations between well-done meat and cancer risk. A major limiting factor in most epidemiological studies is the uncertainty in quantitative estimates of chronic exposure to HAAs and, thus, the association of HAAs formed in cooked meat and cancer risk has been difficult to establish. There is a critical need to establish long-term biomarkers of HAAs that can be implemented in molecular epidemioIogy studies. In this review article, we highlight and contrast the biochemistry of several prototypical carcinogenic aromatic amines and HAAs to which humans are chronically exposed. The biochemical properties and the impact of polymorphisms of the major xenobiotic-metabolizing enzymes on the biological effects of these chemicals are examined. Lastly, the analytical approaches that have been successfully employed to biomonitor aromatic amines and HAAs, and emerging biomarkers of HAAs that may be implemented in molecular epidemiology studies are discussed. PMID:21688801

The relationship between plasma concentration of metoprolol and CYP2D6 genotype in patients with ischemic heart disease.

PubMed

Wojtczak, Anna; Wojtczak, Maciej; Skrętkowicz, Jadwiga

2014-06-01

Metoprolol is the one of the most commonly used β-blockers in the treatment of ischemic heart disease and it is extensively metabolized in the liver undergoing oxidation by CYP2D6 isoenzyme of cytochrome P450. Gene encoding the CYP2D6 enzyme is characterized by genetic polymorphism. The CYP2D6 oxidation polymorphism has a major impact on the effectiveness and safety of the treatment. The aim of the study was to evaluate the relationship between plasma concentration of metoprolol and the CYP2D6 genotype in patients with ischemic heart disease. Fifty patients were interviewed and subsequently enrolled into the study. The patients received metoprolol twice daily at a dose of 50mg. The blood samples were analyzed for two major defective alleles for CYP2D6 - CYP2D6*4 and CYP2D6*3--by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Metoprolol concentration in plasma was determined by using the new and unique high-performance liquid chromatography (HPLC) method in the author's own modification with Corona CAD detector (Charged Aerosol Detection). In the test group, genotypes conditioning poor oxidation (PM) occurred in 3 patients (6%), while 47 patients (94%) had genotypes coding for extensive metabolism (EM). Patients with PM genotypes had significantly higher plasma concentrations of metoprolol than the patients with EM genotype (mean 92.25 ± SD 36.78 ng/ml vs. mean 168.22 ± SD 5.61 ng/ml, respectively). Established relationships were statistically significant (NIR test, p=0.0009). This study demonstrated that the CYP2D6 genotype remains a major determinant of the metoprolol plasma concentrations. The pharmacogenetic effect is likely to have consequences on both, the clinical benefit of metoprolol treatment and adverse drug reactions. The use of Corona CAD detector seems to be a very good alternative method for the determination of metoprolol concentration in plasma. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Mitral valve stenosis caused by abnormal pannus extension over the prosthetic ring and leaflets after Duran ring mitral annuloplasty.

PubMed

Yunoki, Junji; Minato, Naoki; Katayama, Yuji; Sato, Hisashi

2009-01-01

We treated a 61-year-old woman with mitral stenosis caused by pannus formation after Duran ring annuloplasty. Pannus overgrowth on the ring with extension onto both leaflets narrowed the mitral orifice and severely restricted the mobility of the valve leaflets. Mitral valve replacement with a St. Jude Medical mechanical heart valve prosthesis was successfully performed, and the postoperative course was uneventful. Patients undergoing Duran ring annuloplasty should be followed up with the consideration of possible mitral stenosis caused by pannus extension, as the cause for pannus formation remains unclear.

Cardiopulmonary bypass with bivalirudin in type II heparin-induced thrombocytopenia.

PubMed

Clayton, Stephanie B; Acsell, Jeffrey R; Crumbley, Arthur J; Uber, Walter E

2004-12-01

Cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia poses significant challenges. Inadequate pharmacokinetic profiles, monitoring, reversibility, and availability often limit alternative anticoagulation strategies. Bivalirudin, a semisynthetic direct thrombin inhibitor, was recently approved for use in patients undergoing percutaneous coronary interventions. Its unique properties, including a relatively short half-life, an anticoagulation effect that closely correlates with activated clotting time, and an alternate metabolic pathway for elimination, make bivalirudin an attractive agent for cardiopulmonary bypass in patients with type II heparin induced-thrombocytopenia. We report our experience using bivalirudin in 2 patients undergoing coronary artery bypass grafting.

Vertebrate homologues of Frodo are dynamically expressed during embryonic development in tissues undergoing extensive morphogenetic movements.

PubMed

Hunter, Nina L; Hikasa, Hiroki; Dymecki, Susan M; Sokol, Sergei Y

2006-01-01

Frodo has been identified as a protein interacting with Dishevelled, an essential mediator of the Wnt signaling pathway, critical for the determination of cell fate and polarity in embryonic development. In this study, we use specific gene probes to characterize stage- and tissue-specific expression patterns of the mouse Frodo homologue and compare them with Frodo expression patterns in Xenopus embryos. In situ hybridization analysis of mouse Frodo transcripts demonstrates that, similar to Xenopus Frodo, mouse Frodo is expressed in primitive streak mesoderm, neuroectoderm, neural crest, presomitic mesoderm, and somites. In many cases, Frodo expression is confined to tissues undergoing extensive morphogenesis, suggesting that Frodo may be involved in the regulation of cell shape and motility. Highly conserved dynamic expression patterns of Frodo homologues indicate a similar function for these proteins in different vertebrates. 2005 Wiley-Liss, Inc.

Recent advances in metabolic engineering of Saccharomyces cerevisiae: New tools and their applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lian, Jiazhang; Mishra, Shekhar; Zhao, Huimin

Metabolic engineering aims to develop efficient cell factories by rewiring cellular metabolism. As one of the most commonly used cell factories, Saccharomyces cerevisiae has been extensively engineered to produce a wide variety of products at high levels from various feedstocks. In this paper, we summarize the recent development of metabolic engineering approaches to modulate yeast metabolism with representative examples. Particularly, we highlight new tools for biosynthetic pathway optimization (i.e. combinatorial transcriptional engineering and dynamic metabolic flux control) and genome engineering (i.e. clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) system based genome engineering and RNA interference assisted genome evolution)more » to advance metabolic engineering in yeast. Lastly, we also discuss the challenges and perspectives for high throughput metabolic engineering.« less

Recent advances in metabolic engineering of Saccharomyces cerevisiae: New tools and their applications

DOE PAGES

Lian, Jiazhang; Mishra, Shekhar; Zhao, Huimin

2018-04-25

Metabolic engineering aims to develop efficient cell factories by rewiring cellular metabolism. As one of the most commonly used cell factories, Saccharomyces cerevisiae has been extensively engineered to produce a wide variety of products at high levels from various feedstocks. In this paper, we summarize the recent development of metabolic engineering approaches to modulate yeast metabolism with representative examples. Particularly, we highlight new tools for biosynthetic pathway optimization (i.e. combinatorial transcriptional engineering and dynamic metabolic flux control) and genome engineering (i.e. clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) system based genome engineering and RNA interference assisted genome evolution)more » to advance metabolic engineering in yeast. Lastly, we also discuss the challenges and perspectives for high throughput metabolic engineering.« less

Metabolic reprogramming during neuronal differentiation.

PubMed

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

2016-09-01

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

Metabolic reprogramming during neuronal differentiation

PubMed Central

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

2016-01-01

Newly generated neurons pass through a series of well-defined developmental stages, which allow them to integrate into existing neuronal circuits. After exit from the cell cycle, postmitotic neurons undergo neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis and synaptic maturation and plasticity. Lack of a global metabolic analysis during early cortical neuronal development led us to explore the role of cellular metabolism and mitochondrial biology during ex vivo differentiation of primary cortical neurons. Unexpectedly, we observed a huge increase in mitochondrial biogenesis. Changes in mitochondrial mass, morphology and function were correlated with the upregulation of the master regulators of mitochondrial biogenesis, TFAM and PGC-1α. Concomitant with mitochondrial biogenesis, we observed an increase in glucose metabolism during neuronal differentiation, which was linked to an increase in glucose uptake and enhanced GLUT3 mRNA expression and platelet isoform of phosphofructokinase 1 (PFKp) protein expression. In addition, glutamate–glutamine metabolism was also increased during the differentiation of cortical neurons. We identified PI3K–Akt–mTOR signalling as a critical regulator role of energy metabolism in neurons. Selective pharmacological inhibition of these metabolic pathways indicate existence of metabolic checkpoint that need to be satisfied in order to allow neuronal differentiation. PMID:27058317

Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship.

PubMed

Netea-Maier, Romana T; Smit, Johannes W A; Netea, Mihai G

2018-01-28

In order to adapt to the reduced availability of nutrients and oxygen in the tumor microenvironment and the increased requirements of energy and building blocks necessary for maintaining their high proliferation rate, malignant cells undergo metabolic changes that result in an increased production of lactate, nitric oxide, reactive oxygen species, prostaglandins and other byproducts of arachidonic acid metabolism that influence both the composition of the inflammatory microenvironment and the function of the tumor-associated macrophages (TAMs). In response to cues present in the TME, among which products of altered tumor cell metabolism, TAMs are also required to reprogram their metabolism, with activation of glycolysis, fatty acid synthesis and altered nitrogen cycle metabolism. These changes result in functional reprogramming of TAMs which includes changes in the production of cytokines and angiogenetic factors, and contribute to the tumor progression and metastasis. Understanding the metabolic changes governing the intricate relationship between the tumor cells and the TAMs represents an essential step towards developing novel therapeutic approaches targeting the metabolic reprogramming of the immune cells to potentiate their tumoricidal potential and to circumvent therapy resistance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Comparative study of the affinity and metabolism of type I and type II binding quinoline carboxamide analogs by cytochrome P450 3A4

PubMed Central

Dahal, Upendra P.; Joswig-Jones, Carolyn; Jones, Jeffrey P.

2011-01-01

Compounds that coordinate to the heme-iron of cytochrome P450 (CYP) enzymes are assumed to increase metabolic stability. However, recently we observed that the type II binding quinoline carboxamide (QCA) compounds were metabolically less stable. To test if the higher intrinsic clearance of type II binding compounds relative to type I binding compounds is general for other metabolic transformations, we synthesized a library of QCA compounds that could undergo N-dealkylation, O-dealkylation, benzylic hydroxylation and aromatic hydroxylation. The results demonstrated that type II binding QCA analogs were metabolically less stable (2 to 12 fold) at sub-saturating concentration compared to type I binding counterparts for all the transformations. When the rates of different metabolic transformations between type I and type II binding compounds were compared, they were found to be in the order of N-demethylation>benzylic hydroxylation> O-demethylation> aromatic hydroxylation. Finally, for the QCA analogs with aza-heteroaromatic rings, we did not detect metabolism in aza-aromatic rings (pyridine, pyrazine, pyrimidine) indicating electronegativity of the nitrogen can change regioselectivity in CYP metabolism. PMID:22087535

Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study.

PubMed

Rakic Ignjatovic, Anita; Miljkovic, Branislava; Todorovic, Dejan; Timotijevic, Ivana; Pokrajac, Milena

2009-02-01

Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders. VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good. VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.

Tyrosol and its metabolites as antioxidative and anti-inflammatory molecules in human endothelial cells.

PubMed

Muriana, Francisco J G; Montserrat-de la Paz, Sergio; Lucas, Ricardo; Bermudez, Beatriz; Jaramillo, Sara; Morales, Juan C; Abia, Rocio; Lopez, Sergio

2017-08-01

Tyrosol (Tyr) is a phenolic compound found in virgin olive oil. After ingestion, Tyr undergoes extensive first pass intestinal/hepatic metabolism. However, knowledge about the biological effects of Tyr metabolites is scarce. We chemically synthesized Tyr glucuronate (Tyr-GLU) and sulphate (Tyr-SUL) metabolites and explored their properties against oxidative stress and inflammation in TNF-α-treated human umbilical vein endothelial cells (hECs). Tyr and Tyr-SUL prevented the rise of reactive oxygen species, the depletion of glutathione, and the down-regulation of glutathione peroxidase 1, glutamate-cysteine ligase catalytic subunit, and heme oxygenase-1 genes. Tyr-SUL and to a lower extent Tyr and Tyr-GLU prevented the phosphorylation of NF-κB signaling proteins. Tyr-GLU and Tyr-SUL also prevented the over-expression of adhesion molecules at gene, protein, and secretory levels, and the adhesion (Tyr-SUL > Tyr-GLU) of human monocytes to hECs. In vivo, Tyr, and most notably Tyr-SUL in a dose-dependent manner, ameliorated plantar and ear edemas in mice models of acute and chronic inflammation. This study demonstrates the antioxidant and/or anti-inflammatory properties of Tyr metabolites, with Tyr-SUL being the most effective.

Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol

PubMed Central

Morselli, Eugenia; Galluzzi, Lorenzo; Kepp, Oliver; Criollo, Alfredo; Maiuri, Maria Chiara; Tavernarakis, Nektarios; Madeo, Frank; Kroemer, Guido

2009-01-01

Although autophagy has widely been conceived as a self-destructive mechanism that causes cell death, accumulating evidence suggests that autophagy usually mediates cytoprotection, thereby avoiding the apoptotic or necrotic demise of stressed cells. Recent evidence produced by our groups demonstrates that autophagy is also involved in pharmacological manipulations that increase longevity. Exogenous supply of the polyamine spermidine can prolong the lifespan of (while inducing autophagy in) yeast, nematodes and flies. Similarly, resveratrol can trigger autophagy in cells from different organisms, extend lifespan in nematodes, and ameliorate the fitness of human cells undergoing metabolic stress. These beneficial effects are lost when essential autophagy modulators are genetically or pharmacologically inactivated, indicating that autophagy is required for the cytoprotective and/or anti-aging effects of spermidine and resveratrol. Genetic and functional studies indicate that spermidine inhibits histone acetylases, while resveratrol activates the histone deacetylase Sirtuin 1 to confer cytoprotection/longevity. Although it remains elusive whether the same histones (or perhaps other nuclear or cytoplasmic proteins) act as the downstream targets of spermidine and resveratrol, these results point to an essential role of protein hypoacetylation in autophagy control and in the regulation of longevity. PMID:20157579

MAP/microtubule affinity-regulating kinases, microtubule dynamics, and spermatogenesis.

PubMed

Tang, Elizabeth I; Mruk, Dolores D; Cheng, C Yan

2013-05-01

During spermatogenesis, spermatids derived from meiosis simultaneously undergo extensive morphological transformation, to become highly specialized and metabolically quiescent cells, and transport across the seminiferous epithelium. Spermatids are also transported back-and-forth across the seminiferous epithelium during the epithelial cycle until they line up at the luminal edge of the tubule to prepare for spermiation at stage VIII of the cycle. Spermatid transport thus requires the intricate coordination of the cytoskeletons in Sertoli cells (SCs) as spermatids are nonmotile cells lacking the ultrastructures of lamellipodia and filopodia, as well as the organized components of the cytoskeletons. In the course of preparing this brief review, we were surprised to see that, except for some earlier eminent morphological studies, little is known about the regulation of the microtubule (MT) cytoskeleton and the coordination of MT with the actin-based cytoskeleton to regulate spermatid transport during the epithelia cycle, illustrating that this is a largely neglected area of research in the field. Herein, we summarize recent findings in the field regarding the significance of actin- and tubulin-based cytoskeletons in SCs that support spermatid transport; we also highlight specific areas of research that deserve attention in future studies.

Residue depletion of ivermectin in broiler poultry.

PubMed

Mestorino, Nora; Buldain, Daniel; Buchamer, Andrea; Gortari, Lihuel; Daniele, Martín; Marchetti, María Laura

2017-04-01

Helminth infections are widespread in the poultry industry. There is evidence of extra-label use of some drugs, such as ivermectin (IVM), in broiler poultry. Pharmacokinetic and residual studies of IVM in poultry, however, are rather scarce. Our aim was to determine time restrictions for broiler chickens fed with balanced feed mixed with IVM for 21 days, and thus achieve acceptable residual levels for consumption as established by the European Union. Sixty 1-day-old chicks were fed with food supplemented with IVM at 5 mg kg -1 feed for 21 days. Groups of six treated animals were sacrificed at 0, 1, 2, 4, 8, 10, 15, 20 and 28 days after treatment. Liver, skin/fat, kidney and muscle samples were obtained. IVM were determined by liquid chromatography with fluorescence detection after automatic solid-phase extraction with SPE C 18 cartridges. The highest concentrations were measured in the liver, which is logical given that IVM is a drug that undergoes extensive hepatic metabolism. The optimal withdrawal time for edible tissues of these animals to stay within the permitted residual levels were: 12 days for liver, 8 days for skin/fat, 0 days for muscle and 10 days for kidney.

Modeling Synergistic Drug Inhibition of Mycobacterium tuberculosis Growth in Murine Macrophages

DTIC Science & Technology

2011-01-01

important application of metabolic network modeling is the ability to quantitatively model metabolic enzyme inhibition and predict bacterial growth...describe the extensions of this framework to model drug- induced growth inhibition of M. tuberculosis in macrophages.39 Mathematical framework Fig. 1 shows...starting point, we used the previously developed iNJ661v model to represent the metabolic Fig. 1 Mathematical framework: a set of coupled models used to

Do lightning positive leaders really "step"?

NASA Astrophysics Data System (ADS)

Petersen, D.

2015-12-01

It has been known for some time that positive leaders exhibit impulsive charge motion and optical emissions as they extend. However, laboratory and field observations have not produced any evidence of a process analogous to the space leader mechanism of negative leader extension. Instead, observations have suggested that the positive leader tip undergoes a continuous to intermittent series of corona streamer bursts, each burst resulting in a small forward extension of the positive leader channel. Traditionally, it has been held that lightning positive leaders extend in a continuous or quasi-continuous fashion. Lately, however, many have become concerned that this position is incongruous with observations of impulsive activity during lightning positive leader extension. It is increasingly suggested that this impulsive activity is evidence that positive leaders also undergo "stepping". There are two issues that must be addressed. The first issue concerns whether or not the physical processes underlying impulsive extension in negative and positive leaders are distinct. We argue that these processes are in fact physically distinct, and offer new high-speed video evidence to support this position. The second issue regards the proper use of the term "step" as an identifier for the impulsive forward extension of a leader. Traditional use of this term has been applied only to negative leaders, due primarily to their stronger impulsive charge motions and photographic evidence of clearly discontinuous forward progression of the luminous channel. Recently, due to the increasing understanding of the distinct "space leader" process of negative leader extension, the term "step" has increasingly come to be associated with the space leader process itself. Should this emerging association, "step" = space leader attachment, be canonized? If not, then it seems reasonable to use the term "step" to describe impulsive positive leader extension. If, however, we do wish to associate the term "step" with space leader attachment, a process unique to negative leaders, should we devise a term for those process(es) that underly impulsive positive leader extension?

Best practice for perioperative management of patients with cytoreductive surgery and HIPEC.

PubMed

Raspé, C; Flöther, L; Schneider, R; Bucher, M; Piso, P

2017-06-01

Due to the significantly improved outcome and quality of life of patients with different tumor entities after cytoreductive surgery (CRS) and HIPEC, there is an increasing number of centers performing CRS and HIPEC procedures. As this procedure is technically challenging with potential high morbidity and mortality, respectively, institutional experience also in the anesthetic and intensive care departments is essential for optimal treatment and prevention of adverse events. Clinical pathways have to be developed to achieve also good results in more comorbid patients with border line indications and extensive surgical procedures. The anesthesiologist has deal with relevant fluid, blood and protein losses, increased intraabdominal pressure, systemic hypo-/hyperthermia, and increased metabolic rate in patients undergoing cytoreductive surgery with HIPEC. It is of utmost importance to maintain or restore an adequate volume by aggressive substitution of intravenous fluids, which counteracts the increased fluid loss and venous capacitance during this procedure. Supplementary thoracic epidural analgesia, non-invasive ventilation, and physiotherapy are recommended to guarantee adequate pain therapy and postoperative extubation as well as fast-track concepts. Advanced hemodynamic monitoring is essential to help the anesthesiologist picking up information about the real-time fluid status of the patient. Preoperative preconditioning is mandatory in patients scheduled for HIPEC surgery and will result in improved outcome. Postoperatively, volume status optimization, early nutritional support, sufficient anticoagulation, and point of care coagulation management are essential. This is an extensive update on all relevant topics for anesthetists and intensivists dealing with CRS and HIPEC. Copyright © 2016. Published by Elsevier Ltd.

Plant respirometer enables high resolution of oxygen consumption rates

NASA Technical Reports Server (NTRS)

Foster, D. L.

1966-01-01

Plant respirometer permits high resolution of relatively small changes in the rate of oxygen consumed by plant organisms undergoing oxidative metabolism in a nonphotosynthetic state. The two stage supply and monitoring system operates by a differential pressure transducer and provides a calibrated output by digital or analog signals.

Grapevines undergo varying shifts in secondary metabolic profiles when infected with Xylella fastidiosa

USDA-ARS?s Scientific Manuscript database

Pierce’s disease (PD) is a devastating disease of grapevine caused by the bacterial pathogen Xylella fastidiosa (Xf). Key to the development and optimization of PD-tolerant grape cultivars is improved understanding about how grapevines defend themselves against Xf. This study complements histologica...

Microbial minimalism: genome reduction in bacterial pathogens.

PubMed

Moran, Nancy A

2002-03-08

When bacterial lineages make the transition from free-living or facultatively parasitic life cycles to permanent associations with hosts, they undergo a major loss of genes and DNA. Complete genome sequences are providing an understanding of how extreme genome reduction affects evolutionary directions and metabolic capabilities of obligate pathogens and symbionts.

Curcumin and piperine supplementation of obese mice under caloric restriction modulates body fat and interleukin-1beta

USDA-ARS?s Scientific Manuscript database

Background: Dietary bioactive compounds capable of improving metabolic profiles would be of great value, especially for overweight individuals undergoing a caloric restriction (CR) regimen. Curcumin (Cur), a possible anti-obesity compound, and piperine (Pip), a plausible enhancer of Cur's bioavailab...

Incorporation of flavonoid derivatives or pentagalloyl glucose into lignin enhances cell wall saccharification following mild alkaline or acidic pretreatments

USDA-ARS?s Scientific Manuscript database

Partial substitution of normal monolignols with phenolic precursors from other metabolic pathways may improve the susceptibility of lignified biomass to chemical pretreatment and enzymatic saccharification for biofuel production. Flavonoids and gallate esters readily undergo oxidative coupling react...

Obesity modulates inflammation and lipid metabolism oocyte gene expression: A single cell transcriptome perspective

USDA-ARS?s Scientific Manuscript database

This study aimed to compare oocyte gene expression profiles and follicular fluid (FF) content from overweight/obese (OW) women and normal weight (NW) women who were undergoing fertility treatments. Using single cell transcriptomic analyses, we investigated oocyte gene expression using RNA-seq. Serum...

Microbial metabolic activity in soil as measured by dehydrogenase determinations

NASA Technical Reports Server (NTRS)

Casida, L. E., Jr.

1977-01-01

The dehydrogenase technique for measuring the metabolic activity of microorganisms in soil was modified to use a 6-h, 37 C incubation with either glucose or yeast extract as the electron-donating substrate. The rate of formazan production remained constant during this time interval, and cellular multiplication apparently did not occur. The technique was used to follow changes in the overall metabolic activities of microorganisms in soil undergoing incubation with a limiting concentration of added nutrient. The sequence of events was similar to that obtained by using the Warburg respirometer to measure O2 consumption. However, the major peaks of activity occurred earlier with the respirometer. This possibly is due to the lack of atmospheric CO2 during the O2 consumption measurements.

Comparison of multiple gene assembly methods for metabolic engineering

Treesearch

Chenfeng Lu; Karen Mansoorabadi; Thomas Jeffries

2007-01-01

A universal, rapid DNA assembly method for efficient multigene plasmid construction is important for biological research and for optimizing gene expression in industrial microbes. Three different approaches to achieve this goal were evaluated. These included creating long complementary extensions using a uracil-DNA glycosylase technique, overlap extension polymerase...

Rethinking Guard Cell Metabolism1[OPEN

PubMed Central

2016-01-01

Stomata control gaseous fluxes between the internal leaf air spaces and the external atmosphere and, therefore, play a pivotal role in regulating CO2 uptake for photosynthesis as well as water loss through transpiration. Guard cells, which flank the stomata, undergo adjustments in volume, resulting in changes in pore aperture. Stomatal opening is mediated by the complex regulation of ion transport and solute biosynthesis. Ion transport is exceptionally well understood, whereas our knowledge of guard cell metabolism remains limited, despite several decades of research. In this review, we evaluate the current literature on metabolism in guard cells, particularly the roles of starch, sucrose, and malate. We explore the possible origins of sucrose, including guard cell photosynthesis, and discuss new evidence that points to multiple processes and plasticity in guard cell metabolism that enable these cells to function effectively to maintain optimal stomatal aperture. We also discuss the new tools, techniques, and approaches available for further exploring and potentially manipulating guard cell metabolism to improve plant water use and productivity. PMID:27609861

Muscle-specific Deletion of Carnitine Acetyltransferase Compromises Glucose Tolerance and Metabolic Flexibility

PubMed Central

Muoio, Deborah M.; Noland, Robert C.; Kovalik, Jean-Paul; Seiler, Sarah E.; Davies, Michael N.; DeBalsi, Karen L.; Ilkayeva, Olga R.; Stevens, Robert D.; Kheterpal, Indu; Zhang, Jingying; Covington, Jeffrey D.; Bajpeyi, Sudip; Ravussin, Eric; Kraus, William; Koves, Timothy R.; Mynatt, Randall L.

2012-01-01

Summary The concept of “metabolic inflexibility” was first introduced to describe the failure of insulin resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility. PMID:22560225

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

PubMed

Muoio, Deborah M; Noland, Robert C; Kovalik, Jean-Paul; Seiler, Sarah E; Davies, Michael N; DeBalsi, Karen L; Ilkayeva, Olga R; Stevens, Robert D; Kheterpal, Indu; Zhang, Jingying; Covington, Jeffrey D; Bajpeyi, Sudip; Ravussin, Eric; Kraus, William; Koves, Timothy R; Mynatt, Randall L

2012-05-02

The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility. Copyright © 2012 Elsevier Inc. All rights reserved.

PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

PubMed Central

Patsoukis, Nikolaos; Bardhan, Kankana; Chatterjee, Pranam; Sari, Duygu; Liu, Bianling; Bell, Lauren N.; Karoly, Edward D.; Freeman, Gordon J.; Petkova, Victoria; Seth, Pankaj; Li, Lequn; Boussiotis, Vassiliki A.

2015-01-01

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade. PMID:25809635

The choice of dialysate bicarbonate: do different concentrations make a difference?

PubMed

Basile, Carlo; Rossi, Luigi; Lomonte, Carlo

2016-05-01

Metabolic acidosis is a common complication of chronic kidney disease; it is typically caused by the accumulation of sulfate, phosphorus, and organic anions. Metabolic acidosis is correlated with several adverse outcomes, such as morbidity, hospitalization, and mortality. Thus, correction of metabolic acidosis is fundamental for the adequate management of many systemic complications of chronic kidney disease. In patients undergoing hemodialysis, acid-base homeostasis depends on many factors including the following: net acid production, amount of alkali given by the dialysate bath, duration of the interdialytic period, and residual diuresis, if any. Recent literature data suggest that the development of metabolic alkalosis after dialysis may contribute to adverse clinical outcomes. Our review is focused on the potential effects of different dialysate bicarbonate concentrations on hard outcomes such as mortality. Unfortunately, no randomized studies exist about this issue. Acid-base equilibrium is a complex and vital system whose regulation is impaired in chronic kidney disease. We await further studies to assess the extent to which acid-base status is a major determinant of overall survival in patients undergoing hemodialysis. For the present, the clinician should understand that target values for predialysis serum bicarbonate concentration have been established primarily based on observational studies and expert opinion. Based on this, we should keep the predialysis serum bicarbonate level at least at 22 mmol/l. Furthermore, a specific focus should be addressed by the attending nephrologist to the clinical and nutritional status of the major outliers on both the acid and alkaline sides of the curve. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Abdominal obesity and the metabolic syndrome: a surgeon's perspective.

PubMed

Mathieu, Patrick

2008-09-01

Over the past decade, a major shift in the clinical risk factors in the population undergoing a cardiac surgery has been observed. In the general population, an increasing prevalence of obesity has largely contributed to the development of cardiovascular disorders. Obesity is a heterogeneous condition in which body fat distribution largely determines metabolic perturbations. Consequently, individuals characterized by increased abdominal fat deposition and the so-called metabolic syndrome (MetS) have a higher risk of developing coronary artery disease. Recent studies have also emphasized that visceral obesity is a strong risk factor for the development of heart valve diseases. In fact, individuals characterized by visceral obesity and its metabolic consequences, such as the small dense low-density lipoprotein phenotype, have a faster progression rate of aortic stenosis, which is related to increased valvular inflammation. Furthermore, the degenerative process of implanted bioprostheses is increased in subjects with the MetS and/or diabetes, suggesting that a process akin to atherosclerosis could be involved in the failure of bioprostheses. In addition to being an important risk factor for the development of cardiovascular disorders, the MetS is increasing the operative mortality risk following coronary artery bypass graft surgery. Thus, recent evidence supports visceral obesity as a global risk factor that is affecting the development of many heart disorders, and that is also impacting negatively on the results of patients undergoing surgical treatment for cardiovascular diseases. In the present paper, recent concepts surrounding the MetS and its implications in various cardiovascular disorders are reviewed along with the clinical implications.

The life history of a botulinum toxin molecule.

PubMed

Simpson, Lance

2013-06-01

There is an emerging literature describing the absorption, distribution, metabolism and elimination of botulinum toxin. This work reveals that the toxin can be absorbed by both the oral and inhalation routes. The primary mechanism for absorption is binding and transport across epithelial cells. Toxin that enters the body undergoes a distribution phase, which is quite short, and an elimination phase, which is comparatively long. During the distribution phase, botulinum toxin migrates to the peri-neuronal microcompartment in the vicinity of vulnerable cells, such as cholinergic nerve endings. Only these cells have the ability to selectively accumulate the molecule. When the toxin moves from the cell membrane to the cell interior, it undergoes programmed death. This is coincident with release of the catalytically active light chain that paralyzes transmission. Intraneuronal metabolism of light chain is via the ubiquitination-proteasome pathway. Systemic metabolism and elimination is assumed to be via the liver. The analysis of absorption, distribution, metabolism and elimination of the toxin helps to create a life history of the molecule in the body. This has many benefits, including: a) clarifying the mechanisms that underlie the disease botulism, b) providing insights for development of medical countermeasures against the toxin, and c) helping to explain the meaning of a lethal dose of toxin. It is likely that work intended to enhance understanding of the fate of botulinum toxin in the body will intensify. These efforts will include new and powerful analytic tools, such as single molecule-single cell analyses in vitro and real time, 3-dimensional pharmacokinetic studies in vivo. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dynamic regulation of hepatic lipid droplet properties by diet.

PubMed

Crunk, Amanda E; Monks, Jenifer; Murakami, Aya; Jackman, Matthew; Maclean, Paul S; Ladinsky, Mark; Bales, Elise S; Cain, Shannon; Orlicky, David J; McManaman, James L

2013-01-01

Cytoplasmic lipid droplets (CLD) are organelle-like structures that function in neutral lipid storage, transport and metabolism through the actions of specific surface-associated proteins. Although diet and metabolism influence hepatic CLD levels, how they affect CLD protein composition is largely unknown. We used non-biased, shotgun, proteomics in combination with metabolic analysis, quantitative immunoblotting, electron microscopy and confocal imaging to define the effects of low- and high-fat diets on CLD properties in fasted-refed mice. We found that the hepatic CLD proteome is distinct from that of CLD from other mammalian tissues, containing enzymes from multiple metabolic pathways. The hepatic CLD proteome is also differentially affected by dietary fat content and hepatic metabolic status. High fat feeding markedly increased the CLD surface density of perilipin-2, a critical regulator of hepatic neutral lipid storage, whereas it reduced CLD levels of betaine-homocysteine S-methyltransferase, an enzyme regulator of homocysteine levels linked to fatty liver disease and hepatocellular carcinoma. Collectively our data demonstrate that the hepatic CLD proteome is enriched in metabolic enzymes, and that it is qualitatively and quantitatively regulated by diet and metabolism. These findings implicate CLD in the regulation of hepatic metabolic processes, and suggest that their properties undergo reorganization in response to hepatic metabolic demands.

Dynamic Regulation of Hepatic Lipid Droplet Properties by Diet

PubMed Central

Crunk, Amanda E.; Monks, Jenifer; Murakami, Aya; Jackman, Matthew; MacLean, Paul S.; Ladinsky, Mark; Bales, Elise S.; Cain, Shannon; Orlicky, David J.; McManaman, James L.

2013-01-01

Cytoplasmic lipid droplets (CLD) are organelle-like structures that function in neutral lipid storage, transport and metabolism through the actions of specific surface-associated proteins. Although diet and metabolism influence hepatic CLD levels, how they affect CLD protein composition is largely unknown. We used non-biased, shotgun, proteomics in combination with metabolic analysis, quantitative immunoblotting, electron microscopy and confocal imaging to define the effects of low- and high-fat diets on CLD properties in fasted-refed mice. We found that the hepatic CLD proteome is distinct from that of CLD from other mammalian tissues, containing enzymes from multiple metabolic pathways. The hepatic CLD proteome is also differentially affected by dietary fat content and hepatic metabolic status. High fat feeding markedly increased the CLD surface density of perilipin-2, a critical regulator of hepatic neutral lipid storage, whereas it reduced CLD levels of betaine-homocysteine S-methyltransferase, an enzyme regulator of homocysteine levels linked to fatty liver disease and hepatocellular carcinoma. Collectively our data demonstrate that the hepatic CLD proteome is enriched in metabolic enzymes, and that it is qualitatively and quantitatively regulated by diet and metabolism. These findings implicate CLD in the regulation of hepatic metabolic processes, and suggest that their properties undergo reorganization in response to hepatic metabolic demands. PMID:23874434

Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal

PubMed Central

Ito, Kyoko; Ito, Keisuke

2016-01-01

Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical. PMID:27482603

Metabolism and the Control of Cell Fate Decisions and Stem Cell Renewal.

PubMed

Ito, Kyoko; Ito, Keisuke

2016-10-06

Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical.

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

PubMed Central

Corbet, Cyril

2018-01-01

Normal and cancer stem cells (CSCs) share the remarkable potential to self-renew and differentiate into many distinct cell types. Although most of the stem cells remain under quiescence to maintain their undifferentiated state, they can also undergo cell divisions as required to regulate tissue homeostasis. There is now a growing evidence that cell fate determination from stem cells implies a fine-tuned regulation of their energy balance and metabolic status. Stem cells can shift their metabolic substrate utilization, between glycolysis and mitochondrial oxidative metabolism, during specification and/or differentiation, as well as in order to adapt their microenvironmental niche. Pyruvate appears as a key metabolite since it is at the crossroads of cytoplasmic glycolysis and mitochondrial oxidative phosphorylation. This Review describes how metabolic reprogramming, focusing on pyruvate utilization, drives the fate of normal and CSCs by modulating their capacity for self-renewal, clonal expansion/differentiation, as well as metastatic potential and treatment resistance in cancer. This Review also explores potential therapeutic strategies to restore or manipulate stem cell function through the use of small molecules targeting the pyruvate metabolism. PMID:29403375

Effects of Chronic Environmental Cold on Growth, Health and Select Metabolic and Immunologic Responses of Preruminant Calves

USDA-ARS?s Scientific Manuscript database

The physiological response of the preruminant calf to sustained exposure to cold has not been studied extensively. Effects of cold on growth performance and health of preruminant calves as well as functional measures of energy metabolism, fat-soluble vitamin, and immune responsiveness were evaluate...

CYP2A6 genotype and smoking behavior in current smokers screened for lung cancer.

PubMed

Styn, Mindi A; Nukui, Tomoko; Romkes, Marjorie; Perkins, Kenneth A; Land, Stephanie R; Weissfeld, Joel L

2013-05-01

Functional CYP2A6 genetic variation partially determines nicotine metabolism. In 2005, we examined functional CYP2A6 variants associated with reduced metabolism (CYP2A6*2, CYP2A6*9, CYP2A6*4), smoking history, and change in smoking in 878 adult smokers undergoing lung cancer screening in an urban setting. At one year, 216 quit smoking for more than 30 days while 662 continued smoking. Compared to subjects who smoked 30 cigarettes per day at baseline, the odds of a reduced metabolism genotype was 52% higher in subjects smoking 20-29 cigarettes per day and 86% higher in subjects smoking less than 20 cigarettes per day (p-trend = 0.016). Reduced metabolism genotypes appeared unrelated to quitting. Though related to smoking dose, CYP2A6 may not influence cessation.

Bioenergetics of Mammalian Sperm Capacitation

PubMed Central

Ferramosca, Alessandra; Zara, Vincenzo

2014-01-01

After ejaculation, the mammalian male gamete must undergo the capacitation process, which is a prerequisite for egg fertilization. The bioenergetics of sperm capacitation is poorly understood despite its fundamental role in sustaining the biochemical and molecular events occurring during gamete activation. Glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) are the two major metabolic pathways producing ATP which is the primary source of energy for spermatozoa. Since recent data suggest that spermatozoa have the ability to use different metabolic substrates, the main aim of this work is to present a broad overview of the current knowledge on the energy-producing metabolic pathways operating inside sperm mitochondria during capacitation in different mammalian species. Metabolism of glucose and of other energetic substrates, such as pyruvate, lactate, and citrate, is critically analyzed. Such knowledge, besides its obvious importance for basic science, could eventually translate into the development of novel strategies for treatment of male infertility, artificial reproduction, and sperm selection methods. PMID:24791005

Bioenergetics of mammalian sperm capacitation.

PubMed

Ferramosca, Alessandra; Zara, Vincenzo

2014-01-01

After ejaculation, the mammalian male gamete must undergo the capacitation process, which is a prerequisite for egg fertilization. The bioenergetics of sperm capacitation is poorly understood despite its fundamental role in sustaining the biochemical and molecular events occurring during gamete activation. Glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) are the two major metabolic pathways producing ATP which is the primary source of energy for spermatozoa. Since recent data suggest that spermatozoa have the ability to use different metabolic substrates, the main aim of this work is to present a broad overview of the current knowledge on the energy-producing metabolic pathways operating inside sperm mitochondria during capacitation in different mammalian species. Metabolism of glucose and of other energetic substrates, such as pyruvate, lactate, and citrate, is critically analyzed. Such knowledge, besides its obvious importance for basic science, could eventually translate into the development of novel strategies for treatment of male infertility, artificial reproduction, and sperm selection methods.

KSC-98pc1164

NASA Image and Video Library

1998-09-28

The orbiter Atlantis is towed away from the Shuttle Landing Facility after returning home from California atop its Shuttle Carrier Aircraft. The orbiter spent 10 months in Palmdale undergoing extensive inspections and modifications in the orbiter processing facility there. The modifications included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

Dextromethorphan and debrisoquine metabolism and polymorphism of the gene for cytochrome P450 isozyme 2D50 in Thoroughbreds.

PubMed

Corado, Carley R; McKemie, Daniel S; Knych, Heather K

2016-09-01

OBJECTIVE To characterize polymorphisms of the gene for cytochrome P450 isozyme 2D50 (CYP2D50) and the disposition of 2 CYP2D50 probe drugs, dextromethorphan and debrisoquine, in horses. ANIMALS 23 healthy horses (22 Thoroughbreds and 1 Standardbred). PROCEDURES Single-nucleotide polymorphisms (SNPs) in CYP2D50 were identified. Disposition of dextromethorphan (2 mg/kg) and debrisoquine (0.2 mg/kg) were determined after oral (dextromethorphan) or nasogastric (debrisoquine) administration to the horses. Metabolic ratios of plasma dextromethorphan and total dextrorphan (dextrorphan plus dextrorphan-O-β-glucuronide) and 4-hydroxydebrisoquine concentrations were calculated on the basis of the area under the plasma concentration-versus-time curve extrapolated to infinity for the parent drug divided by that for the corresponding metabolite. Pharmacokinetic data were used to categorize horses into the phenotypic drug-metabolism categories poor, extensive, and ultrarapid. Disposition patterns were compared among categories, and relationships between SNPs and metabolism categories were explored. RESULTS Gene sequencing identified 51 SNPs, including 27 nonsynonymous SNPs. Debrisoquine was minimally detected after oral administration. Disposition of dextromethorphan varied markedly among horses. Metabolic ratios for dextromethorphan ranged from 0.03 to 0.46 (mean, 0.12). On the basis of these data, 1 horse was characterized as a poor metabolizer, 18 were characterized as extensive metabolizers, and 3 were characterized as ultrarapid metabolizers. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that CYP2D50 is polymorphic and that the disposition of the probe drug varies markedly in horses. The polymorphisms may be related to rates of drug metabolism. Additional research involving more horses of various breeds is needed to fully explore the functional implication of polymorphisms in CYP2D50.

A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth: The WarburQ effect

PubMed Central

Damiani, Chiara; Colombo, Riccardo; Gaglio, Daniela; Mastroianni, Fabrizia; Westerhoff, Hans Victor; Vanoni, Marco; Alberghina, Lilia

2017-01-01

Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth. PMID:28957320

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

PubMed Central

Feltes, Bruno César; de Faria Poloni, Joice; Nunes, Itamar José Guimarães

2014-01-01

Abstract Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment. PMID:24816220

Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis.

PubMed

Feltes, Bruno César; de Faria Poloni, Joice; Nunes, Itamar José Guimarães; Bonatto, Diego

2014-06-01

Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

A New Perspective on the Heterogeneity of Cancer Glycolysis

PubMed Central

Neugent, Michael L.; Goodwin, Justin; Sankaranarayanan, Ishwarya; Yetkin, Celal Emre; Hsieh, Meng-Hsiung; Kim, Jung-whan

2018-01-01

Tumors are dynamic metabolic systems which highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenecity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells. PMID:29212302

Identification of genetic elements in metabolism by high-throughput mouse phenotyping.

PubMed

Rozman, Jan; Rathkolb, Birgit; Oestereicher, Manuela A; Schütt, Christine; Ravindranath, Aakash Chavan; Leuchtenberger, Stefanie; Sharma, Sapna; Kistler, Martin; Willershäuser, Monja; Brommage, Robert; Meehan, Terrence F; Mason, Jeremy; Haselimashhadi, Hamed; Hough, Tertius; Mallon, Ann-Marie; Wells, Sara; Santos, Luis; Lelliott, Christopher J; White, Jacqueline K; Sorg, Tania; Champy, Marie-France; Bower, Lynette R; Reynolds, Corey L; Flenniken, Ann M; Murray, Stephen A; Nutter, Lauryl M J; Svenson, Karen L; West, David; Tocchini-Valentini, Glauco P; Beaudet, Arthur L; Bosch, Fatima; Braun, Robert B; Dobbie, Michael S; Gao, Xiang; Herault, Yann; Moshiri, Ala; Moore, Bret A; Kent Lloyd, K C; McKerlie, Colin; Masuya, Hiroshi; Tanaka, Nobuhiko; Flicek, Paul; Parkinson, Helen E; Sedlacek, Radislav; Seong, Je Kyung; Wang, Chi-Kuang Leo; Moore, Mark; Brown, Steve D; Tschöp, Matthias H; Wurst, Wolfgang; Klingenspor, Martin; Wolf, Eckhard; Beckers, Johannes; Machicao, Fausto; Peter, Andreas; Staiger, Harald; Häring, Hans-Ulrich; Grallert, Harald; Campillos, Monica; Maier, Holger; Fuchs, Helmut; Gailus-Durner, Valerie; Werner, Thomas; Hrabe de Angelis, Martin

2018-01-18

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome.

Transurethral ultrasound-guided laser-induced prostatectomy

NASA Astrophysics Data System (ADS)

Babayan, Richard K.; Roth, Robert A.

1991-07-01

A transurethral ultrasound-guided Nd:YAG laser delivery system has been developed for use as an alternative approach to the treatment of benign prostatic hyperplasia. The TULIP system has been extensively tested in canine models and is currently undergoing FDA trials in humans.

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux.

PubMed

Ferreira, Caroline M; Oliveira, Matheus P; Paes, Marcia C; Oliveira, Marcus F

2018-06-01

Hematophagous organisms undergo remarkable metabolic changes during the blood digestion process, increasing fermentative glucose metabolism, and reducing respiratory rates, both consequence of functional mitochondrial remodeling. Here, we review the pathways involved in energy metabolism and mitochondrial functionality in a comparative framework across different hematophagous species, and consider how these processes regulate redox homeostasis during blood digestion. The trend across distinct species indicate that a switch in energy metabolism might represent an important defensive mechanism to avoid the potential harmful interaction of oxidants generated from aerobic energy metabolism with products derived from blood digestion. Indeed, in insect vectors, blood feeding transiently reduces respiratory rates and oxidant production, irrespective of tissue and insect model. On the other hand, a different scenario is observed in several unrelated parasite species when exposed to blood digestion products, as respiratory rates reduce and mitochondrial oxidant production increase. The emerging picture indicates that re-wiring of energy metabolism, through reduced mitochondrial function, culminates in improved tolerance to redox insults and seems to represent a key step for hematophagous organisms to cope with the overwhelming and potentially toxic blood meal. © 2018 International Federation for Cell Biology.

Effects of preoperative oral carbohydrate supplementation on postoperative metabolic stress response of patients undergoing elective abdominal surgery.

PubMed

Viganò, Jacopo; Cereda, Emanuele; Caccialanza, Riccardo; Carini, Roberta; Cameletti, Barbara; Spampinato, Marcello; Dionigi, Paolo

2012-08-01

The goal of the present study was to evaluate the effects of preoperative oral carbohydrate supplementation (OCH) on the postoperative metabolic stress response of patients undergoing elective abdominal surgery. The study was designed as a controlled, prospective, cohort study including 38 patients treated with OCH (800 mL the day before surgery and 400 mL within 3 h before the induction of anesthesia) and 38 controls matched for surgical procedure. Fasting glucose, insulin, insulin resistance (HOMA-IR index), cortisol, and interleukin 6 (IL-6) were assessed before and after surgery (postoperative day (POD) 1, 2, and 3). The administration of OCH resulted in lower fasting glucose, HOMA-IR index, cortisol, and IL-6 on both POD 1 and POD 2. At multivariable regression analyses, the reduction of these parameters was independent of sex, age, body mass index, and major abdominal surgery. Particularly, models including OCH treatment explained 70, 63, and 66 % of the variance of the increase in IL-6 levels at POD 1, POD 2, and POD 3, respectively. The effect of OCH on changes in glucose, insulin resistance, and cortisol on POD 1 and POD 2 disappeared after the inclusion of IL-6 in the models. Treatment with OCH was associated with attenuation of the postoperative metabolic stress response. We hypothesize that modulation of the inflammatory response is one of the mechanisms involved.

A proteomic analysis of the chromoplasts isolated from sweet orange fruits [Citrus sinensis (L.) Osbeck].

PubMed

Zeng, Yunliu; Pan, Zhiyong; Ding, Yuduan; Zhu, Andan; Cao, Hongbo; Xu, Qiang; Deng, Xiuxin

2011-11-01

Here, a comprehensive proteomic analysis of the chromoplasts purified from sweet orange using Nycodenz density gradient centrifugation is reported. A GeLC-MS/MS shotgun approach was used to identify the proteins of pooled chromoplast samples. A total of 493 proteins were identified from purified chromoplasts, of which 418 are putative plastid proteins based on in silico sequence homology and functional analyses. Based on the predicted functions of these identified plastid proteins, a large proportion (∼60%) of the chromoplast proteome of sweet orange is constituted by proteins involved in carbohydrate metabolism, amino acid/protein synthesis, and secondary metabolism. Of note, HDS (hydroxymethylbutenyl 4-diphosphate synthase), PAP (plastid-lipid-associated protein), and psHSPs (plastid small heat shock proteins) involved in the synthesis or storage of carotenoid and stress response are among the most abundant proteins identified. A comparison of chromoplast proteomes between sweet orange and tomato suggested a high level of conservation in a broad range of metabolic pathways. However, the citrus chromoplast was characterized by more extensive carotenoid synthesis, extensive amino acid synthesis without nitrogen assimilation, and evidence for lipid metabolism concerning jasmonic acid synthesis. In conclusion, this study provides an insight into the major metabolic pathways as well as some unique characteristics of the sweet orange chromoplasts at the whole proteome level.

Structural Control of Metabolic Flux

PubMed Central

Sajitz-Hermstein, Max; Nikoloski, Zoran

2013-01-01

Organisms have to continuously adapt to changing environmental conditions or undergo developmental transitions. To meet the accompanying change in metabolic demands, the molecular mechanisms of adaptation involve concerted interactions which ultimately induce a modification of the metabolic state, which is characterized by reaction fluxes and metabolite concentrations. These state transitions are the effect of simultaneously manipulating fluxes through several reactions. While metabolic control analysis has provided a powerful framework for elucidating the principles governing this orchestrated action to understand metabolic control, its applications are restricted by the limited availability of kinetic information. Here, we introduce structural metabolic control as a framework to examine individual reactions' potential to control metabolic functions, such as biomass production, based on structural modeling. The capability to carry out a metabolic function is determined using flux balance analysis (FBA). We examine structural metabolic control on the example of the central carbon metabolism of Escherichia coli by the recently introduced framework of functional centrality (FC). This framework is based on the Shapley value from cooperative game theory and FBA, and we demonstrate its superior ability to assign “share of control” to individual reactions with respect to metabolic functions and environmental conditions. A comparative analysis of various scenarios illustrates the usefulness of FC and its relations to other structural approaches pertaining to metabolic control. We propose a Monte Carlo algorithm to estimate FCs for large networks, based on the enumeration of elementary flux modes. We further give detailed biological interpretation of FCs for production of lactate and ATP under various respiratory conditions. PMID:24367246

The Language of Coping: Understanding Filipino Geriatric Patients' Hemodialysis Lived Experiences

ERIC Educational Resources Information Center

de Guzman, Allan B.; Chy, Mark Anthony S.; Concepcion, April Faye P.; Conferido, Alvin John C.; Coretico, Kristine I.

2009-01-01

The majority of patients with chronic kidney disease (CKD) are undergoing maintenance hemodialysis. Hemodialysis is a process of removing metabolic waste, other poisons, and excess fluids from the blood and replacing essential blood constituents through a dialysis machine. With hemodialysis causing stress not only to physical status but also to…

Anagyrine desensitization of peripheral nicotinic acetylcholine receptors. A potential biomarker of quinolizidine alkaloid teratogenesis in cattle.

USDA-ARS?s Scientific Manuscript database

Anagyrine, a teratogenic quinolizidine alkaloid found in certain Lupinus spp., has been proposed to undergo metabolism by pregnant cattle to a piperidine alkaloid which acts inhibit fetal movement, the putative mechanism behind crooked calf syndrome. The objective of this study was to test the hypot...

An astrophysical view of Earth-based metabolic biosignature gases.

PubMed

Seager, Sara; Schrenk, Matthew; Bains, William

2012-01-01

Microbial life on Earth uses a wide range of chemical and energetic resources from diverse habitats. An outcome of this microbial diversity is an extensive and varied list of metabolic byproducts. We review key points of Earth-based microbial metabolism that are useful to the astrophysical search for biosignature gases on exoplanets, including a list of primary and secondary metabolism gas byproducts. Beyond the canonical, unique-to-life biosignature gases on Earth (O(2), O(3), and N(2)O), the list of metabolic byproducts includes gases that might be associated with biosignature gases in appropriate exoplanetary environments. This review aims to serve as a starting point for future astrophysical biosignature gas research.

Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor

PubMed Central

Chaudhri, Virendra K.; Salzler, Gregory G.; Dick, Salihah A.; Buckman, Melanie S.; Sordella, Raffaella; Karoly, Edward D.; Mohney, Robert; Stiles, Brendon M.; Elemento, Olivier; Altorki, Nasser K.; McGraw, Timothy E.

2013-01-01

SUMMARY Cancer cells undergo a metabolic reprogramming but little is known about metabolic alterations of other cells within tumors. We use mass spectrometry-based profiling and a metabolic pathway-based systems analysis to compare 21 primary human lung tumor cancer-associated fibroblast lines (CAFs) to “normal” fibroblast lines (NFs) generated from adjacent non-neoplastic lung tissue. CAFs are pro-tumorigenic, although the mechanisms by which CAFs support tumors have not been elucidated. We have identified several pathways whose metabolite abundance globally distinguished CAFs from NFs, suggesting that metabolic alterations are not limited to cancer cells. In addition, we found metabolic differences between CAFs from high and low glycolytic tumors that might reflect distinct roles of CAFs related to the tumor’s glycolytic capacity. One such change was an increase of dipeptides in CAFs. Dipeptides primarily arise from the breakdown of proteins. We found in CAFs an increase in basal macroautophagy which likely accounts for the increase in dipeptides. Furthermore, we demonstrate a difference between CAFs and NFs in the induction of autophagy promoted by reduced glucose. In sum, our data suggest increased autophagy may account for metabolic differences between CAFs and NFs and may play additional as yet undetermined roles in lung cancer. PMID:23475953

An update on the potential role of intestinal first-pass metabolism for the prediction of drug-drug interactions: the role of PBPK modeling.

PubMed

Alqahtani, Saeed; Bukhari, Ishfaq; Albassam, Ahmed; Alenazi, Maha

2018-05-28

The intestinal absorption process is a combination of several events that are governed by various factors. Several transport mechanisms are involved in drug absorption through enterocytes via active and/or passive processes. The transported molecules then undergo intestinal metabolism, which together with intestinal transport may affect the systemic availability of drugs. Many studies have provided clear evidence on the significant role of intestinal first-pass metabolism on drug bioavailability and degree of drug-drug interactions (DDIs). Areas covered: This review provides an update on the role of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of drug-drug interactions. It also provides a comprehensive overview and summary of the latest update in the role of PBPK modeling in prediction of intestinal metabolism and DDIs in humans. Expert opinion: The contribution of intestinal first-pass metabolism in the oral bioavailability of drugs and prediction of DDIs has become more evident over the last few years. Several in vitro, in situ, and in vivo models have been developed to evaluate the role of first-pass metabolism and to predict DDIs. Currently, physiologically based pharmacokinetic modeling is considered the most valuable tool for the prediction of intestinal first-pass metabolism and DDIs.

Metabolic Control of Vesicular Glutamate Transport and Release

PubMed Central

Juge, Narinobu; Gray, John A.; Omote, Hiroshi; Miyaji, Takaaki; Inoue, Tsuyoshi; Hara, Chiaki; Uneyama, Hisayuki; Edwards, Robert H.; Nicoll, Roger A.; Moriyama, Yoshinori

2010-01-01

Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl−. Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl− acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl− at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses, and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity. PMID:20920794

Cytochromes and iron sulfur proteins in sulfur metabolism of phototrophic bacteria

NASA Technical Reports Server (NTRS)

Fischer, U.

1985-01-01

Dissimilatory sulfur metabolism in phototrophic sulfur bacteria provides the bacteria with electrons for photosynthetic electron transport chain and, with energy. Assimilatory sulfate reduction is necessary for the biosynthesis of sulfur-containing cell components. Sulfide, thiosulfate, and elemental sulfur are the sulfur compounds most commonly used by phototrophic bacteria as electron donors for anoxygenic photosynthesis. Cytochromes or other electron transfer proteins, like high-potential-iron-sulfur protein (HIPIP) function as electron acceptors or donors for most enzymatic steps during the oxidation pathways of sulfide or thiosulfate. Yet, heme- or siroheme-containing proteins themselves undergo enzymatic activities in sulfur metabolism. Sirohemes comprise a porphyrin-like prosthetic group of sulfate reductase. eenzymatic reactions involve electron transfer. Electron donors or acceptors are necessary for each reaction. Cytochromes and iron sulfur problems, are able to transfer electrons.

Computational Tools for Metabolic Engineering

PubMed Central

Copeland, Wilbert B.; Bartley, Bryan A.; Chandran, Deepak; Galdzicki, Michal; Kim, Kyung H.; Sleight, Sean C.; Maranas, Costas D.; Sauro, Herbert M.

2012-01-01

A great variety of software applications are now employed in the metabolic engineering field. These applications have been created to support a wide range of experimental and analysis techniques. Computational tools are utilized throughout the metabolic engineering workflow to extract and interpret relevant information from large data sets, to present complex models in a more manageable form, and to propose efficient network design strategies. In this review, we present a number of tools that can assist in modifying and understanding cellular metabolic networks. The review covers seven areas of relevance to metabolic engineers. These include metabolic reconstruction efforts, network visualization, nucleic acid and protein engineering, metabolic flux analysis, pathway prospecting, post-structural network analysis and culture optimization. The list of available tools is extensive and we can only highlight a small, representative portion of the tools from each area. PMID:22629572

Increased polyamines as protective disease modifiers in congenital muscular dystrophy.

PubMed

Kemaladewi, D U; Benjamin, J S; Hyatt, E; Ivakine, E A; Cohn, R D

2018-06-01

Most Mendelian disorders, including neuromuscular disorders, display extensive clinical heterogeneity that cannot be solely explained by primary genetic mutations. This phenotypic variability is largely attributed to the presence of disease modifiers, which can exacerbate or lessen the severity and progression of the disease. LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a fatal degenerative muscle disease resulting from mutations in the LAMA2 gene encoding Laminin-α2. Progressive muscle weakness is predominantly observed in the lower limbs in LAMA2-CMD patients, whereas upper limbs muscles are significantly less affected. However, very little is known about the molecular mechanism underlying differential pathophysiology between specific muscle groups. Here, we demonstrate that the triceps muscles of the dy2j/dy2j mouse model of LAMA2-CMD demonstrate very mild myopathic findings compared with the tibialis anterior (TA) muscles that undergo severe atrophy and fibrosis, suggesting a protective mechanism in the upper limbs of these mice. Comparative gene expression analysis reveals that S-Adenosylmethionine decarboxylase (Amd1) and Spermine oxidase (Smox), two components of polyamine pathway metabolism, are downregulated in the TA but not in the triceps of dy2j/dy2j mice. As a consequence, the level of polyamine metabolites is significantly lower in the TA than triceps. Normalization of either Amd1 or Smox expression in dy2j/dy2j TA ameliorates muscle fibrosis, reduces overactive profibrotic TGF-β pathway and leads to improved locomotion. In summary, we demonstrate that a deregulated polyamine metabolism is a characteristic feature of severely affected lower limb muscles in LAMA2-CMD. Targeted modulation of this pathway represents a novel therapeutic avenue for this devastating disease.

Cytostatic action of two nitrosoureas derived from cysteamine.

PubMed Central

Bourut, C.; Chenu, E.; Godenèche, D.; Madelmont, J. C.; Maral, R.; Mathé, G.; Meyniel, G.

1986-01-01

2-Chloroethyl nitrosocarbamoylcystamine or ICIG-1325 (CNCC) is a lipid-soluble isomeric mixture of nitrosoureas. Its dose-effect relationship on L1210 leukaemia is characterized by a large maximally efficient dose-range (MEDR), greater than that of other nitrosoureas. CNCC also demonstrated significant therapeutic activity on intracerebrally (i.c.) transplanted L1210 leukaemia and on six transplanted solid tumours, TM2 mammary carcinoma, M555 ovarian carcinoma, B16 melanoma, glioma 26, 3LL, Lewis lung carcinoma and colon 26 carcinoma. It was inactive on fibrosarcoma ICIG-Ci4. Its antitumour activity spectrum is wider than that of the related compounds 2-[3-(2-chloroethyl) 3-nitrosoureido]D-glucopyranose (CZT), (chloro-2-ethyl)-1(ribofuranosyl-isopropylidene-2'-3' paranitrobenzoate-5')-3 nitrosourea (RFCNU), and (chloro-2-ethyl)-1 (ribopyranosyl triacetate-2'-3'-4')-3 nitrosourea (RPCNU). A study of its metabolic disposition in animals has shown that CNCC undergoes extensive first-pass metabolism leading to the formation of four main plasma metabolites. These metabolites are water-soluble nitrosoureas that arose from the bioreduction of the disulphide bridge followed by the methylation and the oxidation of the thiol groups. Experimental screening was performed with these chemically synthesized metabolites. Both N'-(2-chloroethyl)-N-[2-(methylsulphinyl)ethyl]-N'-nitrosourea (CMSOEN2) and N'-(2-chloroethyl)-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (CMSO2EN2) are very active on L1210 leukaemia grafted intraperitoneally (i.p.) and i.c., L40 leukaemia, B16 melanoma, glioma 26 and Lewis lung carcinoma. Their effectiveness is better than that of the parent compound CNCC. In addition,the percentage of mice cured after CMSOEN2 or CMSO2EN2 treatment is increased especially on B16 melanoma and glioma 26.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3801787

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

PubMed

Peltoniemi, Marko A; Hagelberg, Nora M; Olkkola, Klaus T; Saari, Teijo I

2016-09-01

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Dissecting Leishmania infantum Energy Metabolism - A Systems Perspective

PubMed Central

Subramanian, Abhishek; Jhawar, Jitesh; Sarkar, Ram Rup

2015-01-01

Leishmania infantum, causative agent of visceral leishmaniasis in humans, illustrates a complex lifecycle pertaining to two extreme environments, namely, the gut of the sandfly vector and human macrophages. Leishmania is capable of dynamically adapting and tactically switching between these critically hostile situations. The possible metabolic routes ventured by the parasite to achieve this exceptional adaptation to its varying environments are still poorly understood. In this study, we present an extensively reconstructed energy metabolism network of Leishmania infantum as an attempt to identify certain strategic metabolic routes preferred by the parasite to optimize its survival in such dynamic environments. The reconstructed network consists of 142 genes encoding for enzymes performing 237 reactions distributed across five distinct model compartments. We annotated the subcellular locations of different enzymes and their reactions on the basis of strong literature evidence and sequence-based detection of cellular localization signal within a protein sequence. To explore the diverse features of parasite metabolism the metabolic network was implemented and analyzed as a constraint-based model. Using a systems-based approach, we also put forth an extensive set of lethal reaction knockouts; some of which were validated using published data on Leishmania species. Performing a robustness analysis, the model was rigorously validated and tested for the secretion of overflow metabolites specific to Leishmania under varying extracellular oxygen uptake rate. Further, the fate of important non-essential amino acids in L. infantum metabolism was investigated. Stage-specific scenarios of L. infantum energy metabolism were incorporated in the model and key metabolic differences were outlined. Analysis of the model revealed the essentiality of glucose uptake, succinate fermentation, glutamate biosynthesis and an active TCA cycle as driving forces for parasite energy metabolism and its optimal growth. Finally, through our in silico knockout analysis, we could identify possible therapeutic targets that provide experimentally testable hypotheses. PMID:26367006

77 FR 37677 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-22

... List of Ingredients Added to Tobacco in the Manufacture of Cigarette Products--Extension--Office on... death and disability resulting from cigarette smoking and other forms of tobacco use through programs of... in cigarette products. Respondents are commercial cigarette manufacturers, packagers, or importers...

LUC-2-1682 long term maintenance of the Anthony Wayne Suspension Bridge main cables.

DOT National Transportation Integrated Search

2017-01-01

The Anthony Wayne Bridge, Ohio's only suspension bridge, is undergoing an extensive rehabilitation. Prior to taking action to preserve the cables, ODOT must decide what measures to take to evaluate the condition of the cables, how best to rehabilitat...

Anthropometric Indicators Predict Metabolic Syndrome Diagnosis in Maintenance Hemodialysis Patients.

PubMed

Vogt, Barbara Perez; Ponce, Daniela; Caramori, Jacqueline Costa Teixeira

2016-06-01

Obesity has been considered the key in metabolic syndrome (MetS) development, and fat accumulation may be responsible for the occurrence of metabolic abnormalities in hemodialysis patients. The use of gold-standard methods to evaluate obesity is limited, and anthropometric measures may be the simplest methods. However, no study has investigated the association between anthropometric indexes and MetS in these patients. Therefore, the aim was to determine which anthropometric indexes had the best association and prediction for MetS in patients undergoing hemodialysis. Cross-sectional study that included patients older than 18 years, undergoing hemodialysis for at least 3 months. Patients with liver disease and cancer or those receiving corticosteroids or antiretroviral therapy were excluded. Diagnostic criteria from Harmonizing Metabolic Syndrome were used for the diagnosis of MetS. Anthropometric indexes evaluated were body mass index (BMI); percent standard of triceps skinfold thickness and of middle arm muscle circumference; waist circumference (WC); sagittal abdominal diameter; neck circumference; waist-to-hip, waist-to-thigh, and waist-to-height ratios; sagittal index; conicity index; and body fat percentage. Ninety-eight patients were included, 54.1% male, and mean age was 57.8 ± 12.9 years. The prevalence of MetS was 74.5%. Individuals with MetS had increased accumulation of abdominal fat and general obesity. Waist-to-height ratio was the variable independently associated with MetS diagnosis (odds ratio, 1.21; 95% confidence interval, 1.09-1.34; P < .01) and that better predicts MetS, followed by WC and BMI (area under the curve of 0.840, 0.836, and 0.798, respectively, P < .01). Waist-to-height ratio was the best anthropometric predictor of MetS in maintenance hemodialysis patients. © 2015 American Society for Parenteral and Enteral Nutrition.

Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials.

PubMed

Teleni, Laisa; Chan, Raymond J; Chan, Alexandre; Isenring, Elisabeth A; Vela, Ian; Inder, Warrick J; McCarthy, Alexandra L

2016-02-01

Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort. © 2016 Society for Endocrinology.

Consequences of metabolic syndrome on postoperative outcomes after pancreaticoduodenectomy.

PubMed

Zarzavadjian Le Bian, Alban; Fuks, David; Chopinet, Sophie; Gaujoux, Sébastien; Cesaretti, Manuela; Costi, Renato; Belgaumkar, Ajay P; Smadja, Claude; Gayet, Brice

2017-05-07

To analyze immediate postoperative outcomes after pancreaticoduodenectomy regarding metabolic syndrome. In two academic centers, postoperative outcomes of patients undergoing pancreaticoduodenectomy from 2002 to 2014 were prospectively recorded. Patients presenting with metabolic syndrome [defined as at least three criteria among overweight (BMI ≥ 28 kg/m²), diabetes mellitus, arterial hypertension and dyslipidemia] were compared to patients without metabolic syndrome. Among 270 consecutive patients, 29 (11%) presented with metabolic syndrome. In univariable analysis, patients with metabolic syndrome were significantly older (69.4 years vs 62.5 years, P = 0.003) and presented more frequently with soft pancreas (72% vs 22%, P = 0.0001). In-hospital morbidity (83% vs 71%) and mortality (7% vs 6%) did not differ in the two groups so as pancreatic fistula rate (45% vs 30%, P = 0.079) and severity of pancreatic fistula ( P = 0.257). In multivariable analysis, soft pancreas texture ( P = 0.001), pancreatic duct diameter < 3 mm ( P = 0.025) and BMI > 30 kg/m² ( P = 0.041) were identified as independent risk factors of pancreatic fistula after pancreaticoduodenectomy, but not metabolic syndrome. In spite of logical reasoning and appropriate methodology, present series suggests that metabolic syndrome does not jeopardize postoperative outcomes after pancreaticoduodenectomy. Therefore, definition of metabolic syndrome seems to be inappropriate and fatty pancreas needs to be assessed with an international consensual histopathological classification.

"Pull and push back" concepts of longevity and life span extension.

PubMed

Muradian, Khachik

2013-12-01

The negative relation between metabolism and life span is a fundamental gerontological discovery well documented in a variety of ontogenetic and phylogenetic models. But how the long-lived species and populations sustain lower metabolic rate and, in more general terms, what is the efficient way to decline the metabolism? The suggested 'pull and push back' hypothesis assumes that decreased Po2 (hypoxia) and/or increased [Formula: see text] (hypercapnia) may create preconditions for the declined metabolic and aging rates. However, wider implementation of such ideas is compromised because of little advances in modification of the metabolic rate. Artificial atmosphere with controlled [Formula: see text] and [Formula: see text] could be a promising approach because of the minimal external invasions and involvement of the backward and forward loops ensuring physiological self-regulation of the metabolic perturbations. General considerations and existing data indicate that manipulations of [Formula: see text] may be more efficient in life span extension than [Formula: see text]. Thus, maximum life span of mammals positively correlates with the blood [Formula: see text] and HCO3 (-) but not with [Formula: see text]. Yet, proportional decease of the body [Formula: see text] and increase of [Formula: see text] seems the most optimal regime ensuring lower losses of the energy equivalents. Furthermore, especially rewarding results could be expected when such changes are modeled without major external invasions using the animals' inner capacity to consume O2 and generate CO2, as it is typical for the extreme longevity.

Physiology and toxicology of hormone-disrupting chemicals in higher plants.

PubMed

Couée, Ivan; Serra, Anne-Antonella; Ramel, Fanny; Gouesbet, Gwenola; Sulmon, Cécile

2013-06-01

Higher plants are exposed to natural environmental organic chemicals, associated with plant-environment interactions, and xenobiotic environmental organic chemicals, associated with anthropogenic activities. The effects of these chemicals result not only from interaction with metabolic targets, but also from interaction with the complex regulatory networks of hormone signaling. Purpose-designed plant hormone analogues thus show extensive signaling effects on gene regulation and are as such important for understanding plant hormone mechanisms and for manipulating plant growth and development. Some natural environmental chemicals also act on plants through interference with the perception and transduction of endogenous hormone signals. In a number of cases, bioactive xenobiotics, including herbicides that have been designed to affect specific metabolic targets, show extensive gene regulation effects, which are more in accordance with signaling effects than with consequences of metabolic effects. Some of these effects could be due to structural analogies with plant hormones or to interference with hormone metabolism, thus resulting in situations of hormone disruption similar to animal cell endocrine disruption by xenobiotics. These hormone-disrupting effects can be superimposed on parallel metabolic effects, thus indicating that toxicological characterisation of xenobiotics must take into consideration the whole range of signaling and metabolic effects. Hormone-disruptive signaling effects probably predominate when xenobiotic concentrations are low, as occurs in situations of residual low-level pollutions. These hormone-disruptive effects in plants may thus be of importance for understanding cryptic effects of low-dosage xenobiotics, as well as the interactive effects of mixtures of xenobiotic pollutants.

KSC-98pc1165

NASA Image and Video Library

1998-09-28

The orbiter Atlantis, being towed from the Shuttle Landing Facility, is reflected in waters from the Banana Creek next to the towway. The orbiter spent 10 months in Palmdale, CA, undergoing extensive inspections and modifications in the orbiter processing facility there. The modifications included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

Tracing the metabolism of HT-2 toxin and T-2 toxin in barley by isotope-assisted untargeted screening and quantitative LC-HRMS analysis

USDA-ARS?s Scientific Manuscript database

An extensive study of the metabolism of the type-A trichothecene mycotoxins HT-2 toxin and T-2 toxin in barley using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) is reported. A recently developed untargeted approach based on stable isotopic labelling, LC-Orbitrap-MS a...

Measurement of the local muscular metabolism by time-domain near infrared spectroscopy during knee flex-extension induced by functional electrical stimulation

NASA Astrophysics Data System (ADS)

Contini, D.; Spinelli, L.; Torricelli, A.; Ferrante, S.; Pedrocchi, A.; Molteni, F.; Ferrigno, G.; Cubeddu, R.

2009-02-01

We present a preliminary study that combines functional electrical stimulation and time-domain near infrared spectroscopy for a quantitative measurement of the local muscular metabolism during rehabilitation of post-acute stroke patients. Seven healthy subjects and nine post-acute stroke patients underwent a protocol of knee flex-extension of the quadriceps induced by functional electrical stimulation. During the protocol time-domain near infrared spectroscopy measurement were performed on both left and right muscle. Hemodynamic parameters (concentration of oxy- and deoxy-genated hemoglobin) during baseline did not show any significant differences between healthy subject and patients, while functional performances (knee angle amplitude) were distinctly different. Nevertheless, even if their clinical histories were noticeably different, there was no differentiation among functional performances of patients. On the basis of the hemodynamic parameters measured during the recovery phase, instead, it was possible to identify two classes of patients showing a metabolic trend similar or very different to the one obtained by healthy subjects. The presented results suggest that the combination of functional and metabolic information can give an additional tool to the clinicians in the evaluation of the rehabilitation in post-acute stroke patients.

Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement.

PubMed

Santoro, Giovanni C; Carrion, Joseph; Patel, Krishna; Vilchez, Crystal; Veith, Jennifer; Brodie, Jonathan D; Dewey, Stephen L

2017-08-01

Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using 18 FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic efficacy, whereas these posttreatment sex differences contribute to clinical treatment failure more commonly experienced by the former.

Metabolic functions of FABPs— mechanisms and therapeutic implications

PubMed Central

Hotamisligil, Gökhan S.; Bernlohr, David A.

2015-01-01

Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases. PMID:26260145

Methods to Increase the Metabolic Stability of (18)F-Radiotracers.

PubMed

Kuchar, Manuela; Mamat, Constantin

2015-09-03

The majority of pharmaceuticals and other organic compounds incorporating radiotracers that are considered foreign to the body undergo metabolic changes in vivo. Metabolic degradation of these drugs is commonly caused by a system of enzymes of low substrate specificity requirement, which is present mainly in the liver, but drug metabolism may also take place in the kidneys or other organs. Thus, radiotracers and all other pharmaceuticals are faced with enormous challenges to maintain their stability in vivo highlighting the importance of their structure. Often in practice, such biologically active molecules exhibit these properties in vitro, but fail during in vivo studies due to obtaining an increased metabolism within minutes. Many pharmacologically and biologically interesting compounds never see application due to their lack of stability. One of the most important issues of radiotracers development based on fluorine-18 is the stability in vitro and in vivo. Sometimes, the metabolism of (18)F-radiotracers goes along with the cleavage of the C-F bond and with the rejection of [(18)F]fluoride mostly combined with high background and accumulation in the skeleton. This review deals with the impact of radiodefluorination and with approaches to stabilize the C-F bond to avoid the cleavage between fluorine and carbon.

Effects of season, temperature, and body mass on the standard metabolic rate of tegu lizards (Tupinambis merianae).

PubMed

Toledo, Luís F; Brito, Simone P; Milsom, William K; Abe, Augusto S; Andrade, Denis V

2008-01-01

Abstract This study examined how the standard metabolic rate of tegu lizards, a species that undergoes large ontogenetic changes in body weight with associated changes in life-history traits, is affected by changes in body mass, body temperature, season, and life-history traits. We measured rates of oxygen consumption (Vo(2)) in 90 individuals ranging in body mass from 10.4 g to 3.75 kg at three experimental temperatures (17 degrees , 25 degrees , and 30 degrees C) over the four seasons. We found that standard metabolic rate scaled to the power of 0.84 of body mass at all experimental temperatures in all seasons and that thermal sensitivity of metabolism was relatively low (Q(10) approximately 2.0-2.5) over the range from 17 degrees to 30 degrees C regardless of body size or season. Metabolic rates did vary seasonally, being higher in spring and summer than in autumn and winter at the same temperatures, and this was true regardless of animal size. Finally, in this study, the changes in life-history traits that occurred ontogenetically were not accompanied by significant changes in metabolic rate.

Preoperative methylprednisolone does not reduce loss of knee-extension strength after total knee arthroplastyA randomized, double-blind, placebo-controlled trial of 61 patients.

PubMed

Lindberg-Larsen, Viktoria; Bandholm, Thomas Q; Zilmer, Camilla K; Bagger, Jens; Hornsleth, Mette; Kehlet, Henrik

2017-10-01

Background and purpose - Patients undergoing total knee arthroplasty (TKA) face challenges related to postoperative reduction in knee-extension strength. We evaluated whether inhibition of the inflammatory response by a single preoperative dose of methylprednisolone (MP) reduces the pronounced loss of knee-extension strength at discharge after fast-track TKA. Patients and methods - 70 patients undergoing elective unilateral TKA were randomized (1:1) to preoperative intravenous (IV) MP 125 mg (group MP) or isotonic saline IV (group C). All procedures were performed under spinal anesthesia without tourniquet, and with a standardized multimodal analgesic regime. The primary outcome was change in knee-extension strength from baseline to 48 hours postoperatively. Secondary outcomes were knee joint circumference, functional performance using the Timed Up and Go (TUG) test, pain during the aforementioned tests, rescue analgesic requirements, and plasma C-reactive protein (CRP) changes. Results - 61 patients completed the follow-up. The loss in quadriceps muscle strength was similar between groups; group MP 1.04 (0.22-1.91) Nm/kg (-89%) vs. group C 1.02 (0.22-1.57) Nm/kg (-88%). Also between-group differences were similar for knee circumference, TUG test, and pain scores. MP reduced the inflammatory response (CRP) at 24 hours postoperatively; group MP 33 (IQR 21-50) mg/L vs. group C 72 (IQR 58-92) mg/L (p < 0.001), and 48 hours postoperatively; group MP 83 (IQR 56-125) mg/L vs. group C 192 (IQR 147-265) mg/L (p < 0.001), respectively. Interpretation - Preoperative systemic administration of MP 125 mg did not reduce the pronounced loss of knee-extension strength or other functional outcomes at discharge after fast-track TKA despite a reduced systemic inflammatory response.

Preoperative methylprednisolone does not reduce loss of knee-extension strength after total knee arthroplasty

PubMed Central

Lindberg-Larsen, Viktoria; Bandholm, Thomas Q; Zilmer, Camilla K; Bagger, Jens; Hornsleth, Mette; Kehlet, Henrik

2017-01-01

Background and purpose Patients undergoing total knee arthroplasty (TKA) face challenges related to postoperative reduction in knee-extension strength. We evaluated whether inhibition of the inflammatory response by a single preoperative dose of methylprednisolone (MP) reduces the pronounced loss of knee-extension strength at discharge after fast-track TKA. Patients and methods 70 patients undergoing elective unilateral TKA were randomized (1:1) to preoperative intravenous (IV) MP 125 mg (group MP) or isotonic saline IV (group C). All procedures were performed under spinal anesthesia without tourniquet, and with a standardized multimodal analgesic regime. The primary outcome was change in knee-extension strength from baseline to 48 hours postoperatively. Secondary outcomes were knee joint circumference, functional performance using the Timed Up and Go (TUG) test, pain during the aforementioned tests, rescue analgesic requirements, and plasma C-reactive protein (CRP) changes. Results 61 patients completed the follow-up. The loss in quadriceps muscle strength was similar between groups; group MP 1.04 (0.22–1.91) Nm/kg (–89%) vs. group C 1.02 (0.22–1.57) Nm/kg (–88%). Also between-group differences were similar for knee circumference, TUG test, and pain scores. MP reduced the inflammatory response (CRP) at 24 hours postoperatively; group MP 33 (IQR 21–50) mg/L vs. group C 72 (IQR 58–92) mg/L (p < 0.001), and 48 hours postoperatively; group MP 83 (IQR 56–125) mg/L vs. group C 192 (IQR 147–265) mg/L (p < 0.001), respectively. Interpretation Preoperative systemic administration of MP 125 mg did not reduce the pronounced loss of knee-extension strength or other functional outcomes at discharge after fast-track TKA despite a reduced systemic inflammatory response. PMID:28657396

Black aorta in a patient with alkaptonuria (ochronosis).

PubMed

Concistrè, Giovanni; Fiorani, Brenno; Ranocchi, Federico; Casali, Giovanni; Loforte, Antonio; Musumeci, Francesco

2011-06-01

A rare cause of valvular heart disease is the deposition of foreign material in the valvular tissues, including material accumulating as a result of inborn errors of metabolism of the essential amino acids. Alkaptonuria can result in accumulation of homogentisic acid. We report the case of a patient with alkaptonuria undergoing surgery for aortic valve replacement.

Measuring aerobic respiration in stream ecosystems using the resazurin-resorufin system

Treesearch

R. González-Pinzón; R. Haggerty; D.D. Myrold

2012-01-01

The use of smart tracers to study hydrologic systems is becoming more widespread. Smart tracers are compounds that irreversibly react in the presence of a process or condition under investigation. Resazurin (Raz) is a smart tracer that undergoes an irreversible reduction to resorufin (Rru) in the presence of cellular metabolic activity. We quantified the relationship...

77 FR 43086 - Agency Information Collection Request; 60-Day Public Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-23

...; Sterilization of Persons in Federally Assisted Family Planning Projects--OMB No. 0937- 0166--Extension--OPHS..., subpart B (``Sterilization of Persons in Federally Assisted Family Planning Projects''). The consent form solicits information to assure voluntary and informed consent to persons undergoing sterilization in...

Functional Assessment Inventory Manual.

ERIC Educational Resources Information Center

Crewe, Nancy M.; Athelstan, Gary T.

This manual, which provides extensive new instructions for administering the Functional Assessment Inventory (FAI), is intended to enable counselors to begin using the inventory without undergoing any special training. The first two sections deal with the need for functional assessment and issues in the development and use of the inventory. The…

78 FR 65323 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-31

...)--Extension-- Office on Smoking and Health, National Center for Chronic Disease Prevention and Health... cigarette smoking. Adolescents who use smokeless tobacco are more likely to become cigarette smokers. The Centers for Disease Control and Prevention (CDC), Office on Smoking and Health (OSH), has primary...

76 FR 33023 - Safety Advisory; Unauthorized Marking of Compressed Gas Cylinders

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-07

... cylinders. The cylinders were neither marked nor certified by an authorized independent inspection agency... mark, the cylinder did not undergo the complete series of safety tests and inspections required by the... contents under pressure during normal transportation and use. Extensive property damage, serious personal...

76 FR 16841 - Proposed Extension of Existing Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-25

... Longshore and Harbor Workers' Compensation Act (LHWCA). These acts provide vocational rehabilitation... provide that eligible injured workers are to be furnished vocational rehabilitation services, and Sec. 8111(b) of the FECA and Sec. 908(g) of the LHWCA provide that persons undergoing such vocational...

77 FR 6824 - Proposed Extension of Existing Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-09

... Act (FECA). This act provides vocational rehabilitation services to eligible workers with disabilities. Section 8111(b) of the FECA provides that that person(s) undergoing such vocational rehabilitation shall... interested in comments which: Evaluate whether the proposed collection of information is necessary for the...

77 FR 2065 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-13

... interview with the claimant to explain the results and to allow the claimant to confirm or question the... Project EEOICPA Dose Reconstruction Interviews and Forms (0920-0530, Expiration 03/30/2012)--Extension... Act, NIOSH is providing voluntary interview opportunities to claimants (or their survivors...

Should metabolic evaluation be performed in patients with struvite stones?

PubMed

Iqbal, Muhammad Waqas; Shin, Richard H; Youssef, Ramy F; Kaplan, Adam G; Cabrera, Fernando J; Hanna, Jonathan; Scales, Charles D; Ferrandino, Michael N; Preminger, Glenn M; Lipkin, Michael E

2017-04-01

Previous studies suggested that patients with pure struvite calculi rarely have underlying metabolic abnormalities. Therefore, most of these patients do not undergo metabolic studies. We report our experience with these patients and their response to directed medical therapy. Between 1/2005 and 9/2012, 75 patients treated with percutaneous nephrolithotomy for struvite stones were identified. Of these, 7 had pure struvite stones (Group 1), 32 had mixed struvite stones (Group 2), both with metabolic evaluation, and 17 had pure struvite stones without metabolic evaluation (Group 3). The frequency of metabolic abnormalities and stone activity (defined as stone growth or stone-related events) was compared between groups. The median age was 55 years and 64 % were female. No significant difference in race, infection history, family history, stone location or volume existed between groups. Metabolic abnormalities were found in 57 % of Group 1 and 81 % of Group 2 patients. A similar proportion of Group 1 and 2 patients received modification to or continuation of metabolic therapy, whereas no Group 3 patients received any directed therapy. In patients with >6 months follow-up, the stone activity rate between Groups 1 and 2 appeared similar whereas Group 3 trended towards higher stone activity rate. Metabolic abnormalities in pure struvite stone formers appear to be more common than previously reported. Directed medical therapy in these patients may reduce stone activity. The role of metabolic evaluation and directed medical therapy needs reconsideration in patients with pure struvite stones.

Metabolite damage and repair in metabolic engineering design.

PubMed

Sun, Jiayi; Jeffryes, James G; Henry, Christopher S; Bruner, Steven D; Hanson, Andrew D

2017-11-01

The necessarily sharp focus of metabolic engineering and metabolic synthetic biology on pathways and their fluxes has tended to divert attention from the damaging enzymatic and chemical side-reactions that pathway metabolites can undergo. Although historically overlooked and underappreciated, such metabolite damage reactions are now known to occur throughout metabolism and to generate (formerly enigmatic) peaks detected in metabolomics datasets. It is also now known that metabolite damage is often countered by dedicated repair enzymes that undo or prevent it. Metabolite damage and repair are highly relevant to engineered pathway design: metabolite damage reactions can reduce flux rates and product yields, and repair enzymes can provide robust, host-independent solutions. Herein, after introducing the core principles of metabolite damage and repair, we use case histories to document how damage and repair processes affect efficient operation of engineered pathways - particularly those that are heterologous, non-natural, or cell-free. We then review how metabolite damage reactions can be predicted, how repair reactions can be prospected, and how metabolite damage and repair can be built into genome-scale metabolic models. Lastly, we propose a versatile 'plug and play' set of well-characterized metabolite repair enzymes to solve metabolite damage problems known or likely to occur in metabolic engineering and synthetic biology projects. Copyright © 2017 International Metabolic Engineering Society. All rights reserved.

Respiration metabolism of Group B Streptococcus is activated by environmental haem and quinone and contributes to virulence.

PubMed

Yamamoto, Yuji; Poyart, Claire; Trieu-Cuot, Patrick; Lamberet, Gilles; Gruss, Alexandra; Gaudu, Philippe

2005-04-01

Group B Streptococcus (GBS) is a common constituent of the vaginal microflora, but its transmission to newborns can cause life-threatening sepsis, pneumonia and meningitis. Energy metabolism of this opportunist pathogen has been deduced to be strictly fermentative. We discovered that GBS undergoes respiration metabolism if its environment supplies two essential respiratory components: quinone and haem. Respiration metabolism led to significant changes in growth characteristics, including a doubling of biomass and an altered metabolite profile under the tested conditions. The GBS respiratory chain is inactivated by: (i) withdrawing haem and/or quinone, (ii) treating cultures with a respiration inhibitor or (iii) inactivating the cydA gene product, a subunit of cytochrome bd quinol oxidase, in all cases resulting in exclusively fermentative growth. cydA inactivation reduced GBS growth in human blood and strongly attenuated virulence in a neonatal rat sepsis model, suggesting that the animal host may supply the components that activate GBS respiration. These results suggest a role of respiration metabolism in GBS dissemination. Our findings show that environmental factors can increase the flexibility of GBS metabolism by activating a newly identified respiration chain. The need for two environmental factors may explain why GBS respiration metabolism was not found in previous studies.

Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system

PubMed Central

Kim, Teayoun; Yang, Qinglin

2013-01-01

Peroxisome-proliferator-activated receptors (PPARs) comprise three subtypes (PPARα, δ and γ) to form a nuclear receptor superfamily. PPARs act as key transcriptional regulators of lipid metabolism, mitochondrial biogenesis, and anti-oxidant defense. While their roles in regulating lipid metabolism have been well established, the role of PPARs in regulating redox activity remains incompletely understood. Since redox activity is an integral part of oxidative metabolism, it is not surprising that changes in PPAR signaling in a specific cell or tissue will lead to alteration of redox state. The effects of PPAR signaling are directly related to PPAR expression, protein activities and PPAR interactions with their coregulators. The three subtypes of PPARs regulate cellular lipid and energy metabolism in most tissues in the body with overlapping and preferential effects on different metabolic steps depending on a specific tissue. Adding to the complexity, specific ligands of each PPAR subtype may also display different potencies and specificities of their role on regulating the redox pathways. Moreover, the intensity and extension of redox regulation by each PPAR subtype are varied depending on different tissues and cell types. Both beneficial and adverse effects of PPAR ligands against cardiovascular disorders have been extensively studied by many groups. The purpose of the review is to summarize the effects of each PPAR on regulating redox and the underlying mechanisms, as well as to discuss the implications in the cardiovascular system. PMID:23802046

A proteomic analysis of the chromoplasts isolated from sweet orange fruits [Citrus sinensis (L.) Osbeck

PubMed Central

Zeng, Yunliu; Pan, Zhiyong; Ding, Yuduan; Zhu, Andan; Cao, Hongbo; Xu, Qiang; Deng, Xiuxin

2011-01-01

Here, a comprehensive proteomic analysis of the chromoplasts purified from sweet orange using Nycodenz density gradient centrifugation is reported. A GeLC-MS/MS shotgun approach was used to identify the proteins of pooled chromoplast samples. A total of 493 proteins were identified from purified chromoplasts, of which 418 are putative plastid proteins based on in silico sequence homology and functional analyses. Based on the predicted functions of these identified plastid proteins, a large proportion (∼60%) of the chromoplast proteome of sweet orange is constituted by proteins involved in carbohydrate metabolism, amino acid/protein synthesis, and secondary metabolism. Of note, HDS (hydroxymethylbutenyl 4-diphosphate synthase), PAP (plastid-lipid-associated protein), and psHSPs (plastid small heat shock proteins) involved in the synthesis or storage of carotenoid and stress response are among the most abundant proteins identified. A comparison of chromoplast proteomes between sweet orange and tomato suggested a high level of conservation in a broad range of metabolic pathways. However, the citrus chromoplast was characterized by more extensive carotenoid synthesis, extensive amino acid synthesis without nitrogen assimilation, and evidence for lipid metabolism concerning jasmonic acid synthesis. In conclusion, this study provides an insight into the major metabolic pathways as well as some unique characteristics of the sweet orange chromoplasts at the whole proteome level. PMID:21841170

Ramadan fasting and dental treatment considerations: a review.

PubMed

Shaeesta, Khaleelahmed Bhavikatti; Prabhuji, M Lv; Shruthi, J R

2015-01-01

During the sacred month of Ramadan, Muslims abstain from the consumption of food from dawn until dusk. Extended fasting hours produce changes in the body's metabolism during this period. A majority of the population who fast also restrict themselves from undergoing dental treatments due to a fear of breaking the fast. Even among health professionals, a certain amount of uncertainty prevails about the implications of treating a patient who is fasting. To help clinicians carry out safe and effective treatment without hampering a patient's religious beliefs, the present article focuses on the effect of Ramadan fasting on the body's metabolism and the ramifications for treatment aspects, including medications and dental procedures.

Diazo Groups Endure Metabolism and Enable Chemoselectivity in Cellulo

PubMed Central

2015-01-01

We introduce a stabilized diazo group as a reporter for chemical biology. ManDiaz, which is a diazo derivative of N-acetylmannosamine, is found to endure cellular metabolism and label the surface of a mammalian cell. There its diazo group can undergo a 1,3-dipolar cycloaddition with a strained alkyne, providing a signal comparable to that from the azido congener, ManNAz. The chemoselectivity of diazo and alkynyl groups enables dual labeling of cells that is not possible with azido and alkynyl groups. Thus, the diazo group, which is approximately half the size of an azido group, provides unique opportunities for orthogonal labeling of cellular components. PMID:25658416

Diazo groups endure metabolism and enable chemoselectivity in cellulo.

PubMed

Andersen, Kristen A; Aronoff, Matthew R; McGrath, Nicholas A; Raines, Ronald T

2015-02-25

We introduce a stabilized diazo group as a reporter for chemical biology. ManDiaz, which is a diazo derivative of N-acetylmannosamine, is found to endure cellular metabolism and label the surface of a mammalian cell. There its diazo group can undergo a 1,3-dipolar cycloaddition with a strained alkyne, providing a signal comparable to that from the azido congener, ManNAz. The chemoselectivity of diazo and alkynyl groups enables dual labeling of cells that is not possible with azido and alkynyl groups. Thus, the diazo group, which is approximately half the size of an azido group, provides unique opportunities for orthogonal labeling of cellular components.

Role of sleep quality in the metabolic syndrome

PubMed Central

Koren, Dorit; Dumin, Magdalena; Gozal, David

2016-01-01

Emerging evidence has assigned an important role to sleep as a modulator of metabolic homeostasis. The impact of variations in sleep duration, sleep-disordered breathing, and chronotype to cardiometabolic function encompasses a wide array of perturbations spanning from obesity, insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease risk and mortality in both adults and children. Here, we critically and extensively review the published literature on such important issues and provide a comprehensive overview of the most salient pathophysiologic pathways underlying the links between sleep, sleep disorders, and cardiometabolic functioning. PMID:27601926

Anaerobic Metabolism and Bioremediation of Explosives-Contaminated Soil

NASA Astrophysics Data System (ADS)

Boopathy, Raj

Nitroaromatic compounds pollute soil, water, and food via use of pesticides, plastics, pharmaceuticals, landfill dumping of industrial wastes, and the military use of explosives. Biotransformation of trinitrotoluene and other nitroaromatics by aerobic bacteria in the laboratory has been frequently reported, but the anaerobic bacterial metabolism of nitroaromatics has not been studied as extensively perhaps due to the difficulty in working with anaerobic cultures and the slow growth of anaerobes. Sulfate-reducing and methanogenic bacteria can metabolize nitroaromatic compounds under anaerobic conditions if appropriate electron donors and electron acceptors are present in the environment.

Metabolite screening of aromatic amine hair dyes using in vitro hepatic models.

PubMed

Skare, J A; Hewitt, N J; Doyle, E; Powrie, R; Elcombe, C

2009-11-01

Aromatic amines and heterocyclic amines are widely used ingredients in permanent hair dyes. However, little has been published on their potential for oxidation via hepatic cytochrome P450s. Therefore, the authors screened nine such compounds for their potential to undergo oxidative metabolism in human liver microsomes. Toluene-2,5-diamine (TDA), p-aminophenol, m-aminophenol, p-methylaminophenol, N,N'-bis(2-hydroxyethyl)-p-phenylenediamine, and 1-hydroxyethyl-4,5-diaminopyrazole showed no evidence of oxidative metabolism. Oxidized metabolites of 4-amino-2-hydroxytoluene (AHT), 2-methyl-5- hydroxyethylaminophenol (MHEAP), and phenyl methyl pyrazolone (PMP) were detected, but there was no evidence of beta-nicotinamide adenine dinucleotide phosphate (NADPH)-dependent covalent binding to microsomal protein, suggesting that these are not reactive metabolites. Metabolism of AHT, MHEAP, PMP, and TDA was further studied in human hepatocytes. All these compounds underwent conjugation, but no oxidative metabolites were found. The results suggest that none of the hair dye ingredients tested showed evidence of hepatic metabolism to potentially biologically reactive oxidized metabolites.

Comparative metabolism of tramadol and tapentadol: a toxicological perspective.

PubMed

Barbosa, Joana; Faria, Juliana; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

2016-11-01

Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy.

TCR revision generates functional CD4+ T cells1

PubMed Central

Hale, J. Scott; Wubeshet, Maramawit; Fink, Pamela J.

2010-01-01

CD4+Vβ5+ peripheral T cells in B6 mice respond to encounter with a peripherally-expressed endogenous superantigen by undergoing either deletion or TCR revision. In this latter process, cells lose surface Vβ5 expression and undergo RAG-dependent rearrangement of endogenous TCRβ genes, driving surface expression of novel TCRs. While post-revision CD4+Vβ5−TCRβ+ T cells accumulate with age in Vβ5 transgenic mice and bear a diverse TCR Vβ repertoire, it is unknown whether they respond to homeostatic and antigenic stimuli, and thus may benefit the host. We now demonstrate that post-revision cells are functional. These cells have a high rate of steady-state homeostatic proliferation in situ and they undergo extensive MHC class II-dependent lymphopenia-induced proliferation. Importantly, post-revision cells do not proliferate in response to the tolerizing superantigen, implicating TCR revision as a mechanism of tolerance induction and demonstrating that TCR-dependent activation of post-revision cells is not driven by the transgene-encoded receptor. Post-revision cells proliferate extensively to commensal bacterial Ags and can generate I-Ab-restricted responses to Ag by producing IFNγ following Listeria monocytogenes challenge. These data show that rescued post-revision T cells are responsive to homeostatic signals and recognize self and foreign peptides in the context of self MHC, and are thus useful to the host. PMID:20971922

TCR revision generates functional CD4+ T cells.

PubMed

Hale, J Scott; Wubeshet, Maramawit; Fink, Pamela J

2010-12-01

CD4(+)Vβ5(+) peripheral T cells in C57BL/6 mice respond to encounter with a peripherally expressed endogenous superantigen by undergoing either deletion or TCR revision. In this latter process, cells lose surface Vβ5 expression and undergo RAG-dependent rearrangement of endogenous TCRβ genes, driving surface expression of novel TCRs. Although postrevision CD4(+)Vβ5(-)TCRβ(+) T cells accumulate with age in Vβ5 transgenic mice and bear a diverse TCR Vβ repertoire, it is unknown whether they respond to homeostatic and antigenic stimuli and thus may benefit the host. We demonstrate in this study that postrevision cells are functional. These cells have a high rate of steady-state homeostatic proliferation in situ, and they undergo extensive MHC class II-dependent lymphopenia-induced proliferation. Importantly, postrevision cells do not proliferate in response to the tolerizing superantigen, implicating TCR revision as a mechanism of tolerance induction and demonstrating that TCR-dependent activation of postrevision cells is not driven by the transgene-encoded receptor. Postrevision cells proliferate extensively to commensal bacterial Ags and can generate I-A(b)-restricted responses to Ag by producing IFN-γ following Listeria monocytogenes challenge. These data show that rescued postrevision T cells are responsive to homeostatic signals and recognize self- and foreign peptides in the context of self-MHC and are thus useful to the host.

Reciprocal Regulation of Endocytosis and Metabolism

PubMed Central

Antonescu, Costin N.; McGraw, Timothy E.; Klip, Amira

2014-01-01

The cellular uptake of many nutrients and micronutrients governs both their cellular availability and their systemic homeostasis. The cellular rate of nutrient or ion uptake (e.g., glucose, Fe3+, K+) or efflux (e.g., Na+) is governed by a complement of membrane transporters and receptors that show dynamic localization at both the plasma membrane and defined intracellular membrane compartments. Regulation of the rate and mechanism of endocytosis controls the amounts of these proteins on the cell surface, which in many cases determines nutrient uptake or secretion. Moreover, the metabolic action of diverse hormones is initiated upon binding to surface receptors that then undergo regulated endocytosis and show distinct signaling patterns once internalized. Here, we examine how the endocytosis of nutrient transporters and carriers as well as signaling receptors governs cellular metabolism and thereby systemic (whole-body) metabolite homeostasis. PMID:24984778

Metabolic control of vesicular glutamate transport and release.

PubMed

Juge, Narinobu; Gray, John A; Omote, Hiroshi; Miyaji, Takaaki; Inoue, Tsuyoshi; Hara, Chiaki; Uneyama, Hisayuki; Edwards, Robert H; Nicoll, Roger A; Moriyama, Yoshinori

2010-10-06

Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity. Copyright © 2010 Elsevier Inc. All rights reserved.

[A case of extensive pulmonary atelectasis after intubation in a patient undergoing elective tympanoplasty].

PubMed

Sugimoto, Kenzaburo; Satoh, Masaaki; Kai, Makiko; Sata, Naho; Takeuchi, Mamoru

2013-10-01

A 33-year-old male, without significant medical history, underwent elective tympanoplasty. It was difficult to manage his airway because of overbites, small jaw, and short neck. After intubation, his left chest revealed obvious abnormality in sound and movement, and showed free air in the mediastinum on X ray. CT revealed extensive atelectasis. Although he is a current smoker, the length of preoperative smoking cessation necessary to decrease postoperative pulmonary complications is not clear. This case demonstrates the importance of preoperative preparation including education in smoking damage.

The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment.

PubMed

An, Yuan; Sun, Zhuangzhuang; Zhang, Yajuan; Liu, Bin; Guan, Yuanyuan; Lu, Meisong

2014-03-01

Previous studies have indicated that berberine is an effective insulin sensitizer with comparable activity to metformin (Diabetes 2006, 55, 2256). Reduced insulin sensitivity is reportedly a factor adversely affecting the outcome of IVF in patients with polycystic ovary syndrome (PCOS) (Human Reproduction 2006, 21, 1416). Our objective was to evaluate the clinical, metabolic and endocrine effects of berberine vs metformin in PCOS women scheduled for IVF treatment and to explore the potential benefits to the IVF process. We performed a prospective study in 150 infertile women with PCOS undergoing IVF treatment. Patients were randomized to receive berberine, metformin or placebo tablets for 3 months before ovarian stimulation. The clinical, endocrine, metabolic parameters and the outcome of IVF. Compared with placebo, greater reductions in total testosterone, free androgen index, fasting glucose, fasting insulin and HOMA-IR, and increases in SHBG, were observed in the berberine and metformin groups. Three months of treatment with berberine or metformin before the IVF cycle increased the pregnancy rate and reduced the incidence of severe ovarian hyperstimulation syndrome. Furthermore, treatment with berberine, in comparison with metformin, was associated with decreases in BMI, lipid parameters and total FSH requirement, and an increase in live birth rate with fewer gastrointestinal adverse events. Berberine and metformin treatments prior to IVF improved the pregnancy outcome by normalizing the clinical, endocrine and metabolic parameters in PCOS women. Berberine has a more pronounced therapeutic effect and achieved more live births with fewer side effects than metformin. © 2013 John Wiley & Sons Ltd.

Modulating autophagy in cancer therapy: Advancements and challenges for cancer cell death sensitization.

PubMed

Bhat, Punya; Kriel, Jurgen; Shubha Priya, Babu; Basappa; Shivananju, Nanjunda Swamy; Loos, Ben

2018-01-01

Autophagy is a major protein degradation pathway capable of upholding cellular metabolism under nutrient limiting conditions, making it a valuable resource to highly proliferating tumour cells. Although the regulatory machinery of the autophagic pathway has been well characterized, accurate modulation of this pathway remains complex in the context of clinical translatability for improved cancer therapies. In particular, the dynamic relationship between the rate of protein degradation through autophagy, i.e. autophagic flux, and the susceptibility of tumours to undergo apoptosis remains largely unclear. Adding to inefficient clinical translation is the lack of measurement techniques that accurately depict autophagic flux. Paradoxically, both increased autophagic flux as well as autophagy inhibition have been shown to sensitize cancer cells to undergo cell death, indicating the highly context dependent nature of this pathway. In this article, we aim to disentangle the role of autophagy modulation in tumour suppression by assessing existing literature in the context of autophagic flux and cellular metabolism at the interface of mitochondrial function. We highlight the urgency to not only assess autophagic flux more accurately, but also to center autophagy manipulation within the unique and inherent metabolic properties of cancer cells. Lastly, we discuss the challenges faced when targeting autophagy in the clinical setting. In doing so, it is hoped that a better understanding of autophagy in cancer therapy is revealed in order to overcome tumour chemoresistance through more controlled autophagy modulation in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

Modulation of the specific glutathionylation of mitochondrial proteins in the yeast Saccharomyces cerevisiae under basal and stress conditions.

PubMed

Gergondey, Rachel; Garcia, Camille; Marchand, Christophe H; Lemaire, Stephane D; Camadro, Jean-Michel; Auchère, Françoise

2017-03-15

The potential biological consequences of oxidative stress and changes in glutathione levels include the oxidation of susceptible protein thiols and reversible covalent binding of glutathione to the -SH groups of proteins by S-glutathionylation. Mitochondria are central to the response to oxidative stress and redox signaling. It is therefore crucial to explore the adaptive response to changes in thiol-dependent redox status in these organelles. We optimized the purification protocol of glutathionylated proteins in the yeast Saccharomyces cerevisiae and present a detailed proteomic analysis of the targets of protein glutathionylation in cells undergoing constitutive metabolism and after exposure to various stress conditions. This work establishes the physiological importance of the glutathionylation process in S. cerevisiae under basal conditions and provides evidence for an atypical and unexpected cellular distribution of the process between the cytosol and mitochondria. In addition, our data indicate that each oxidative condition (diamide, GSSG, H 2 O 2 , or the presence of iron) elicits an adaptive metabolic response affecting specific mitochondrial metabolic pathways, mainly involved in the energetic maintenance of the cells. The correlation of protein modifications with intracellular glutathione levels suggests that protein deglutathionylation may play a role in protecting mitochondria from oxidative stress. This work provides further insights into the diversity of proteins undergoing glutathionylation and the role of this post-translational modification as a regulatory process in the adaptive response of the cell. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Sources and Bioactive Properties of Conjugated Dietary Fatty Acids.

PubMed

Hennessy, Alan A; Ross, Paul R; Fitzgerald, Gerald F; Stanton, Catherine

2016-04-01

The group of conjugated fatty acids known as conjugated linoleic acid (CLA) isomers have been extensively studied with regard to their bioactive potential in treating some of the most prominent human health malignancies. However, CLA isomers are not the only group of potentially bioactive conjugated fatty acids currently undergoing study. In this regard, isomers of conjugated α-linolenic acid, conjugated nonadecadienoic acid and conjugated eicosapentaenoic acid, to name but a few, have undergone experimental assessment. These studies have indicated many of these conjugated fatty acid isomers commonly possess anti-carcinogenic, anti-adipogenic, anti-inflammatory and immune modulating properties, a number of which will be discussed in this review. The mechanisms through which these bioactivities are mediated have not yet been fully elucidated. However, existing evidence indicates that these fatty acids may play a role in modulating the expression of several oncogenes, cell cycle regulators, and genes associated with energy metabolism. Despite such bioactive potential, interest in these conjugated fatty acids has remained low relative to the CLA isomers. This may be partly attributed to the relatively recent emergence of these fatty acids as bioactives, but also due to a lack of awareness regarding sources from which they can be produced. In this review, we will also highlight the common sources of these conjugated fatty acids, including plants, algae, microbes and chemosynthesis.

Redox regulation of the Calvin–Benson cycle: something old, something new

PubMed Central

Michelet, Laure; Zaffagnini, Mirko; Morisse, Samuel; Sparla, Francesca; Pérez-Pérez, María Esther; Francia, Francesco; Danon, Antoine; Marchand, Christophe H.; Fermani, Simona; Trost, Paolo; Lemaire, Stéphane D.

2013-01-01

Reversible redox post-translational modifications such as oxido-reduction of disulfide bonds, S-nitrosylation, and S-glutathionylation, play a prominent role in the regulation of cell metabolism and signaling in all organisms. These modifications are mainly controlled by members of the thioredoxin and glutaredoxin families. Early studies in photosynthetic organisms have identified the Calvin–Benson cycle, the photosynthetic pathway responsible for carbon assimilation, as a redox regulated process. Indeed, 4 out of 11 enzymes of the cycle were shown to have a low activity in the dark and to be activated in the light through thioredoxin-dependent reduction of regulatory disulfide bonds. The underlying molecular mechanisms were extensively studied at the biochemical and structural level. Unexpectedly, recent biochemical and proteomic studies have suggested that all enzymes of the cycle and several associated regulatory proteins may undergo redox regulation through multiple redox post-translational modifications including glutathionylation and nitrosylation. The aim of this review is to detail the well-established mechanisms of redox regulation of Calvin–Benson cycle enzymes as well as the most recent reports indicating that this pathway is tightly controlled by multiple interconnected redox post-translational modifications. This redox control is likely allowing fine tuning of the Calvin–Benson cycle required for adaptation to varying environmental conditions, especially during responses to biotic and abiotic stresses. PMID:24324475

Ethnopharmacology, phytochemistry, and biological activities of Cymbopogon citratus (DC.) Stapf extracts.

PubMed

Ekpenyong, Christopher E; Akpan, Ernest; Nyoh, Azah

2015-05-01

Cymbopogon citratus is a widely distributed perennial herb belonging to the Poaceae family and has been extensively consumed for its medicinal, cosmetic, and nutritional effects for centuries. A large number of reports have been published describing the pharmacological, biological, and therapeutic actions of this herb. In this review, we summarized the literatures on related studies (up to January, 2014) that highlighted the pharmacologic and biological effects of the major phytochemicals isolated from C. citratus extracts and its essential oil. The components of the essential oils found in C. citratus have a similar pharmacokinetic properties, including absorption, distribution, metabolism, and excretion. They are quickly absorbed following oral, pulmonary, and dermal administration. Based on the published reports, it can also be inferred that, after absorption from the small intestine, some phytochemicals in C. citratus can undergo oxidation, glucuronidation, sulfation, and/or O-methylation. Excretion is through urine, feces and/or expired volatiles. The biotransformation reactions of C. citratus bioactive constituents are essential for its relatively safe consumption and therapeutic applications. The data available so far warrant further studies evaluating C. citratus pharmacokinetics. Reliable pharmacokinetic data in humans would be critical for a better understanding of the the systemic handling of C. citratus. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Early Probe and Drug Discovery in Academia: A Minireview.

PubMed

Roy, Anuradha

2018-02-09

Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.

Design of a transdermal delivery system for aspirin as an antithrombotic drug.

PubMed

Ammar, H O; Ghorab, M; El-Nahhas, S A; Kamel, R

2006-12-11

Aspirin has become the gold standard to which newer antiplatelet drugs are compared for reducing risks of cardiovascular diseases, while keeping low cost. Oral aspirin has a repertoire of gastrointestinal side effects even at low doses and requires high frequent dosing because it undergoes extensive presystemic metabolism. Transdermal delivery offers an alternative route that bypasses the gut and may be more convenient and safer for aspirin delivery especially during long-term use. This study comprised formulation of aspirin in different topical bases. Release studies revealed that hydrocarbon gel allowed highest drug release. In vitro permeation studies revealed high drug permeation from hydrocarbon gel. Several chemical penetration enhancers were monitored for augmenting the permeation from this base. Combination of propylene glycol and alcohol showed maximum enhancing effect and, hence, was selected for biological investigation. The biological performance of the selected formulation was assessed by measuring the inhibition of platelet aggregation relevant to different dosage regimens aiming to minimize both drug dose and frequency of application. The results demonstrated the feasibility of successfully influencing platelet function and revealed that the drug therapeutic efficacy in transdermal delivery system is dose independent. Biological performance was re-assessed after storage and the results revealed stability and persistent therapeutic efficacy.

Understanding chronic neutropenia: life is short.

PubMed

Bartels, Marije; Murphy, Kate; Rieter, Ester; Bruin, Marrie

2016-01-01

The pathophysiological mechanisms underlying chronic neutropenia are extensive, varying from haematopoietic stem cell disorders resulting in defective neutrophil production, to accelerated apoptosis of neutrophil progenitors or circulating mature neutrophils. While the knowledge concerning genetic defects associated with congenital neutropenia or bone marrow failure is increasing rapidly, the functional role and consequences of these genetic alterations is often not well understood. In addition, there is a large group of diseases, including primary immunodeficiencies and metabolic diseases, in which chronic neutropenia is one of the symptoms, while there is no clear bone marrow pathology or haematopoietic stem cell dysfunction. Altogether, these disease entities illustrate the complexity of normal neutrophil development, the functional role of the (bone marrow) microenvironment and the increased propensity to undergo apoptosis, which is typical for neutrophils. The large variety of disorders associated with chronic neutropenia makes classification almost impossible and possibly not desirable, based on the clinical phenotypes. However, a better understanding of the regulation of normal myeloid differentiation and neutrophil development is of great importance in the diagnostic evaluation of unexplained chronic neutropenia. In this review we propose insights in the pathophysiology of chronic neutropenia in the context of the functional role of key players during normal neutrophil development, neutrophil release and neutrophil survival. © 2015 John Wiley & Sons Ltd.

Carboxypeptidase-mediated metabolism of calcitonin gene-related peptide in human gingival crevicular fluid--a rôle in periodontal inflammation?

PubMed

Lundy, F T; Salmon, A L; Lamey, P J; Shaw, C; Linden, G J

2000-07-01

Metabolism by peptidases plays an important rôle in modulating the levels of biologically-active neuropeptides. The metabolism of the anti-inflammatory neuropeptide calcitonin gene-related peptide (GCRP), but not the pro-inflammatory neuropeptides substance P (SP) and neurokinin A (NKA) by components of the gingival crevicular fluid (GCF), could potentiate the inflammatory process in periodontitis. To characterise the extracellular hydrolysis of CGRP as a mechanism for the selective inactivation of this neuropeptide in GCF from periodontitis sites. Samples of GCF from periodontitis patients and periodontally-healthy subjects were incubated with synthetic human SP, NKA or CGRP. Reaction between the GCF constituents and synthetic peptides was allowed to progress from 0-180 min. Results of neuropeptide metabolism at each time were analysed by matrix-assisted laser desorption/ionisation mass spectrometry. There was no evidence of metabolism of SP, NKA or CGRP by constituents of healthy GCF. Metabolism of synthetic SP and NKA was minimal even after extensive incubation with periodontitis GCF. However, loss of carboxy-terminal amino acids was evident after only 1 min incubation with periodontitis GCF. The pattern of CGRP metabolism, which proceeded from the C-terminus, indicated that the neuropeptide was degraded by a carboxypeptidase. After 180 min, there was extensive carboxypeptidase degradation of CGRP to an 11 amino acid peptide. It is concluded that carboxypeptidase activity in GCF from periodontitis patients is responsible for rapid breakdown of CGRP but not SP or NKA. The rapid action of this carboxypeptidase on the anti-inflammatory neuropeptide CGRP is suggestive of a pathophysiological rôle for the enzyme in selectively degrading CGRP, thereby potentiating periodontal inflammation.

Children With Serious Illness: Behavioral Correlates of Separation and Isolation.

ERIC Educational Resources Information Center

Hollenbeck, A. R.; And Others

The deleterious effects of separation and deprivation using children who were undergoing chemotherapy for childhood cancer was investigated. Extensive observational and physiological records were obtained on four children under five years of age during six weeks of treatment in a protected environment. In general, findings parallel those reported…

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2010-03-30

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2012-03-01

..., exp. 9/30/2012)--Extension-- Office on Smoking and Health, National Center for Chronic Disease... substitute for cigarette smoking. Adolescents who use smokeless tobacco are more likely to become cigarette smokers. The Centers for Disease Control and Prevention (CDC), Office on Smoking and Health (OSH), has...

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Appetitive Pavlovian Goal-Tracking Memories Reconsolidate Only under Specific Conditions

ERIC Educational Resources Information Center

Reichelt, Amy C.; Lee, Jonathan L. C.

2013-01-01

Despite extensive evidence that appetitive memories undergo reconsolidation, two notable failures to observe reconsolidation have been reported: instrumental responding and goal-tracking. However, these studies do not provide conclusive evidence for a lack of memory reconsolidation due to the numerous boundary conditions that dictate whether a…

Solar chemistry of metal complexes

NASA Astrophysics Data System (ADS)

Gray, H. B.; Maverick, A. W.

1981-12-01

Electronic excited states of certain transition metal complexes undergo oxidation-reduction reactions that store chemical energy. Such reactions have been extensively explored for mononuclear complexes. Two classes of polynuclear species exhibit similar properties, and these complexes are now being studied as possible homogeneous sensitizer-catalysts for hydrogen production from aqueous solutions.

What Presidents Need To Know about the Impact of Networking.

ERIC Educational Resources Information Center

Leadership Abstracts, 1993

1993-01-01

Many colleges and universities are undergoing cultural changes as a result of extensive voice, data, and video networking. Local area networks link large portions of most campuses, and national networks have evolved from specialized services for researchers in computer-related disciplines to general utilities on many campuses. Campuswide systems…

76 FR 28787 - Agency Forms Undergoing Paperwork Reduction Act Review

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2011-05-18

.... Proposed Project Respiratory Protective Devices--42 CFR part 84--Regulation 0920- 0109- Extension--National...). Background and Brief Description This data collection was formerly named Respiratory Protective Devices 30... respiratory protective devices is found in the Mine Safety and Health Amendments Act of 1977 (30 U.S.C. 577a...

Investigation of the Enzymes Involved in Lantibiotic Biosynthesis: Lacticin 481 and Haloduracin

ERIC Educational Resources Information Center

Ihnken, Leigh Anne Furgerson

2009-01-01

Lantibiotics are cyclic peptides that exhibit a range of biological properties, including antimicrobial activity. They are ribosomally-synthesized as linear precursor peptides that consist of two regions, an N-terminal leader peptide and a C-terminal propeptide (or structural) region. The structural region undergoes extensive enzyme-catalyzed…

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2013-05-29

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Metabolic Studies in Military Nutrition.

DTIC Science & Technology

1977-05-01

The Surgeon General’s Office over a period of years has undertaken an extensive research program into the chemistry, nutrition , and wholesomeness of...Research and Nutrition Laboratory has undertaken the studies of the wholesomeness of food preserved by ionizing radiation. Work on radiated food has been...physiological, metabolic, and nutritional research in normal young adult men has been going on making use of volunteer human test subjects.

Comprehensive analysis of a Metabolic Model for lipid production in Rhodosporidium toruloides.

PubMed

Castañeda, María Teresita; Nuñez, Sebastián; Garelli, Fabricio; Voget, Claudio; Battista, Hernán De

2018-05-19

The yeast Rhodosporidium toruloides has been extensively studied for its application in biolipid production. The knowledge of its metabolism capabilities and the application of constraint-based flux analysis methodology provide useful information for process prediction and optimization. The accuracy of the resulting predictions is highly dependent on metabolic models. A metabolic reconstruction for R. toruloides metabolism has been recently published. On the basis of this model, we developed a curated version that unblocks the central nitrogen metabolism and, in addition, completes charge and mass balances in some reactions neglected in the former model. Then, a comprehensive analysis of network capability was performed with the curated model and compared with the published metabolic reconstruction. The flux distribution obtained by lipid optimization with Flux Balance Analysis was able to replicate the internal biochemical changes that lead to lipogenesis in oleaginous microorganisms. These results motivate the development of a genome-scale model for complete elucidation of R. toruloides metabolism. Copyright © 2018 Elsevier B.V. All rights reserved.

Brain–computer interfaces: communication and restoration of movement in paralysis

PubMed Central

Birbaumer, Niels; Cohen, Leonardo G

2007-01-01

The review describes the status of brain–computer or brain–machine interface research. We focus on non-invasive brain–computer interfaces (BCIs) and their clinical utility for direct brain communication in paralysis and motor restoration in stroke. A large gap between the promises of invasive animal and human BCI preparations and the clinical reality characterizes the literature: while intact monkeys learn to execute more or less complex upper limb movements with spike patterns from motor brain regions alone without concomitant peripheral motor activity usually after extensive training, clinical applications in human diseases such as amyotrophic lateral sclerosis and paralysis from stroke or spinal cord lesions show only limited success, with the exception of verbal communication in paralysed and locked-in patients. BCIs based on electroencephalographic potentials or oscillations are ready to undergo large clinical studies and commercial production as an adjunct or a major assisted communication device for paralysed and locked-in patients. However, attempts to train completely locked-in patients with BCI communication after entering the complete locked-in state with no remaining eye movement failed. We propose that a lack of contingencies between goal directed thoughts and intentions may be at the heart of this problem. Experiments with chronically curarized rats support our hypothesis; operant conditioning and voluntary control of autonomic physiological functions turned out to be impossible in this preparation. In addition to assisted communication, BCIs consisting of operant learning of EEG slow cortical potentials and sensorimotor rhythm were demonstrated to be successful in drug resistant focal epilepsy and attention deficit disorder. First studies of non-invasive BCIs using sensorimotor rhythm of the EEG and MEG in restoration of paralysed hand movements in chronic stroke and single cases of high spinal cord lesions show some promise, but need extensive evaluation in well-controlled experiments. Invasive BMIs based on neuronal spike patterns, local field potentials or electrocorticogram may constitute the strategy of choice in severe cases of stroke and spinal cord paralysis. Future directions of BCI research should include the regulation of brain metabolism and blood flow and electrical and magnetic stimulation of the human brain (invasive and non-invasive). A series of studies using BOLD response regulation with functional magnetic resonance imaging (fMRI) and near infrared spectroscopy demonstrated a tight correlation between voluntary changes in brain metabolism and behaviour. PMID:17234696

Major cardiac surgery induces an increase in sex steroids in prepubertal children.

PubMed

Heckmann, Matthias; d'Uscio, Claudia H; de Laffolie, Jan; Neuhaeuser, Christoph; Bödeker, Rolf-Hasso; Thul, Josef; Schranz, Dietmar; Frey, Brigitte M

2014-03-01

While the neuroprotective benefits of estrogen and progesterone in critical illness are well established, the data regarding the effects of androgens are conflicting. Surgical repair of congenital heart disease is associated with significant morbidity and mortality, but there are scant data regarding the postoperative metabolism of sex steroids in this setting. The objective of this prospective observational study was to compare the postoperative sex steroid patterns in pediatric patients undergoing major cardiac surgery (MCS) versus those undergoing less intensive non-cardiac surgery. Urinary excretion rates of estrogen, progesterone, and androgen metabolites (μg/mmol creatinine/m(2) body surface area) were determined in 24-h urine samples before and after surgery using gas chromatography-mass spectrometry in 29 children undergoing scheduled MCS and in 17 control children undergoing conventional non-cardiac surgery. Eight of the MCS patients had Down's syndrome. There were no significant differences in age, weight, or sex between the groups. Seven patients from the MCS group showed multi-organ dysfunction after surgery. Before surgery, the median concentrations of 17β-estradiol, pregnanediol, 5α-dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) were (control/MCS) 0.1/0.1 (NS), 12.4/11.3 (NS), 4.7/4.4 (NS), and 2.9/1.1 (p=0.02). Postoperatively, the median delta 17β-estradiol, delta pregnanediol, delta DHT, and delta DHEA were (control/MCS) 0.2/6.4 (p=0.0002), -3.2/23.4 (p=0.013), -0.6/3.7 (p=0.0004), and 0.5/4.2 (p=0.004). Postoperative changes did not differ according to sex. We conclude that MCS, but not less intensive non-cardiac surgery, induced a distinct postoperative increase in sex steroid levels. These findings suggest that sex steroids have a role in postoperative metabolism following MCS in prepubertal children. Copyright © 2013 Elsevier Ltd. All rights reserved.

Side-chain hydroxylation in the metabolism of 8-aminoquinoline antiparasitic agents.

PubMed

Idowu, O R; Peggins, J O; Brewer, T G

1995-01-01

Primaquine, 8-(4-amino-1-methylbutylamino)-6-methoxyquinoline, is an antimalarial 8-aminoquinoline derivative. Although it has been in use since 1952, its metabolism has not been clearly defined. This is due to the instability of the expected aminophenol metabolites and their amphoteric nature, which makes their isolation difficult. Recent studies on the metabolism of WR 238605, a new primaquine analog, has shown that these problems may be solved by extracting the metabolites in the presence of ethyl chloroformate. Subsequent identification of the ethoxycarbonyl derivatives of the metabolites has made it possible to define the in vitro metabolism of primaquine. The primary metabolic pathways of primaquine involved hydroxylation of the phenyl ring of the quinoline nucleus and C-hydroxylation of the 3'-position of the 8-aminoalkylamino side chain. Ring-hydroxylation of primaquine gives rise to 5-hydroxyprimaquine, which on demethylation produces 5-hydroxy-6-demethylprimaquine. Side-chain hydroxylation of primaquine gives rise to 3'-hydroxyprimaquine, which also undergoes O-demethylation to 3'-hydroxy-6-demethylprimaquine. 6-Demethylprimaquine, a putative metabolite of primaquine, also underwent metabolism involving 3'-hydroxylation of the side chain. WR 6026, 8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline, is an antileishmanial 8-aminoquinoline derivative. The in vitro metabolism of WR 6026 also results in the formation of side chain-oxygenated metabolites. The present results, together with previous observations on the metabolism of WR 238605 and closely related primaquine analog, suggest that side-chain oxygenation is an important metabolic pathway of antiparasitic 8-aminoquinoline compounds in general.

Gender differences in metabolic syndrome components among the Korean 66-year-old population with metabolic syndrome.

PubMed

Lee, Sangjin; Ko, Young; Kwak, Chanyeong; Yim, Eun-Shil

2016-01-23

Gender is thought to be an important factor in metabolic syndrome and its outcomes. Despite a number of studies that have demonstrated differences in metabolism and its components that are dependent on gender, limited information about gender differences on the characteristics of metabolic syndrome and its components is available regarding the Korean old adult population. This study aimed to identify gender differences in characteristics of the metabolic syndrome and other risk factors for cardiovascular disease. Secondary analysis of data from a nationwide cross-sectional survey for health examination at the time of transitioning from midlife to old age was performed. Multiple logistic regression models were used to estimate adjusted odds ratios and 95% confidence intervals for gender differences among the Korean 66-year-old population with metabolic syndrome. Gender differences in metabolic syndrome components that contributed to the diagnosis of metabolic syndrome were identified. In males, the most common component was high blood sugar levels (87.5%), followed by elevated triglyceride levels (83.5%) and high blood pressure (83.1%). In females, the most commonly identified component was elevated triglyceride levels (79.0%), followed by high blood sugar levels (78.6%) and high blood pressure (78.5%). Gender differences for other risk factors for cardiovascular disease, including family history, health habits, and body mass index were observed. Gender-specific public health policies and management strategies to prevent cardiovascular disease among the older adult population should be developed for Koreans undergoing the physiological transition to old age.

Incidence, nature, and etiology of metabolic alkalosis in dogs and cats.

PubMed

Ha, Y-S; Hopper, K; Epstein, S E

2013-01-01

The incidence and causes of metabolic alkalosis in dogs and cats have not been fully investigated. To describe the incidence, nature, and etiology of metabolic alkalosis in dogs and cats undergoing blood gas analysis at a veterinary teaching hospital. Dogs and cats at a veterinary medical teaching hospital. Acid-base and electrolyte results for dogs and cats measured during a 13-month period were retrospectively collected from a computer database. Only the first measured (venous or arterial) blood gas analyzed in a single hospitalization period was included. Animals with a base excess above the reference range for the species were included. A total of 1,805 dogs and cats were included. Of these, 349 (19%) were identified as having an increased standardized base excess, 319 dogs and 30 cats. The mixed acid-base disorder of metabolic alkalosis with respiratory acidosis was the most common abnormality identified in both dogs and cats. Hypokalemia and hypochloremia were more common in animals with metabolic alkalosis compared to animals without metabolic alkalosis. The 4 most commonly identified underlying diseases were respiratory disease, gastrointestinal tract obstruction, furosemide administration, and renal disease. Metabolic alkalosis was less common than metabolic acidosis in the same population of animals. Evidence of contraction alkalosis was present in many patients in this study. Hypokalemia and hypochloremia were more frequent in patients with metabolic alkalosis and suggest the importance of evaluation of acid-base status in conjunction with serum electrolyte concentrations. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Biological and nonbiological modifications of carbamates

PubMed Central

Knaak, James B.

1971-01-01

Methylcarbamate insecticides undergo hydrolysis, oxidation, dealkylation, and conjugation in animals, plants, and insects to form similar or identical products. Carbaryl is hydroxylated in biological systems to form hydroxy, dihydro-dihydroxy, and N-hydroxymethyl carbaryl and is hydrolysed to form 1-naphthol. The products are conjugated, stored, or excreted. Carbofuran is hydroxylated at the 3 position and propoxur at the 5 position to form hydroxylated derivatives. N-hydroxymethyl derivatives of these two carbamates may also be formed. Hydrolysis appears to be the major metabolic pathway of carbofuran in the animal. Aldicarb is oxidized to its sulfoxide and then hydrolysed to the oxime sulfoxide in animals and plants. Plants hydrolyse the oxime sulfoxide to form the corresponding aldehyde, which is an intermediate in the formation of 2-methyl-2-(methyl-sulfinyl)propanol. Methomyl, which is structurally similar to aldicarb, is metabolized in plants to acetonitrile, carbon dioxide, and methylamine. Bux and Meobal undergo hydrolysis and hydroxylation to form N-hydroxy methylcarbamates, as well as hydroxybutylphenyl and hydroxymethylphenyl methylcarbamates. Zectran, which contains a dimethylamino group, is converted to the methylamino, amino, and methylformamido derivatives by insects and plants. In soil and water, methylcarbamate insecticides are hydrolysed to their respective phenols or oximes. PMID:4999481

Surprisal analysis characterizes the free energy time course of cancer cells undergoing epithelial-to-mesenchymal transition.

PubMed

Zadran, Sohila; Arumugam, Rameshkumar; Herschman, Harvey; Phelps, Michael E; Levine, R D

2014-09-09

The epithelial-to-mesenchymal transition (EMT) initiates the invasive and metastatic behavior of many epithelial cancers. Mechanisms underlying EMT are not fully known. Surprisal analysis of mRNA time course data from lung and pancreatic cancer cells stimulated to undergo TGF-β1-induced EMT identifies two phenotypes. Examination of the time course for these phenotypes reveals that EMT reprogramming is a multistep process characterized by initiation, maturation, and stabilization stages that correlate with changes in cell metabolism. Surprisal analysis characterizes the free energy time course of the expression levels throughout the transition in terms of two state variables. The landscape of the free energy changes during the EMT for the lung cancer cells shows a stable intermediate state. Existing data suggest this is the previously proposed maturation stage. Using a single-cell ATP assay, we demonstrate that the TGF-β1-induced EMT for lung cancer cells, particularly during the maturation stage, coincides with a metabolic shift resulting in increased cytosolic ATP levels. Surprisal analysis also characterizes the absolute expression levels of the mRNAs and thereby examines the homeostasis of the transcription system during EMT.

[Metabolic therapy with iodine 131 in patients with chronic renal failure. Clinical case].

PubMed

Vázquez-Rodríguez Barbero, Inmaculada; Espadas-Maeso, María José; Muñoz-Morales, Ana; Flores-Gómez, Pilar; Serrano-Carretero, María Belén; Castedo-Sal, Juan José; Sánchez Rey-Castro, Elena; Zamorano-Córdoba, Antonio

2015-01-01

62 year-old male with CKD stage 5 in dialysis program since 2012 who underwent surgery for papillary thyroid carcinoma with lymph node metastasis. Subsequently, the patient was admitted to the Unit of Metabolic Therapy at his reference hospital, where he is administered 80 millicuries of iodine-131 as a treatment associated with the surgery, unable to have his conventional dialysis, nursing interventions required in various stages of implementation of the continuous extrarenal clearance techniques (TCDE) were performed. The following care values were addressed targeted to patients undergoing treatment with I(131): specific equipment, personal protective measures and major diagnoses and nursing interventions. TCDE, despite being attributed to very critical patients, they can be extrapolated to other patients in a given time. TCDE allowed these patients to undergo dialysis in a safe environment for staff, ensuring proper disposal of contaminated liquids. TCDE were an effective treatment for the removal of I131, a single ssesion being necessary to normalize the levels of radioactivity. Coordination between services allewed ensure proper and effective treatment for the patient. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Changes in the Golgi Apparatus of Neocortical and Hippocampal Neurons in the Hibernating Hamster.

PubMed

Antón-Fernández, Alejandro; León-Espinosa, Gonzalo; DeFelipe, Javier; Muñoz, Alberto

2015-01-01

Hibernating animals have been used as models to study several aspects of the plastic changes that occur in the metabolism and physiology of neurons. These models are also of interest in the study of Alzheimer's disease because the microtubule-associated protein tau is hyperphosphorylated during the hibernation state known as torpor, similar to the pretangle stage of Alzheimer's disease. Hibernating animals undergo torpor periods with drops in body temperature and metabolic rate, and a virtual cessation of neural activity. These processes are accompanied by morphological and neurochemical changes in neurons, which reverse a few hours after coming out of the torpor state. Since tau has been implicated in the structural regulation of the neuronal Golgi apparatus (GA) we have used Western Blot and immunocytochemistry to analyze whether the GA is modified in cortical neurons of the Syrian hamster at different hibernation stages. The results show that, during the hibernation cycle, the GA undergo important structural changes along with differential modifications in expression levels and distribution patterns of Golgi structural proteins. These changes were accompanied by significant transitory reductions in the volume and surface area of the GA elements during torpor and arousal stages as compared with euthermic animals.

Changes in the Golgi Apparatus of Neocortical and Hippocampal Neurons in the Hibernating Hamster

PubMed Central

Antón-Fernández, Alejandro; León-Espinosa, Gonzalo; DeFelipe, Javier; Muñoz, Alberto

2015-01-01

Hibernating animals have been used as models to study several aspects of the plastic changes that occur in the metabolism and physiology of neurons. These models are also of interest in the study of Alzheimer's disease because the microtubule-associated protein tau is hyperphosphorylated during the hibernation state known as torpor, similar to the pretangle stage of Alzheimer's disease. Hibernating animals undergo torpor periods with drops in body temperature and metabolic rate, and a virtual cessation of neural activity. These processes are accompanied by morphological and neurochemical changes in neurons, which reverse a few hours after coming out of the torpor state. Since tau has been implicated in the structural regulation of the neuronal Golgi apparatus (GA) we have used Western Blot and immunocytochemistry to analyze whether the GA is modified in cortical neurons of the Syrian hamster at different hibernation stages. The results show that, during the hibernation cycle, the GA undergo important structural changes along with differential modifications in expression levels and distribution patterns of Golgi structural proteins. These changes were accompanied by significant transitory reductions in the volume and surface area of the GA elements during torpor and arousal stages as compared with euthermic animals. PMID:26696838

Structure and mechanisms of Escherichia coli aspartate transcarbamoylase.

PubMed

Lipscomb, William N; Kantrowitz, Evan R

2012-03-20

Enzymes catalyze a particular reaction in cells, but only a few control the rate of this reaction and the metabolic pathway that follows. One specific mechanism for such enzymatic control of a metabolic pathway involves molecular feedback, whereby a metabolite further down the pathway acts at a unique site on the control enzyme to alter its activity allosterically. This regulation may be positive or negative (or both), depending upon the particular system. Another method of enzymatic control involves the cooperative binding of the substrate, which allows a large change in enzyme activity to emanate from only a small change in substrate concentration. Allosteric regulation and homotropic cooperativity are often known to involve significant conformational changes in the structure of the protein. Escherichia coli aspartate transcarbamoylase (ATCase) is the textbook example of an enzyme that regulates a metabolic pathway, namely, pyrimidine nucleotide biosynthesis, by feedback control and by the cooperative binding of the substrate, L-aspartate. The catalytic and regulatory mechanisms of this enzyme have been extensively studied. A series of X-ray crystal structures of the enzyme in the presence and absence of substrates, products, and analogues have provided details, at the molecular level, of the conformational changes that the enzyme undergoes as it shifts between its low-activity, low-affinity form (T state) to its high-activity, high-affinity form (R state). These structural data provide insights into not only how this enzyme catalyzes the reaction between l-aspartate and carbamoyl phosphate to form N-carbamoyl-L-aspartate and inorganic phosphate, but also how the allosteric effectors modulate this activity. In this Account, we summarize studies on the structure of the enzyme and describe how these structural data provide insights into the catalytic and regulatory mechanisms of the enzyme. The ATCase-catalyzed reaction is regulated by nucleotide binding some 60 Å from the active site, inducing structural alterations that modulate catalytic activity. The delineation of the structure and function in this particular model system will help in understanding the molecular basis of cooperativity and allosteric regulation in other systems as well.

Identification of Three Novel Ring Expansion Metabolites of KAE609, a New Spiroindolone Agent for the Treatment of Malaria, in Rats, Dogs, and Humans.

PubMed

Huskey, Su-Er W; Zhu, Chun-qi; Lin, Melissa M; Forseth, Ry R; Gu, Helen; Simon, Oliver; Eggimann, Fabian K; Kittelmann, Matthias; Luneau, Alexandre; Vargas, Alexandra; Li, Hongmei; Wang, Lai; Einolf, Heidi J; Zhang, Jin; Favara, Sarah; He, Handan; Mangold, James B

2016-05-01

KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. After oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Among the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1,2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied; thus, further investigation was conducted using human recombinant cytochrome P450 enzymes. The ring expansion reaction was found to be primarily catalyzed by cytochrome P450 (CYP) 3A4 yielding M37. M37 was subsequently oxidized to M18 by CYP3A4 and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless, whereas M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

KSC-98pc1166

NASA Image and Video Library

1998-09-28

The orbiter Atlantis, being towed from the Shuttle Landing Facility toward the Vehicle Assembly Building (VAB) , intersects the morning sun's rays. In the background, to the right of the VAB, are the Orbiter Processing Facility 1 and 2. Atlantis spent 10 months in Palmdale, CA, undergoing extensive inspections and modifications in the orbiter processing facility there. The modifications included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. Atlantis will undergo preparations at KSC in Orbiter Processing Facility 2 for its planned flight in June 1999

Outcomes in adult pectus excavatum patients undergoing Nuss repair

PubMed Central

Ewais, MennatAllah M; Chaparala, Shivani; Uhl, Rebecca

2018-01-01

Pectus excavatum (PEx) is one of the most common congenital chest wall deformities. Depending on the severity, presentation of PEx may range from minor cosmetic issues to disabling cardiopulmonary symptoms. The effect of PEx on adult patients has not been extensively studied. Symptoms may not occur until the patient ages, and they may worsen over the years. More recent publications have implied that PEx may have significant cardiopulmonary implications and repair is of medical benefit. Adults presenting for PEx repair can undergo a successful repair with a minimally invasive “Nuss” approach. Resolution of symptoms, improved quality of life, and satisfying results are reported. PMID:29430201

[Determination of resting energy expenditure in critically ill children experiencing mechanical ventilation].

PubMed

Dong, Hong-ba; Yang, Yan-wen; Wang, Ying; Hong, Li

2012-11-01

Energy metabolism of critically ill children has its own characteristics, especially for those undergoing mechanical ventilation. We tried to assess the energy expenditure status and evaluate the use of predictive equations in such children. Moreover, the characteristics of the energy metabolism among various situation were explored. Fifty critically ill children undergoing mechanical ventilation were selected in this study. Data produced during the 24 hours of mechanical ventilation were collected for computation of severity of illness. Resting energy expenditure (REE) was determined at 24 hours after mechanical ventilation (MREE). Predictive resting energy expenditure (PREE) was calculated for each subject using age-appropriate equations (Schofield-HTWT, White). The study was approved by the hospital medical ethics committee and obtained parental written informed consent. The pediatric risk of mortality score 3 (PRISM3) and pediatric critical illness score (PCIS) were (7 ± 3) and (82 ± 4), respectively. MREE, Schofield-HTWT equation PREE and White equation PREE were (404.80 ± 178.28), (462.82 ± 160.38) and (427.97 ± 152.30) kcal/d, respectively; 70% were hypometabolic and 10% were hypermetabolic. MREE and PREE which were calculated using Schofield-HTWT equation and White equation, both were higher than MREE (P = 0.029). Correlation analysis was performed between PRISM3 and PCIS with MREE. There were no statistically significant correlation (P > 0.05). The hypometabolic response is apparent in critically ill children with mechanical ventilation; Schofield-HTWT equation and White equation could not predict energy requirements within acceptable clinical accuracy. In critically ill children undergoing mechanical ventilation, the energy expenditure is not correlated with the severity of illness.

Bioanalytical methods for determination of tamoxifen and its phase I metabolites: a review.

PubMed

Teunissen, S F; Rosing, H; Schinkel, A H; Schellens, J H M; Beijnen, J H

2010-12-17

The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL(-1) range. Although tamoxifen is also metabolized into phase II metabolites, the number of publications reporting on phase II metabolism of tamoxifen is scarce. Therefore the focus of this review is on phase I metabolites of tamoxifen. We conclude that in the past decades tamoxifen metabolism has been studied extensively and numerous metabolites have been identified. Assays have been developed for both the identification and quantification of tamoxifen and its metabolites in an array of biological samples. This review can be used as a resource for method transfer and development of analytical methods used to support pharmacokinetic and pharmacodynamic studies of tamoxifen and its phase I metabolites. Copyright © 2010 Elsevier B.V. All rights reserved.

Studies on the fate of flocoumafen in the Japanese quail (Coturnix coturnix japonica).

PubMed

Huckle, K R; Warburton, P A; Forbes, S; Logan, C J

1989-01-01

1. 14C-Flocoumafen, administered to Japanese quail as a single oral or i.p. dose, was rapidly and extensively eliminated in excreta; most was eliminated within 24 h. Extensive metabolism of the rodenticide was seen, with at least 8 metabolites detected; unchanged flocoumafen comprised 9% dose. The elimination kinetics and metabolic profiles were qualitatively similar after oral and i.p. dosing. 2. The major metabolites (60% dose) were labile to beta-glucuronidase, liberating aglycones with identical chromatographic mobilities to those of the unchanged flocoumafen isomers. 3. Radioactivity was retained mostly in the liver; largely as unchanged flocoumafen associated with the mitochondrial and microsomal fractions. Elimination of radioactivity from most tissues was biphasic with an initially rapid depletion (5 days) followed by a slow terminal elimination phase. The elimination half life from liver was greater than 100 days. 4. Livers of quail receiving extended dietary exposure to flocoumafen at 5, 15 and 50 ppm had concentrations of flocoumafen (1.0 nmol/g) that were independent of dose, indicating a capacity-limited binding site. These hepatic concentrations were similar to those after a single oral dose and were also similar to those in rats. The data indicate the presence in quail liver of a saturable high affinity flocoumafin binding site with similar characteristics and capacity to that in the rat. 5. The selective toxicity of flocoumafen to rats (highly toxic) and quail (moderately toxic) appears to arise from differences in metabolism rather than from anticoagulant binding in the liver. When hepatic binding sites of rats are saturated anticoagulant action becomes lethal, whereas quail are able to survive and extensively metabolize the compound.

Profound metabolic acidosis and oxoprolinuria in an adult.

PubMed

Hodgman, Michael J; Horn, James F; Stork, Christine M; Marraffa, Jeanna M; Holland, Michael G; Cantor, Richard; Carmel, Patti M

2007-09-01

Profound metabolic acidosis in critically ill adults sometimes remains unexplained despite extensive evaluation. A 58-year-old female presented in a confused state to the emergency department; she had been confused for several days. Laboratory evaluation revealed a high anion gap metabolic acidosis and modestly elevated acetaminophen level. Lactic acid was only modestly elevated. There was no evidence of ketoacids, salicylate, methanol, or ethylene glycol. A urine sample submitted on day 1 of hospitalization revealed a markedly elevated level of 5-oxoproline. Originally described in children with an inherited defect of glutathione synthetase, 5-oxoproline is an unusual cause of metabolic acidosis. More recently this disturbance has been recognized in critically ill adults without a recognized inherited metabolic disorder. In most of these cases there has been the concomitant use of acetaminophen. Any causal relationship between acetaminophen and this disturbance is speculative. In critically ill adults with unexplained metabolic acidosis, 5-Oxoproline should be considered in the differential.

Ceftizoxime use in trauma celiotomy: pharmacokinetics and patient outcomes.

PubMed

Rosemurgy, A S; Dillon, K R; Kurto, H A; Albrink, M H

1995-11-01

Seriously injured patients undergo vigorous resuscitation upon arrival at the emergency department and through the immediate perioperative period. Although resuscitation leads to volume loading and fluid shifts, drug dosing and dosing intervals are often not altered to account for changes in total body volume or circulatory volume. To address this, a prospective study of pharmacokinetics of ceftizoxime in 53 injured adults who underwent emergency celiotomy was conducted. Further, the relationship between serum ceftizoxime concentrations and infectious outcomes was evaluated. Per protocol, injured adults undergoing emergency celiotomy received prophylactic ceftizoxime treatment according to standard dosing regimens. Of the patients, 6 (11.5%) experienced postoperative infections and had lower peak serum ceftizoxime levels in the recovery room than patients not experiencing infection. For severely injured adults with extensive blood loss or undergoing lengthy operations requiring rigorous volume resuscitation, doses of ceftizoxime, and indeed all antibiotics, may need to be increased beyond conventional standards to minimize infectious complications.

Metabolism of arginine by aging and 7 day old pumpkin seedlings.

PubMed

Splittstoesser, W E

1969-03-01

The metabolism of arginine by etiolated pumpkin (Cucurbita moschata) seedlings was studied over various time and age intervals by injecting arginine-U-(14)C into the cotyledons. At most, 25% of the (14)C was transported from the cotyledon to the axis tissue and the amount of this transport decreased with increasing age of the seedlings. The cotyledons of 25 day old plants contained 60% of the administered (14)C as unmetabolized arginine. Little (14)C was in sugars and it appeared that arginine was the primary translocation product. Time course studies showed that arginine was extensively metabolized and the labeling patterns suggest that different pathways were in operation in the axis and cotyledons. The amount of arginine incorporated into cotyledonary protein show that synthesis and turnover were occurring at rapid rate. Only 25% of the label incorporated into protein by 1.5 hr remained after 96 hr. The label in protein was stable in the axis tissue. By 96 hr 50% of the administered label occurred as (14)CO(2) and it appeared that arginine was metabolized, through glutamate, by the citrio acid cycle in the cotyledons. The experiments showed that an extensive conversion of arginine carbon into other amino acids did not occur.

Bidirectional reaction steps in metabolic networks: I. Modeling and simulation of carbon isotope labeling experiments.

PubMed

Wiechert, W; de Graaf, A A

1997-07-05

The extension of metabolite balancing with carbon labeling experiments, as described by Marx et al. (Biotechnol. Bioeng. 49: 11-29), results in a much more detailed stationary metabolic flux analysis. As opposed to basic metabolite flux balancing alone, this method enables both flux directions of bidirectional reaction steps to be quantitated. However, the mathematical treatment of carbon labeling systems is much more complicated, because it requires the solution of numerous balance equations that are bilinear with respect to fluxes and fractional labeling. In this study, a universal modeling framework is presented for describing the metabolite and carbon atom flux in a metabolic network. Bidirectional reaction steps are extensively treated and their impact on the system's labeling state is investigated. Various kinds of modeling assumptions, as usually made for metabolic fluxes, are expressed by linear constraint equations. A numerical algorithm for the solution of the resulting linear constrained set of nonlinear equations is developed. The numerical stability problems caused by large bidirectional fluxes are solved by a specially developed transformation method. Finally, the simulation of carbon labeling experiments is facilitated by a flexible software tool for network synthesis. An illustrative simulation study on flux identifiability from available flux and labeling measurements in the cyclic pentose phosphate pathway of a recombinant strain of Zymomonas mobilis concludes this contribution.

Progressive Inhibition by Water Deficit of Cell Wall Extensibility and Growth along the Elongation Zone of Maize Roots Is Related to Increased Lignin Metabolism and Progressive Stelar Accumulation of Wall Phenolics1

PubMed Central

Fan, Ling; Linker, Raphael; Gepstein, Shimon; Tanimoto, Eiichi; Yamamoto, Ryoichi; Neumann, Peter M.

2006-01-01

Water deficit caused by addition of polyethylene glycol 6000 at −0.5 MPa water potential to well-aerated nutrient solution for 48 h inhibited the elongation of maize (Zea mays) seedling primary roots. Segmental growth rates in the root elongation zone were maintained 0 to 3 mm behind the tip, but in comparison with well-watered control roots, progressive growth inhibition was initiated by water deficit as expanding cells crossed the region 3 to 9 mm behind the tip. The mechanical extensibility of the cell walls was also progressively inhibited. We investigated the possible involvement in root growth inhibition by water deficit of alterations in metabolism and accumulation of wall-linked phenolic substances. Water deficit increased expression in the root elongation zone of transcripts of two genes involved in lignin biosynthesis, cinnamoyl-CoA reductase 1 and 2, after only 1 h, i.e. before decreases in wall extensibility. Further increases in transcript expression and increased lignin staining were detected after 48 h. Progressive stress-induced increases in wall-linked phenolics at 3 to 6 and 6 to 9 mm behind the root tip were detected by comparing Fourier transform infrared spectra and UV-fluorescence images of isolated cell walls from water deficit and control roots. Increased UV fluorescence and lignin staining colocated to vascular tissues in the stele. Longitudinal bisection of the elongation zone resulted in inward curvature, suggesting that inner, stelar tissues were also rate limiting for root growth. We suggest that spatially localized changes in wall-phenolic metabolism are involved in the progressive inhibition of wall extensibility and root growth and may facilitate root acclimation to drying environments. PMID:16384904

Loss of Brain Aerobic Glycolysis in Normal Human Aging.

PubMed

Goyal, Manu S; Vlassenko, Andrei G; Blazey, Tyler M; Su, Yi; Couture, Lars E; Durbin, Tony J; Bateman, Randall J; Benzinger, Tammie L-S; Morris, John C; Raichle, Marcus E

2017-08-01

The normal aging human brain experiences global decreases in metabolism, but whether this affects the topography of brain metabolism is unknown. Here we describe PET-based measurements of brain glucose uptake, oxygen utilization, and blood flow in cognitively normal adults from 20 to 82 years of age. Age-related decreases in brain glucose uptake exceed that of oxygen use, resulting in loss of brain aerobic glycolysis (AG). Whereas the topographies of total brain glucose uptake, oxygen utilization, and blood flow remain largely stable with age, brain AG topography changes significantly. Brain regions with high AG in young adults show the greatest change, as do regions with prolonged developmental transcriptional features (i.e., neoteny). The normal aging human brain thus undergoes characteristic metabolic changes, largely driven by global loss and topographic changes in brain AG. Copyright © 2017 Elsevier Inc. All rights reserved.

Evolutionary interplay between sister cytochrome P450 genes shapes plasticity in plant metabolism.

PubMed

Liu, Zhenhua; Tavares, Raquel; Forsythe, Evan S; André, François; Lugan, Raphaël; Jonasson, Gabriella; Boutet-Mercey, Stéphanie; Tohge, Takayuki; Beilstein, Mark A; Werck-Reichhart, Danièle; Renault, Hugues

2016-10-07

Expansion of the cytochrome P450 gene family is often proposed to have a critical role in the evolution of metabolic complexity, in particular in microorganisms, insects and plants. However, the molecular mechanisms underlying the evolution of this complexity are poorly understood. Here we describe the evolutionary history of a plant P450 retrogene, which emerged and underwent fixation in the common ancestor of Brassicales, before undergoing tandem duplication in the ancestor of Brassicaceae. Duplication leads first to gain of dual functions in one of the copies. Both sister genes are retained through subsequent speciation but eventually return to a single copy in two of three diverging lineages. In the lineage in which both copies are maintained, the ancestral functions are split between paralogs and a novel function arises in the copy under relaxed selection. Our work illustrates how retrotransposition and gene duplication can favour the emergence of novel metabolic functions.

Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke

PubMed Central

Rink, Cameron

2011-01-01

Abstract The significance of the hypoxia component of stroke injury is highlighted by hypermetabolic brain tissue enriched with arachidonic acid (AA), a 22:6n-3 polyunsaturated fatty acid. In an ischemic stroke environment in which cerebral blood flow is arrested, oxygen-starved brain tissue initiates the rapid cleavage of AA from the membrane phospholipid bilayer. Once free, AA undergoes both enzyme-independent and enzyme-mediated oxidative metabolism, resulting in the formation of number of biologically active metabolites which themselves contribute to pathological stroke outcomes. This review is intended to examine two divergent roles of molecular dioxygen in brain tissue as (1) a substrate for life-sustaining homeostatic metabolism of glucose and (2) a substrate for pathogenic metabolism of AA under conditions of stroke. Recent developments in research concerning supplemental oxygen therapy as an intervention to correct the hypoxic component of stroke injury are discussed. Antioxid. Redox Signal. 14, 1889–1903. PMID:20673202

Cerebral oxygen metabolism in neonatal hypoxic ischemic encephalopathy during and after therapeutic hypothermia

PubMed Central

Dehaes, Mathieu; Aggarwal, Alpna; Lin, Pei-Yi; Rosa Fortuno, C; Fenoglio, Angela; Roche-Labarbe, Nadège; Soul, Janet S; Franceschini, Maria Angela; Grant, P Ellen

2014-01-01

Pathophysiologic mechanisms involved in neonatal hypoxic ischemic encephalopathy (HIE) are associated with complex changes of blood flow and metabolism. Therapeutic hypothermia (TH) is effective in reducing the extent of brain injury, but it remains uncertain how TH affects cerebral blood flow (CBF) and metabolism. Ten neonates undergoing TH for HIE and seventeen healthy controls were recruited from the NICU and the well baby nursery, respectively. A combination of frequency domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) systems was used to non-invasively measure cerebral hemodynamic and metabolic variables at the bedside. Results showed that cerebral oxygen metabolism (CMRO2i) and CBF indices (CBFi) in neonates with HIE during TH were significantly lower than post-TH and age-matched control values. Also, cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) were significantly higher in neonates with HIE during TH compared with age-matched control neonates. Post-TH CBV was significantly decreased compared with values during TH whereas SO2 remained unchanged after the therapy. Thus, FDNIRS–DCS can provide information complimentary to SO2 and can assess individual cerebral metabolic responses to TH. Combined FDNIRS–DCS parameters improve the understanding of the underlying physiology and have the potential to serve as bedside biomarkers of treatment response and optimization. PMID:24064492

Metabolite damage and repair in metabolic engineering design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Jiayi; Jeffryes, James G.; Henry, Christopher S.

The necessarily sharp focus of metabolic engineering and metabolic synthetic biology on pathways and their fluxes has tended to divert attention from the damaging enzymatic and chemical side-reactions that pathway metabolites can undergo. Although historically overlooked and underappreciated, such metabolite damage reactions are now known to occur throughout metabolism and to generate (formerly enigmatic) peaks detected in metabolomics datasets. It is also now known that metabolite damage is often countered by dedicated repair enzymes that undo or prevent it. Metabolite damage and repair are highly relevant to engineered pathway design: metabolite damage reactions can reduce flux rates and product yields,more » and repair enzymes can provide robust, host-independent solutions. Herein, after introducing the core principles of metabolite damage and repair, we use case histories to document how damage and repair processes affect efficient operation of engineered pathways - particularly those that are heterologous, non-natural, or cell-free. We then review how metabolite damage reactions can be predicted, how repair reactions can be prospected, and how metabolite damage and repair can be built into genome-scale metabolic models. Lastly, we propose a versatile 'plug and play' set of well-characterized metabolite repair enzymes to solve metabolite damage problems known or likely to occur in metabolic engineering and synthetic biology projects.« less

Foreign compounds and intermediary metabolism: sulfoxidation bridges the divide.

PubMed

Mitchell, S C; Steventon, G B

2009-03-01

It is widely appreciated that as a xenobiotic travels through an organism and interacts with the biochemical machinery of a living system, it most probably will undergo a number of metabolic alterations usually leading to a cluster of differing chemical species. Indeed, the modern 'metabonomic' approach, where earlier studied drug metabolism profiles have been reassessed, has indicated that there are normally many more previously unrecognised minor metabolites, and when all such biotransformation products are considered, then their total number is legion. It is now being recognised also that the same metabolic alteration of a substrate, especially a xenobiotic substrate, may be catalysed by more than one enzyme and that the previously sacrosanct notion of an enzyme's 'substrate specificity' may well be inverted to read a substrate's 'enzyme preference'. The following brief article attempts to highlight another aspect where our general acceptance of the 'status quo' needs to be reconsidered. The conventionally acknowledged division between the collection of enzymes that undertake intermediary metabolism and the group of enzymes responsible for xenobiotic metabolism may be becoming blurred. It may well be a prudent time to reassess the current dichotomous view. Overcoming inertia, with a realignment of ideas or alteration of perception, may permit new concepts to emerge leading to a more profound understanding and hopefully eventual benefits for mankind.

Stabilization of LKB1 and Akt by neddylation regulates energy metabolism in liver cancer

PubMed Central

Barbier-Torres, Lucía; Delgado, Teresa C.; García-Rodríguez, Juan L.; Zubiete-Franco, Imanol; Fernández-Ramos, David; Buqué, Xabier; Cano, Ainara; Juan, Virginia Gutiérrez-de; Fernández-Domínguez, Itziar; Lopitz-Otsoa, Fernando; Fernández-Tussy, Pablo; Boix, Loreto; Bruix, Jordi; Villa, Erica; Castro, Azucena; Lu, Shelly C.; Aspichueta, Patricia; Xirodimas, Dimitris; Varela-Rey, Marta; Mato, José M.; Beraza, Naiara; Martínez-Chantar, María L.

2015-01-01

The current view of cancer progression highlights that cancer cells must undergo through a post-translational regulation and metabolic reprogramming to progress in an unfriendly environment. In here, the importance of neddylation modification in liver cancer was investigated. We found that hepatic neddylation was specifically enriched in liver cancer patients with bad prognosis. In addition, the treatment with the neddylation inhibitor MLN4924 in Phb1-KO mice, an animal model of hepatocellular carcinoma showing elevated neddylation, reverted the malignant phenotype. Tumor cell death in vivo translating into liver tumor regression was associated with augmented phosphatidylcholine synthesis by the PEMT pathway, known as a liver-specific tumor suppressor, and restored mitochondrial function and TCA cycle flux. Otherwise, in protumoral hepatocytes, neddylation inhibition resulted in metabolic reprogramming rendering a decrease in oxidative phosphorylation and concomitant tumor cell apoptosis. Moreover, Akt and LKB1, hallmarks of proliferative metabolism, were altered in liver cancer being new targets of neddylation. Importantly, we show that neddylation-induced metabolic reprogramming and apoptosis were dependent on LKB1 and Akt stabilization. Overall, our results implicate neddylation/signaling/metabolism, partly mediated by LKB1 and Akt, in the development of liver cancer, paving the way for novel therapeutic approaches targeting neddylation in hepatocellular carcinoma. PMID:25650664

Sequential anaerobic/aerobic biodegradation of chloroethenes--aspects of field application.

PubMed

Tiehm, Andreas; Schmidt, Kathrin R

2011-06-01

Because of a range of different industrial activities, sites contaminated with chloroethenes are a world-wide problem. Chloroethenes can be biodegraded by reductive dechlorination under anaerobic conditions as well as by oxidation under aerobic conditions. The tendency of chloroethenes to undergo reductive dechlorination decreases with a decreasing number of chlorine substituents, whereas with less chlorine substituents chloroethenes more easily undergo oxidative degradation. There is currently a growing interest in aerobic metabolic degradation of chloroethenes, which demonstrates advantages compared to cometabolic degradation pathways. Sequential anaerobic/aerobic biodegradation can overcome the disadvantages of reductive dechlorination and leads to complete mineralization of the chlorinated pollutants. This approach shows promise for site remediation in natural settings and in engineered systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

Probing Students' Ideas of the Principle of Equivalence

ERIC Educational Resources Information Center

Bandyopadhyay, Atanu; Kumar, Arvind

2011-01-01

The principle of equivalence was the first vital clue to Einstein in his extension of special relativity to general relativity, the modern theory of gravitation. In this paper we investigate in some detail students' understanding of this principle in a variety of contexts, when they are undergoing an introductory course on general relativity. The…

Integrated Functional and Executional Modelling of Software Using Web-Based Databases

NASA Technical Reports Server (NTRS)

Kulkarni, Deepak; Marietta, Roberta

1998-01-01

NASA's software subsystems undergo extensive modification and updates over the operational lifetimes. It is imperative that modified software should satisfy safety goals. This report discusses the difficulties encountered in doing so and discusses a solution based on integrated modelling of software, use of automatic information extraction tools, web technology and databases.

From SHAPE Signatures to 3-D Structures | Center for Cancer Research

Cancer.gov

RNAs undergo extensive folding to form sophisticated based-paired secondary structures that are, in part, indicators of more complex three-dimensional structures.  These 3-D shapes are an integral part of the cellular gene-expression machinery. Deconstructing these structures is no small matter, yet it is critical to understanding their function.

Teacher Education Reform and Challenges in Norway

ERIC Educational Resources Information Center

Munthe, Elaine; Malmo, Kari-Anne Svensen; Rogne, Magne

2011-01-01

Teacher education in Norway is nationally regulated and is currently undergoing extensive changes. This paper briefly outlines the various education routes for teachers and some of the ongoing work to improve teacher education, but concentrates mainly on the reform that has come the farthest: initial teacher education for grades 1-7 and grades…

Assessing and Cultivating Support for Strategic Planning: Searching for Best Practices in a Reform Environment

ERIC Educational Resources Information Center

Welsh, John F.; Nunez, William J.; Petrosko, Joseph

2006-01-01

This study examines the similarities and differences in faculty and administrator perspectives on strategic planning in Kentucky, a state in the United States undergoing extensive reform of its public, postsecondary system. The findings suggest that three variables are critical to faculty and administrative support for strategic planning…

77 FR 4982 - Notice of Request for Extension of Approval of an Information Collection; Treatments for Fruits...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-01

... approval of an information collection associated with regulations for the irradiation treatment of fruits... interstate from Hawaii, Puerto Rico, and the U.S. Virgin Islands must undergo irradiation treatment. Requirements for irradiation treatment of fruits and vegetables are contained in 7 CFR part 305...

Forest Vegetation Management: Developments in the Science and Practice

Treesearch

James H. Miller

2006-01-01

The practices of forest vegetation management (FVM) have been widely adopted and continue to undergo country-specific modifications through extensive research. Beginnings of this component discipline of silviculture were in weed science in the 1960s and focused primarily on translating developing herbicide technology underway in agriculture to forestry uses. It was an...

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.

Profiles in drug metabolism and toxicology: Richard Tecwyn Williams (1909-1979).

PubMed

Jones, Alan Wayne

2015-01-01

This article pays homage to the life and work of a veritable pioneer in toxicology and drug metabolism, namely a Welshman, Richard Tecwyn Williams, FRS. Professor Williams, or RT as he was known, made major contributions to knowledge about the metabolism and toxicology of drugs and xenobiotics during a scientific career spanning nearly 50 years. Author or coauthor of close to 400 research articles and reviews, including a classic book, entitled Detoxication Mechanisms, Williams and his research school investigated virtually all aspects of drug metabolism, especially conjugations. In particular, the concepts of phase 1 and phase II metabolic pathways were introduced by Williams; the biliary excretion of drugs was extensively studied as were species differences in drug metabolism and detoxication. Besides investigating the metabolism of many pharmaceutical drugs, such as sulfonamides and thalidomide, Williams and his group investigated the disposition and fate in the body of organic pesticides and recreational drugs of abuse, such as amphetamine, methamphetamine and lysergic acid diethylamide (LSD).

Fluorescence correlation spectroscopy to measure the metabolism of high-density lipoprotein

NASA Astrophysics Data System (ADS)

Deitrick, Russell; Gibson, Emily; Razzaghi, Hamid

2009-10-01

High-density lipoprotein (HDL), referred to as the ``good cholesterol'', carries free cholesterol to the liver to be filtered from the bloodstream and is important to our understanding of atherosclerosis. HDL is metabolized in part by the enzyme Endothelial Lipase (EL). With this project we will use fluorescence correlation spectroscopy (FCS) to study the metabolism of HDL by EL comparing wild type with different genetic mutations. FCS is an advanced microscopy technique in which we record fluctuations in the fluorescence of dye-labeled molecules (in this case, HDL labeled with Nile Red) as they freely diffuse through a small focal volume. This data can be analyzed mathematically using the cross-correlation function, from which we can ultimately ascertain much information. In our case, we are interested in the diffusion coefficient which, via the Stokes-Einstein relation for a sphere, we can determine the size of HDL as it undergoes the process of metabolism. Preliminary results seem to indicate that the metabolic process occurs very quickly, that the final size of HDL depends primarily on the concentration of EL, and that the wild and mutant variants of EL have a similar effectiveness. In following experiments, we hope to investigate these relationships further.

Trans-methylation reactions in plants: focus on the activated methyl cycle.

PubMed

Rahikainen, Moona; Alegre, Sara; Trotta, Andrea; Pascual, Jesús; Kangasjärvi, Saijaliisa

2018-02-01

Trans-methylation reactions are vital in basic metabolism, epigenetic regulation, RNA metabolism, and posttranslational control of protein function and therefore fundamental in determining the physiological processes in all living organisms. The plant kingdom is additionally characterized by the production of secondary metabolites that undergo specific hydroxylation, oxidation and methylation reactions to obtain a wide array of different chemical structures. Increasing research efforts have started to reveal the enzymatic pathways underlying the biosynthesis of complex metabolites in plants. Further engineering of these enzymatic machineries offers significant possibilities in the development of bio-based technologies, but necessitates deep understanding of their potential metabolic and regulatory interactions. Trans-methylation reactions are tightly coupled with the so-called activated methyl cycle (AMC), an essential metabolic circuit that maintains the trans-methylation capacity in all living cells. Tight regulation of the AMC is crucial in ensuring accurate trans-methylation reactions in different subcellular compartments, cell types, developmental stages and environmental conditions. This review addresses the organization and posttranslational regulation of the AMC and elaborates its critical role in determining metabolic regulation through modulation of methyl utilization in stress-exposed plants. © 2017 Scandinavian Plant Physiology Society.

Ischaemic memory imaging using metabolic radiopharmaceuticals: overview of clinical settings and ongoing investigations.

PubMed

Yoshinaga, Keiichiro; Naya, Masanao; Shiga, Tohru; Suzuki, Eriko; Tamaki, Nagara

2014-02-01

"Ischaemic memory" is defined as a prolonged functional and/or biochemical alteration remaining after a particular episode of severe myocardial ischaemia. The biochemical alteration has been reported as metabolic stunning. Metabolic imaging has been used to detect the footprint left by previous ischaemic episodes evident due to delayed recovery of myocardial metabolism (persistent dominant glucose utilization with suppression of fatty acid oxidation). β-Methyl-p-[(123)I]iodophenylpentadecanoic acid (BMIPP) is a single-photon emission computed tomography (SPECT) radiotracer widely used for metabolic imaging in clinical settings in Japan. In patients with suspected coronary artery disease but no previous myocardial infarction, BMIPP has shown acceptable diagnostic accuracy. In particular, BMIPP plays an important role in the identification of prior ischaemic insult in patients arriving at emergency departments with acute chest pain syndrome. Recent data also show the usefulness of (123)I-BMIPP SPECT for predicting cardiovascular events in patients undergoing haemodialysis. Similarly, SPECT or PET imaging with (18)F-FDG injected during peak exercise or after exercise under fasting conditions shows an increase in FDG uptake in postischaemic areas. This article will overview the roles of ischaemic memory imaging both under established indications and in ongoing investigations.

Clinical predictors of elective total joint replacement in persons with end-stage knee osteoarthritis.

PubMed

Zeni, Joseph A; Axe, Michael J; Snyder-Mackler, Lynn

2010-05-06

Arthritis is a leading cause of disability in the United States. Total knee arthroplasty (TKA) has become the gold standard to manage the pain and disability associated with knee osteoarthritis (OA). Although more than 400,000 primary TKA surgeries are performed each year in the United States, not all individuals with knee OA elect to undergo the procedure. No clear consensus exists on criteria to determine who should undergo TKA. The purpose of this study was to determine which clinical factors will predict the decision to undergo TKA in individuals with end-stage knee OA. Knowledge of these factors will aid in clinical decision making for the timing of TKA. Functional data from one hundred twenty persons with end-stage knee OA were obtained through a database. All of the individuals complained of knee pain during daily activities and had radiographic evidence of OA. Functional and clinical tests, collectively referred to as the Delaware Osteoarthritis Profile, were completed by a physical therapist. This profile consisted of measuring height, weight, quadriceps strength and active knee range of motion, while functional mobility was assessed using the Timed Up and Go (TUG) test and the Stair Climbing Task (SCT). Self-perceived functional ability was measured using the activities of daily living subscale of the Knee Outcome Survey (KOS-ADLS). A logistic regression model was used to identify variables predictive of TKA use. Forty subjects (33%) underwent TKA within two years of evaluation. These subjects were significantly older and had significantly slower TUG and SCT times (p < 0.05). Persons that underwent TKA were also significantly weaker, had lower self-reported function and had less knee extension than persons who did not undergo TKA. No differences between groups were seen for BMI, gender, knee flexion ROM and unilateral versus bilateral joint disease. Using backward regression, age, knee extension ROM and KOS-ADLS together significantly predicted whether or not a person would undergo TKA (p

Seasonality of submesoscale dynamics in the Kuroshio Extension

NASA Astrophysics Data System (ADS)

Rocha, Cesar B.; Gille, Sarah T.; Chereskin, Teresa K.; Menemenlis, Dimitris

2016-11-01

Recent studies show that the vigorous seasonal cycle of the mixed layer modulates upper ocean submesoscale turbulence. Here we provide model-based evidence that the seasonally changing upper ocean stratification in the Kuroshio Extension also modulates submesoscale (here 10-100 km) inertia-gravity waves. Summertime restratification weakens submesoscale turbulence but enhances inertia-gravity waves near the surface. Thus, submesoscale turbulence and inertia-gravity waves undergo vigorous out-of-phase seasonal cycles. These results imply a strong seasonal modulation of the accuracy of geostrophic velocity diagnosed from submesoscale sea surface height delivered by the Surface Water and Ocean Topography satellite mission.

Retinoid-xenobiotic interactions: the Ying and the Yang

PubMed Central

2015-01-01

The literature provides compelling evidence pointing to tight metabolic interactions between retinoids and xenobiotics. These are extensive and important for understanding xenobiotic actions in the body. Within the body, retinoids affect xenobiotic metabolism and actions and conversely, xenobiotics affect retinoid metabolism and actions. This article summarizes data that establish the importance of retinoid-dependent metabolic pathways for sustaining the body’s responses to xenobiotic exposure, including the roles of all-trans- and 9-cis-retinoic acid for protecting mammals from harmful xenobiotic effects and for ensuring xenobiotic elimination from the body. This review will also consider molecular mechanisms underlying xenobiotic toxicity focusing on how this may contribute to retinoid deficiency and disruption of normal retinoid homeostasis. Special attention is paid to xenobiotic molecular targets (nuclear receptors, regulatory proteins, enzymes, and transporters) which affect retinoid metabolism and signaling. PMID:26311625

Treatment of potato tubers with the synthetic cytokinin 1-(alpha-ethylbenzyl)-3-nitroguanidine results in rapid termination of endodormancy and induction of transcripts associated with cell proliferation and growth

USDA-ARS?s Scientific Manuscript database

Perennial plants undergo repression of meristematic activity in a process called dormancy. Dormancy is a complex metabolic process with implications for plant breeding and crop yield. Endodormancy, a specific subclass of dormancy, originates within tissue which is in a repressed state of growth and ...

Dairy food consumption and meal-induced cortisol response interact to influence weight loss in overweight women undergoing a 12-week meal-controlled weight loss intervention

USDA-ARS?s Scientific Manuscript database

Dairy foods enhance weight loss in animal models possibly by modifying the metabolic effects of cortisol. This study aimed to determine in overweight women (ages 20-45; n=51) whether inclusion of dairy foods in an energy-restricted diet affects basal and stimulated cortisol concentrations, and whet...

Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments

PubMed Central

Tefera, Tesfaye W.; Borges, Karin

2017-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease primarily characterized by loss of motor neurons in brain and spinal cord. The death of motor neurons leads to denervation of muscle which in turn causes muscle weakness and paralysis, decreased respiratory function and eventually death. Growing evidence indicates disturbances in energy metabolism in patients with ALS and animal models of ALS, which are likely to contribute to disease progression. Particularly, defects in glucose metabolism and mitochondrial dysfunction limit the availability of ATP to CNS tissues and muscle. Several metabolic approaches improving mitochondrial function have been investigated in vitro and in vivo and showed varying effects in ALS. The effects of metabolic approaches in ALS models encompass delays in onset of motor symptoms, protection of motor neurons and extension of survival, which signifies an important role of metabolism in the pathogenesis of the disease. There is now an urgent need to test metabolic approaches in controlled clinical trials. In addition, more detailed studies to better characterize the abnormalities in energy metabolism in patients with ALS and ALS models are necessary to develop metabolically targeted effective therapies that can slow the progression of the disease and prolong life for patients with ALS. PMID:28119559

Metabolism as an Integral Cog in the Mammalian Circadian Clockwork

PubMed Central

Gamble, Karen L.; Young, Martin E.

2013-01-01

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

Brivaracetam: a novel antiepileptic drug for focal-onset seizures.

PubMed

Stephen, Linda J; Brodie, Martin J

2018-01-01

Brivaracetam (BRV), the n -propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7-8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50-200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

Alterations in Hepatic Glucose and Energy Metabolism as a Result of Calorie and Carbohydrate Restriction

PubMed Central

Browning, Jeffrey D.; Weis, Brian; Davis, Jeannie; Satapati, Santhosh; Merritt, Matthew; Malloy, Craig R.; Burgess, Shawn C.

2009-01-01

Carbohydrate-restriction is a common weight-loss approach that modifies hepatic metabolism by increasing gluconeogenesis and ketosis. Because little is known regarding the effect of carbohydrate-restriction on the origin of gluconeogenic precursors (gluconeogenesis from glycerol (GNGglycerol) and lactate/amino acids (GNGPEP)) or its consequence to hepatic energy homeostasis, we studied these parameters in a group of overweight/obese subjects undergoing weight-loss via dietary restriction. We used 2H and 13C tracers and nuclear magnetic resonance spectroscopy to measure the sources of hepatic glucose and TCA cycle flux in weight-stable subjects(n=7) and subjects following carbohydrate-(n=7) or calorie-restriction(n=7). The majority of hepatic glucose production in carbohydrate-restricted subjects came from GNGPEP. The contribution of glycerol to gluconeogenesis was similar in all groups despite evidence of increased fat oxidation in carbohydrate-restricted subjects. A strong correlation between TCA cycle flux and GNGPEP was found, though the reliance on TCA cycle energy production for gluconeogenesis was attenuated in subjects undergoing carbohydrate restriction. Together, these data imply that the TCA cycle is the energetic patron of gluconeogenesis. However, the relationship between these two pathways is modified by carbohydrate restriction, suggesting an increased reliance of the hepatocyte on energy generated outside of the TCA cycle when GNGPEP is maximal. In conclusion, carbohydrate-restriction modifies hepatic gluconeogenesis by increasing reliance on substrates like lactate or amino acids but not glycerol. This modification is associated with a reorganization of hepatic energy metabolism suggestive of enhanced hepatic β-oxidation. PMID:18925642

LakeMetabolizer: An R package for estimating lake metabolism from free-water oxygen using diverse statistical models

USGS Publications Warehouse

Winslow, Luke; Zwart, Jacob A.; Batt, Ryan D.; Dugan, Hilary; Woolway, R. Iestyn; Corman, Jessica; Hanson, Paul C.; Read, Jordan S.

2016-01-01

Metabolism is a fundamental process in ecosystems that crosses multiple scales of organization from individual organisms to whole ecosystems. To improve sharing and reuse of published metabolism models, we developed LakeMetabolizer, an R package for estimating lake metabolism from in situ time series of dissolved oxygen, water temperature, and, optionally, additional environmental variables. LakeMetabolizer implements 5 different metabolism models with diverse statistical underpinnings: bookkeeping, ordinary least squares, maximum likelihood, Kalman filter, and Bayesian. Each of these 5 metabolism models can be combined with 1 of 7 models for computing the coefficient of gas exchange across the air–water interface (k). LakeMetabolizer also features a variety of supporting functions that compute conversions and implement calculations commonly applied to raw data prior to estimating metabolism (e.g., oxygen saturation and optical conversion models). These tools have been organized into an R package that contains example data, example use-cases, and function documentation. The release package version is available on the Comprehensive R Archive Network (CRAN), and the full open-source GPL-licensed code is freely available for examination and extension online. With this unified, open-source, and freely available package, we hope to improve access and facilitate the application of metabolism in studies and management of lentic ecosystems.

Advanced Stoichiometric Analysis of Metabolic Networks of Mammalian Systems

PubMed Central

Orman, Mehmet A.; Berthiaume, Francois; Androulakis, Ioannis P.; Ierapetritou, Marianthi G.

2013-01-01

Metabolic engineering tools have been widely applied to living organisms to gain a comprehensive understanding about cellular networks and to improve cellular properties. Metabolic flux analysis (MFA), flux balance analysis (FBA), and metabolic pathway analysis (MPA) are among the most popular tools in stoichiometric network analysis. Although application of these tools into well-known microbial systems is extensive in the literature, various barriers prevent them from being utilized in mammalian cells. Limited experimental data, complex regulatory mechanisms, and the requirement of more complex nutrient media are some major obstacles in mammalian cell systems. However, mammalian cells have been used to produce therapeutic proteins, to characterize disease states or related abnormal metabolic conditions, and to analyze the toxicological effects of some medicinally important drugs. Therefore, there is a growing need for extending metabolic engineering principles to mammalian cells in order to understand their underlying metabolic functions. In this review article, advanced metabolic engineering tools developed for stoichiometric analysis including MFA, FBA, and MPA are described. Applications of these tools in mammalian cells are discussed in detail, and the challenges and opportunities are highlighted. PMID:22196224

Predicting the Extension of Biomedical Ontologies

PubMed Central

Pesquita, Catia; Couto, Francisco M.

2012-01-01

Developing and extending a biomedical ontology is a very demanding task that can never be considered complete given our ever-evolving understanding of the life sciences. Extension in particular can benefit from the automation of some of its steps, thus releasing experts to focus on harder tasks. Here we present a strategy to support the automation of change capturing within ontology extension where the need for new concepts or relations is identified. Our strategy is based on predicting areas of an ontology that will undergo extension in a future version by applying supervised learning over features of previous ontology versions. We used the Gene Ontology as our test bed and obtained encouraging results with average f-measure reaching 0.79 for a subset of biological process terms. Our strategy was also able to outperform state of the art change capturing methods. In addition we have identified several issues concerning prediction of ontology evolution, and have delineated a general framework for ontology extension prediction. Our strategy can be applied to any biomedical ontology with versioning, to help focus either manual or semi-automated extension methods on areas of the ontology that need extension. PMID:23028267

Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders

PubMed Central

MacLeod, Erin L.; Hall, Kevin D.; McGuire, Peter J.

2015-01-01

SUMMARY Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection. PMID:26260782

Computational modeling to predict nitrogen balance during acute metabolic decompensation in patients with urea cycle disorders.

PubMed

MacLeod, Erin L; Hall, Kevin D; McGuire, Peter J

2016-01-01

Nutritional management of acute metabolic decompensation in amino acid inborn errors of metabolism (AA IEM) aims to restore nitrogen balance. While nutritional recommendations have been published, they have never been rigorously evaluated. Furthermore, despite these recommendations, there is a wide variation in the nutritional strategies employed amongst providers, particularly regarding the inclusion of parenteral lipids for protein-free caloric support. Since randomized clinical trials during acute metabolic decompensation are difficult and potentially dangerous, mathematical modeling of metabolism can serve as a surrogate for the preclinical evaluation of nutritional interventions aimed at restoring nitrogen balance during acute decompensation in AA IEM. A validated computational model of human macronutrient metabolism was adapted to predict nitrogen balance in response to various nutritional interventions in a simulated patient with a urea cycle disorder (UCD) during acute metabolic decompensation due to dietary non-adherence or infection. The nutritional interventions were constructed from published recommendations as well as clinical anecdotes. Overall, dextrose alone (DEX) was predicted to be better at restoring nitrogen balance and limiting nitrogen excretion during dietary non-adherence and infection scenarios, suggesting that the published recommended nutritional strategy involving dextrose and parenteral lipids (ISO) may be suboptimal. The implications for patients with AA IEM are that the medical course during acute metabolic decompensation may be influenced by the choice of protein-free caloric support. These results are also applicable to intensive care patients undergoing catabolism (postoperative phase or sepsis), where parenteral nutritional support aimed at restoring nitrogen balance may be more tailored regarding metabolic fuel selection.

Metabolism as a key to histone deacetylase inhibition

PubMed Central

Rajendran, Praveen; Williams, David E.; Ho, Emily; Dashwood, Roderick H.

2012-01-01

There is growing interest in the epigenetic mechanisms that are dysregulated in cancer and other human pathologies. Under this broad umbrella, modulators of histone deacetylase (HDAC) activity have gained interest as both cancer chemopreventive and therapeutic agents. Of the first generation, FDA-approved HDAC inhibitors to have progressed to clinical trials, vorinostat represents a “direct acting” compound with structural features suitable for docking into the HDAC pocket, whereas romidepsin can be considered a prodrug that undergoes reductive metabolism to generate the active intermediate (a zinc-binding thiol). It is now evident that other agents, including those in the human diet, can be converted by metabolism to intermediates that affect HDAC activity. Examples are cited of short-chain fatty acids, seleno-α-keto acids, small molecule thiols, mercapturic acid metabolites, indoles, and polyphenols. The findings are discussed in the context of putative endogenous HDAC inhibitors generated by intermediary metabolism (e.g. pyruvate), the yin–yang of HDAC inhibition versus HDAC activation, and the screening assays that might be most appropriate for discovery of novel HDAC inhibitors in the future. PMID:21599534

Metabolic reprogramming as a novel regulator of skeletal muscle development and regeneration.

PubMed

Ryall, James G

2013-09-01

Adult skeletal muscle contains a resident population of stem cells, termed satellite cells, that exist in a quiescent state. In response to an activating signal (such as physical trauma), satellite cells enter the cell cycle and undergo multiple rounds of proliferation, followed by differentiation, fusion, and maturation. Over the last 10-15 years, our understanding of the transcriptional regulation of this stem cell population has greatly expanded, but there remains a dearth of knowledge with regard to the initiating signal leading to these changes in transcription. The recent renewed interest in the metabolic regulation of both cancer and stem cells, combined with previous findings indicating that satellite cells preferentially colocalize with blood vessels, suggests that satellite cell function may be regulated by changes in cellular metabolism. This review aims to describe what is currently known about satellite cell metabolism during changes in cell fate, as well as to describe some of the exciting findings in other cell types and how these might relate to satellite cells. © 2013 The Author Journal compilation © 2013 FEBS.

Association of adiponectin/leptin ratio with carbohydrate and lipid metabolism parameters in HIV-infected patients during antiretroviral therapy.

PubMed

Tiliscan, Catalin; Arama, Victoria; Mihailescu, Raluca; Munteanu, Daniela; Iacob, Diana Gabriela; Popescu, Cristina; Catana, Remulus; Negru, Anca; Lobodan, Alina; Arama, Stefan Sorin

2018-02-16

Adiponectin and leptin are adipose tissue hormones that regulate important lipid and glucose metabolic pathways. Our objective was to evaluate the interplay of these hormones described by the adiponectin/leptin ratio (ALR) in correlation to lipid and carbohydrate metabolism parameters in nondiabetic HIV-infected patients during antiretroviral therapy (ART). We enrolled consecutive nondiabetic patients with confirmed HIV infection, undergoing stable ART regimens for at least six months. Blood samples were collected and tested for immunological and virological parameters, adiponectin and leptin, fasting insulin, fasting plasma glucose, fasting triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol. ALR was computed for each patient. Resistance to insulin was assessed by calculating the Quantitative Insulin Sensitivity Check Index (QUICKI). We enrolled 87 HIV-infected persons, with a mean age of 31.7 years (range: 18-65), including 47 men (mean age = 32.8 years) and 40 women (mean age = 30.5 years). The median value of ALR was 6.8 (interquartile range - IQR = 17.1). In male patients, ALR was inversely associated with the serum level of triglycerides (R = 0.285, p = 0.05), total cholesterol (R = 0.326, p = 0.02), and LDL cholesterol (R = 0.298, p = 0.04). Also for the male cohort, an increase in ALR seemed to improve insulin sensitivity (R = 0.323, p = 0.02) and serum HDL cholesterol (R = 0.597, p = 0.01). None of these correlations were observed in HIV-infected women. Adiponectin and leptin seem to play important but different gender-specific roles in the pathogenesis of lipid and glucose metabolism of HIV-infected patients undergoing antiretroviral therapy. ALR, adiponectin/leptin ratio; BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; QUICKI, Quantitative Insulin Sensitivity Check Index.

KSC-98pc1160

NASA Image and Video Library

1998-09-27

KENNEDY SPACE CENTER, FLA. -- The Shuttle Carrier Aircraft with orbiter Atlantis on top touches down at the Shuttle Landing Facility. Atlantis returns home after a 10-month stay in the Palmdale, CA, orbiter processing facility undergoing extensive inspections and modifications. They included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. The flight from Palmdale included a fueling stop in Ft. Hood, TX, and overnight stay at Ft. Campbell, KY. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

KSC-98pc1167

NASA Image and Video Library

1998-09-28

Seen from behind, the orbiter Atlantis approaches the entrance of Orbiter Processing Facility 2 (OPF-2) where it will undergo preparations for its planned flight in June 1999. Atlantis spent 10 months in Palmdale, CA, undergoing extensive inspections and modifications in the orbiter processing facility there. The modifications included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. OPF-2 consists of a 2,700-square-meter (29,000 square ft.) high bay. The building measures 29 meters (95 ft). high, 121 meters (397 ft.) long and 71 meters (233 ft.) wide

KSC-98pc1161

NASA Image and Video Library

1998-09-27

KENNEDY SPACE CENTER, FLA. -- The Shuttle Carrier Aircraft gently lands its piggyback cargo orbiter Atlantis at the Shuttle Landing Facility. Atlantis returns home after a 10-month stay in the Palmdale, CA, orbiter processing facility undergoing extensive inspections and modifications. They included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. The flight from Palmdale included a fueling stop in Ft. Hood, TX, and overnight stay at Ft. Campbell, KY. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

KSC-98pc1159

NASA Image and Video Library

1998-09-27

KENNEDY SPACE CENTER, FLA. -- The Shuttle Carrier Aircraft with orbiter Atlantis on top arrives at the Shuttle Landing Facility. Atlantis returns home after a 10-month stay in the Palmdale, CA, orbiter processing facility undergoing extensive inspections and modifications. They included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. The flight from Palmdale included a fueling stop in Ft. Hood, TX, and overnight stay at Ft. Campbell, KY. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

KSC-98pc1168

NASA Image and Video Library

1998-09-28

Seen from behind, the orbiter Atlantis moves into the Orbiter Processing Facility 2 (OPF-2) where it will undergo preparations for its planned flight in June 1999. Atlantis spent 10 months in Palmdale, CA, undergoing extensive inspections and modifications in the orbiter processing facility there. The modifications included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. OPF-2 consists of two 2,700-square-meter (29,000 square feet) high bays. It measures 29 meters (95 ft). high, 121 meters (397 ft) long and 71 meters (233 ft) wide

A polyphasic study on the taxonomic position of industrial sour dough yeasts.

PubMed

Mäntynen, V H; Korhola, M; Gudmundsson, H; Turakainen, H; Alfredsson, G A; Salovaara, H; Lindström, K

1999-02-01

The sour dough bread making process is extensively used to produce wholesome palatable rye bread. The process is traditionally done using a back-slopping procedure. Traditional sour doughs in Finland comprise of lactic acid bacteria and yeasts. The yeasts present in these doughs have been enriched in the doughs due to their metabolic activities, e.g. acid tolerance. We characterized the yeasts in five major sour bread bakeries in Finland. We found that most of the commercial sour doughs contained yeasts which were similar to Candida milleri on the basis of 18S rDNA and EF-3 PCR-RFLP patterns and metabolic activities. Some of the bakery yeasts exhibited extensive karyotype polymorphism. The minimum growth temperature was 8 degrees C for C. milleri and also for most of sour dough yeasts.

Kinetic and Mechanistic Studies of the Deuterium Exchange in Classical Keto-Enol Tautomeric Equilibrium Reactions

ERIC Educational Resources Information Center

Nichols, Michael A.; Waner, Mark J.

2010-01-01

An extension of the classic keto-enol tautomerization of beta-dicarbonyl compounds into a kinetic analysis of deuterium exchange is presented. It is shown that acetylacetone and ethyl acetoacetate undergo nearly complete deuterium exchange of the alpha-methylene carbon when dissolved in methanol-d[subscript 4]. The extent of deuteration may be…

78 FR 78838 - Grant of Interim Extension of the Term of U.S. Patent No. 5,496,801; Recombinant Human...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-27

... Hormone AGENCY: United States Patent and Trademark Office, Commerce. ACTION: Notice of interim patent term... No. 5,496,801. The patent claims the human biological product recombinant human parathyroid hormone... human parathyroid hormone, was filed on October 24, 2013, and is currently undergoing regulatory review...

The origin of large local uplift in extensional regions

USGS Publications Warehouse

King, G.; Ellis, M.

1990-01-01

Large localized uplift is commonly observed in continental regions undergoing extension. These observations can be modelled by planar, high-angle normal faulting of an elastic upper crust overlying an inviscid lower crust. Isostasy provides the necessary driving force. The model quantifies the role of flexural rigidity, density variations in the crust, and erosion and deposition of sediment.

Older Age Confers a Higher Risk of 30-Day Morbidity and Mortality Following Laparoscopic Bariatric Surgery: an Analysis of the Metabolic and Bariatric Surgery Quality Improvement Program.

PubMed

Haskins, Ivy N; Ju, Tammy; Whitlock, Ashlyn E; Rivas, Lisbi; Amdur, Richard L; Lin, Paul P; Vaziri, Khashayar

2018-04-17

There is a paucity of literature describing the association of age with the risk of adverse events following bariatric surgery. The purpose of this study is to investigate the association of age with 30-day morbidity and mortality following laparoscopic bariatric surgery using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. All adult patients undergoing laparoscopic Roux-en-Y gastric bypass (RNGYB) or sleeve gastrectomy (SG) were identified within the MBSAQIP database. Patients were divided into five equal age quintiles. Binary outcomes of interest, including cardiac, pulmonary, wound, septic, clotting, and renal events, in addition to the incidence of related 30-day unplanned reintervention, related 30-day mortality, and a composite morbidity and mortality outcome were compared across the age quintiles and procedures. A total of 266,544 patients met inclusion criteria. Older age was associated with an increased risk of all morbidity outcomes except venous thromboembolism events, 30-day mortality, and the composite morbidity and mortality outcome. Patients who underwent Roux-en-Y gastric bypass had worse outcomes per quintile for almost every outcome of interest when compared to patients who underwent sleeve gastrectomy. Older patients and patients who undergo Roux-en-Y gastric bypass are at an increased risk of perioperative morbidity and mortality following laparoscopic bariatric surgery. Additional studies are needed to determine the association of age with long-term weight loss and cardiometabolic comorbidity resolution following bariatric surgery in order to determine if the increased perioperative risk is offset by improved long-term outcomes in older patients undergoing bariatric surgery.

Effect of preoperative consumption of high carbohydrate drink (Pre-Op) on postoperative metabolic stress reaction in patients undergoing radical prostatectomy.

PubMed

Canbay, Özgür; Adar, Serdar; Karagöz, Ayşe Heves; Çelebi, Nalan; Bilen, Cenk Yücel

2014-07-01

To investigate the effects of oral carbohydrate solution consumed until 2 h before the surgery in the patients that would undergo open radical retropubic prostatectomy on postoperative metabolic stress, patient anxiety, and comfort. A total of 50 adult patients, who were in ASA I-II group and would undergo open radical retropubic prostatectomy, were included in the study. While Group 1 = CH (n = 25) received oral glucose solution, Group 2 = FAM (n = 25) was famished starting from 24:00 h. Blood glucose, insulin, and procalcitonin levels of the patients were recorded, and the patients completed state-trait anxiety inventory (STAI) test, which reflects the anxiety level of the patients, both before surgery and on the postoperative 24th hour. In order to evaluate patient comfort, senses of hunger, thirst, nausea, and cold were assessed in the morning prior to the surgery. No difference was observed between the two groups in terms of demographic data and insulin resistance levels (p > 0.05). Comparing with the preoperative levels, insulin resistance showed statistically significant elevation in both groups (p < 0.05). Procalcitonin levels were similarly increased in both groups in the postoperative period (p < 0.05). Preoperative and postoperative STAI state scores were similar in both groups (p > 0.05). With regard to preoperative patient comfort, sense of hunger was present in lesser number of subjects and at lower level in Group 1 (p < 0.05). Preoperative consumption of high carbohydrate drink (Pre-op) decreases insulin resistance and enhances patient comfort leading to lesser sense of hunger and thirst in the preoperative period in open radical retropubic prostatectomies.

Treating mineral metabolism disorders in patients undergoing long hemodialysis: a search for an optimal strategy.

PubMed

Jean, Guillaume; Vanel, Thierry; Terrat, Jean-Claude; Hurot, Jean-Marc; Lorriaux, Christie; Mayor, Brice; Chazot, Charles

2009-10-01

In hemodialysis (HD) patients, mineral metabolism (MM) disorders have been associated with an increased mortality rate. We report the evolution of MM parameters in a stable HD population undergoing long hemodialysis by performing an annual cross-sectional analysis for every year from 1994 to 2008. The therapeutic strategy has changed: the dialysate calcium concentration has decreased from a mean of 1.7 +/- 0.1 to 1.5 +/- 0.07 mmol/L and has been adapted to parathyroid hormone serum levels (from 1 to 1.75 mmol/L). The use of calcium-based and aluminum-based phosphate binders has decreased and they have been replaced by sevelamer; alfacalcidol has partly been replaced by native vitamin D. The percentage of patients with a parathyroid hormone serum level between 150 and 300 pg/mL has increased from 9% to 67% (P<0.001); the percentage of patients with phosphataemia between 1.15 and 1.78 mmol/L has increased from 39% to 84% (P<0.001). The percentage of those with albumin-corrected calcemia between 2.1 and 2.37 mmol/L has increased from 29% to 61% (P<0.001), and that of patients with a calcium-phosphorous product (Ca x P) level >4.4 mmol/L decreased from 8.8% to 2% (P=0.02). Although patients undergo long and intensive HD treatment, MM disorders are common. However, an appropriate strategy, mostly consisting of native vitamin D supplementation, progressive replacement of calcium-based phosphate binders with non-calcium-based ones, and individualization of dialysis session duration and dialysate calcium concentration, would result in a drastic improvement.

Association of conjunctival and corneal calcification with vascular calcification among hepatitis-C-seropositive hemodialysis patients.

PubMed

AbouSeif, Khaled; Sany, Dawlat; Elshahawy, Yasser; Seddik, Ayman; Rahman, Khedr; Gaber, Moustapha

2016-01-01

Disorders associated with the hepatitis C virus (HCV) have been reported including cardiovascular, metabolic, and central nervous system diseases. Since chronic HCV infections may be curable, their identification as causal contributors to cardiovascular risk could offer new perspectives in the prevention of cardiovascular disease. The aim of this study is to investigate the association between HCV and aortic arch calcification (AAC) and corneal and conjunctival calcification (CCC) in maintenance hemodialysis (MHD) patients; further, we assessed the correlation of CCC with vascular calcification. A total of 100 patients undergoing hemodialysis (HD) in our hospital were included in this study. Patients underwent a complete ocular examination including intraocular pressure, and CCC was looked for by slit lamp and fundoscopy. CCC was graded according to modified Porter and Crombie classification system described by Tokuyama et al. Helical computerized tomographic chest examination was used to evaluate the grading of AAC. Demographic, hematological, biochemical, and dialysis-related data were obtained. There was significant difference between seropositive (n = 51) and seronegative patients (n = 49) regarding grading of AAC and CCC (P <0.001). Significant positive correlation was found between grading of CCC, AAC, age (P <0.001), duration on HD (P <0.001), HCV-antibody positivity (P <0.001), serum calcium level (P <0.001), serum phosphorus level (P <0.001), calcium × phosphorus product (P <0.001), and i-parathormone level (P < 0.001). In addition, CCC grading positively correlated with AAC. Our results suggest that patients undergoing HD infected with the HCV have high degree of CCC, AAC, and mineral metabolism disorder. The strong correlation between CCC and AAC indicates that CCC evaluation is an easy, fast, non-invasive method, and might be used as an indirect indicator to detect vascular calcification in patients undergoing MHD.

Correlated FLIM and PLIM for cell metabolism

NASA Astrophysics Data System (ADS)

Rück, A.; Breymayer, J.; Kalinina, S.

2016-03-01

Correlated imaging of phosphorescence and fluorescence lifetime parameters of metabolic markers is a challenge for direct investigating mechanisms related to cell metabolism and oxygen tension. A large variety of clinical phenotypes is associated with mitochondrial defects accomplished with changes in cell metabolism. In many cases the hypoxic microenvironment of cancer cells shifts metabolism from oxidative phosphorylation (OXPHOS) to anaerobic or aerobic glycolysis, a process known as "Warburg" effect. Also during stem cell differentiation a switch in cell metabolism is observed. A defective mitochondrial function associated with hypoxia has been invoked in many complex disorders such as type 2 diabetes, Alzheimers disease, cardiac ischemia/reperfusion injury, tissue inflammation and cancer. Cellular responses to oxygen tension have been studied extensively, optical imaging techniques based on time correlated single photon counting (TCSPC) to detect the underlying metabolic mechanisms are therefore of prominent interest. They offer the possibility by inspecting fluorescence decay characteristics of intrinsic coenzymes to directly image metabolic pathways. Moreover oxygen tension can be determined by considering the phosphorescence lifetime of a phosphorescent probe. The combination of both fluorescence lifetime imaging (FLIM) of coenzymes like NADH and FAD and phosphorescence lifetime (PLIM) of phosphorescent dyes could provide valuable information about correlation of metabolic pathways and oxygen tension.

Genome-Scale Metabolic Modeling of Archaea Lends Insight into Diversity of Metabolic Function

PubMed Central

2017-01-01

Decades of biochemical, bioinformatic, and sequencing data are currently being systematically compiled into genome-scale metabolic reconstructions (GEMs). Such reconstructions are knowledge-bases useful for engineering, modeling, and comparative analysis. Here we review the fifteen GEMs of archaeal species that have been constructed to date. They represent primarily members of the Euryarchaeota with three-quarters comprising representative of methanogens. Unlike other reviews on GEMs, we specially focus on archaea. We briefly review the GEM construction process and the genealogy of the archaeal models. The major insights gained during the construction of these models are then reviewed with specific focus on novel metabolic pathway predictions and growth characteristics. Metabolic pathway usage is discussed in the context of the composition of each organism's biomass and their specific energy and growth requirements. We show how the metabolic models can be used to study the evolution of metabolism in archaea. Conservation of particular metabolic pathways can be studied by comparing reactions using the genes associated with their enzymes. This demonstrates the utility of GEMs to evolutionary studies, far beyond their original purpose of metabolic modeling; however, much needs to be done before archaeal models are as extensively complete as those for bacteria. PMID:28133437

Does Inflammation Determine Whether Obesity Is Metabolically Healthy or Unhealthy? The Aging Perspective

PubMed Central

Alam, Iftikhar; Ng, Tze Pin; Larbi, Anis

2012-01-01

Obesity is a major health issue in developed as well as developing countries. While obesity is associated with relatively good health status in some individuals, it may become a health issue for others. Obesity in the context of inflammation has been studied extensively. However, whether obesity in its various forms has the same adverse effects is a matter of debate and requires further research. During its natural history, metabolically healthy obesity (MHO) converts into metabolically unhealthy obesity (MUHO). What causes this transition to occur and what is the role of obesity-related mediators of inflammation during this transition is discussed in this paper. PMID:23091306

Reversible Hypokalemia and Bartter-Like Syndrome during Prolonged Systemic Therapy with Colistimethate Sodium in an Adult Patient.

PubMed

Kamal Eldin, Tarek; Tosone, Grazia; Capuano, Alfredo; Orlando, Raffaele

2017-12-01

We present the case of a 58-year-old woman who developed hypokalaemia and metabolic alkalosis 2 weeks after therapy with colistimethate sodium for the treatment of chronic lower limb ulcer infection by extensively drug-resistant (XDR) Pseudomonas aeruginosa. The metabolic changes observed resembled Bartter syndrome, a group of congenital disorders affecting the distal segments of the renal tubules. The metabolic abnormalities reversed spontaneously 6 days after drug discontinuation. Acquired forms of Bartter syndrome have been reported during courses of antibiotic therapy; however, to our knowledge, this is the first documented case associated with colistimethate therapy in an adult.

Mixed model of dietary fat effect on postprandial glucose-insulin metabolism from carbohydrates in type 1 diabetes.

PubMed

Yamamoto Noguchi, Claudia Cecilia; Kunikane, Noriaki; Hashimoto, Shogo; Furutani, Eiko

2015-08-01

In this study we introduce an extension of a previously developed model of glucose-insulin metabolism in type 1 diabetes (T1D) from carbohydrates that includes the effect of dietary fat on postprandial glycemia. We include two compartments that represent plasma triglyceride and nonesterified fatty acid (NEFA) concentration, in addition to a mathematical representation of delayed gastric emptying and insulin resistance, which are the most well-known effects of dietary fat metabolism. Simulation results show that postprandial glucose as well as lipid levels in our model approximates clinical data from T1D patients.

Kinetic modeling of plant metabolism and its predictive power: peppermint essential oil biosynthesis as an example.

PubMed

Lange, Bernd Markus; Rios-Estepa, Rigoberto

2014-01-01

The integration of mathematical modeling with analytical experimentation in an iterative fashion is a powerful approach to advance our understanding of the architecture and regulation of metabolic networks. Ultimately, such knowledge is highly valuable to support efforts aimed at modulating flux through target pathways by molecular breeding and/or metabolic engineering. In this article we describe a kinetic mathematical model of peppermint essential oil biosynthesis, a pathway that has been studied extensively for more than two decades. Modeling assumptions and approximations are described in detail. We provide step-by-step instructions on how to run simulations of dynamic changes in pathway metabolites concentrations.

Effect of Bioprocessing on the In Vitro Colonic Microbial Metabolism of Phenolic Acids from Rye Bran Fortified Breads.

PubMed

Koistinen, Ville M; Nordlund, Emilia; Katina, Kati; Mattila, Ismo; Poutanen, Kaisa; Hanhineva, Kati; Aura, Anna-Marja

2017-03-08

Cereal bran is an important source of dietary fiber and bioactive compounds, such as phenolic acids. We aimed to study the phenolic acid metabolism of native and bioprocessed rye bran fortified refined wheat bread and to elucidate the microbial metabolic route of phenolic acids. After incubation in an in vitro colon model, the metabolites were analyzed using two different methods applying mass spectrometry. While phenolic acids were released more extensively from the bioprocessed bran bread and ferulic acid had consistently higher concentrations in the bread type during fermentation, there were only minor differences in the appearance of microbial metabolites, including the diminished levels of certain phenylacetic acids in the bioprocessed bran. This may be due to rye matrix properties, saturation of ferulic acid metabolism, or a rapid formation of intermediary metabolites left undetected. In addition, we provide expansion to the known metabolic pathways of phenolic acids.

Simulating ideal assistive devices to reduce the metabolic cost of walking with heavy loads.

PubMed

Dembia, Christopher L; Silder, Amy; Uchida, Thomas K; Hicks, Jennifer L; Delp, Scott L

2017-01-01

Wearable robotic devices can restore and enhance mobility. There is growing interest in designing devices that reduce the metabolic cost of walking; however, designers lack guidelines for which joints to assist and when to provide the assistance. To help address this problem, we used musculoskeletal simulation to predict how hypothetical devices affect muscle activity and metabolic cost when walking with heavy loads. We explored 7 massless devices, each providing unrestricted torque at one degree of freedom in one direction (hip abduction, hip flexion, hip extension, knee flexion, knee extension, ankle plantarflexion, or ankle dorsiflexion). We used the Computed Muscle Control algorithm in OpenSim to find device torque profiles that minimized the sum of squared muscle activations while tracking measured kinematics of loaded walking without assistance. We then examined the metabolic savings provided by each device, the corresponding device torque profiles, and the resulting changes in muscle activity. We found that the hip flexion, knee flexion, and hip abduction devices provided greater metabolic savings than the ankle plantarflexion device. The hip abduction device had the greatest ratio of metabolic savings to peak instantaneous positive device power, suggesting that frontal-plane hip assistance may be an efficient way to reduce metabolic cost. Overall, the device torque profiles generally differed from the corresponding net joint moment generated by muscles without assistance, and occasionally exceeded the net joint moment to reduce muscle activity at other degrees of freedom. Many devices affected the activity of muscles elsewhere in the limb; for example, the hip flexion device affected muscles that span the ankle joint. Our results may help experimentalists decide which joint motions to target when building devices and can provide intuition for how devices may interact with the musculoskeletal system. The simulations are freely available online, allowing others to reproduce and extend our work.

Simulating ideal assistive devices to reduce the metabolic cost of walking with heavy loads

PubMed Central

Silder, Amy; Uchida, Thomas K.; Hicks, Jennifer L.; Delp, Scott L.

2017-01-01

Wearable robotic devices can restore and enhance mobility. There is growing interest in designing devices that reduce the metabolic cost of walking; however, designers lack guidelines for which joints to assist and when to provide the assistance. To help address this problem, we used musculoskeletal simulation to predict how hypothetical devices affect muscle activity and metabolic cost when walking with heavy loads. We explored 7 massless devices, each providing unrestricted torque at one degree of freedom in one direction (hip abduction, hip flexion, hip extension, knee flexion, knee extension, ankle plantarflexion, or ankle dorsiflexion). We used the Computed Muscle Control algorithm in OpenSim to find device torque profiles that minimized the sum of squared muscle activations while tracking measured kinematics of loaded walking without assistance. We then examined the metabolic savings provided by each device, the corresponding device torque profiles, and the resulting changes in muscle activity. We found that the hip flexion, knee flexion, and hip abduction devices provided greater metabolic savings than the ankle plantarflexion device. The hip abduction device had the greatest ratio of metabolic savings to peak instantaneous positive device power, suggesting that frontal-plane hip assistance may be an efficient way to reduce metabolic cost. Overall, the device torque profiles generally differed from the corresponding net joint moment generated by muscles without assistance, and occasionally exceeded the net joint moment to reduce muscle activity at other degrees of freedom. Many devices affected the activity of muscles elsewhere in the limb; for example, the hip flexion device affected muscles that span the ankle joint. Our results may help experimentalists decide which joint motions to target when building devices and can provide intuition for how devices may interact with the musculoskeletal system. The simulations are freely available online, allowing others to reproduce and extend our work. PMID:28700630

Complete Biosynthesis of Anthocyanins Using E. coli Polycultures.

PubMed

Jones, J Andrew; Vernacchio, Victoria R; Collins, Shannon M; Shirke, Abhijit N; Xiu, Yu; Englaender, Jacob A; Cress, Brady F; McCutcheon, Catherine C; Linhardt, Robert J; Gross, Richard A; Koffas, Mattheos A G

2017-06-06

Fermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to pharmaceuticals. These strategies have yet to find wide industrial utilization due to their inability to economically compete with traditional extraction and chemical production methods. Here, we engineer for the first time the complex microbial biosynthesis of an anthocyanin plant natural product, starting from sugar. This was accomplished through the development of a synthetic, 4-strain Escherichia coli polyculture collectively expressing 15 exogenous or modified pathway enzymes from diverse plants and other microbes. This synthetic consortium-based approach enables the functional expression and connection of lengthy pathways while effectively managing the accompanying metabolic burden. The de novo production of specific anthocyanin molecules, such as calistephin, has been an elusive metabolic engineering target for over a decade. The utilization of our polyculture strategy affords milligram-per-liter production titers. This study also lays the groundwork for significant advances in strain and process design toward the development of cost-competitive biochemical production hosts through nontraditional methodologies. IMPORTANCE To efficiently express active extensive recombinant pathways with high flux in microbial hosts requires careful balance and allocation of metabolic resources such as ATP, reducing equivalents, and malonyl coenzyme A (malonyl-CoA), as well as various other pathway-dependent cofactors and precursors. To address this issue, we report the design, characterization, and implementation of the first synthetic 4-strain polyculture. Division of the overexpression of 15 enzymes and transcription factors over 4 independent strain modules allowed for the division of metabolic burden and for independent strain optimization for module-specific metabolite needs. This study represents the most complex synthetic consortia constructed to date for metabolic engineering applications and provides a new paradigm in metabolic engineering for the reconstitution of extensive metabolic pathways in nonnative hosts. Copyright © 2017 Jones et al.

Efficient Mitochondrial Glutamine Targeting Prevails Over Glioblastoma Metabolic Plasticity.

PubMed

Oizel, Kristell; Chauvin, Cynthia; Oliver, Lisa; Gratas, Catherine; Geraldo, Fanny; Jarry, Ulrich; Scotet, Emmanuel; Rabe, Marion; Alves-Guerra, Marie-Clotilde; Teusan, Raluca; Gautier, Fabien; Loussouarn, Delphine; Compan, Vincent; Martinou, Jean-Claude; Vallette, François M; Pecqueur, Claire

2017-10-15

Purpose: Glioblastoma (GBM) is the most common and malignant form of primary human brain tumor in adults, with an average survival at diagnosis of 18 months. Metabolism is a new attractive therapeutic target in cancer; however, little is known about metabolic heterogeneity and plasticity within GBM tumors. We therefore aimed to investigate metabolic phenotyping of primary cultures in the context of molecular tumor heterogeneity to provide a proof of concept for personalized metabolic targeting of GBM. Experimental Design: We have analyzed extensively several primary GBM cultures using transcriptomics, metabolic phenotyping assays, and mitochondrial respirometry. Results: We found that metabolic phenotyping clearly identifies 2 clusters, GLN High and GLN Low , mainly based on metabolic plasticity and glutamine (GLN) utilization. Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLN High GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria. Furthermore, phenotypic and molecular analyses show that highly proliferative GLN High cultures are CD133 neg and display a mesenchymal signature in contrast to CD133 pos GLN Low GBM cells. Conclusions: Our results show that metabolic phenotyping identified an essential metabolic pathway in a GBM cell subtype, and provide a proof of concept for theranostic metabolic targeting. Clin Cancer Res; 23(20); 6292-304. ©2017 AACR . ©2017 American Association for Cancer Research.

Metabolomics of cereals under biotic stress: current knowledge and techniques

PubMed Central

Balmer, Dirk; Flors, Victor; Glauser, Gaetan; Mauch-Mani, Brigitte

2013-01-01

Prone to attacks by pathogens and pests, plants employ intricate chemical defense mechanisms consisting of metabolic adaptations. However, many plant attackers are manipulating the host metabolism to counteract defense responses and to induce favorable nutritional conditions. Advances in analytical chemistry have allowed the generation of extensive metabolic profiles during plant-pathogen and pest interactions. Thereby, metabolic processes were found to be highly specific for given tissues, species, and plant-pathogen/pest interactions. The clusters of identified compounds not only serve as base in the quest of novel defense compounds, but also as markers for the characterization of the plants' defensive state. The latter is especially useful in agronomic applications where meaningful markers are essential for crop protection. Cereals such as maize make use of their metabolic arsenal during both local and systemic defense responses, and the chemical response is highly adapted to specific attackers. Here, we summarize highlights and recent findings of metabolic patterns of cereals under pathogen and pest attack. PMID:23630531

Global metabolic interaction network of the human gut microbiota for context-specific community-scale analysis

PubMed Central

Sung, Jaeyun; Kim, Seunghyeon; Cabatbat, Josephine Jill T.; Jang, Sungho; Jin, Yong-Su; Jung, Gyoo Yeol; Chia, Nicholas; Kim, Pan-Jun

2017-01-01

A system-level framework of complex microbe–microbe and host–microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ∼570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut. PMID:28585563

Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay).

PubMed

Panchabhai, Tanmay S; Noronha, Shaun F; Davis, Sanish; Shinde, Vishal M; Kshirsagar, Nilima A; Gogtay, Nithya J

2006-10-24

Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population). All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC. It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM). A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy.

Global metabolic interaction network of the human gut microbiota for context-specific community-scale analysis.

PubMed

Sung, Jaeyun; Kim, Seunghyeon; Cabatbat, Josephine Jill T; Jang, Sungho; Jin, Yong-Su; Jung, Gyoo Yeol; Chia, Nicholas; Kim, Pan-Jun

2017-06-06

A system-level framework of complex microbe-microbe and host-microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ∼570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut.

Nectar resource limitation affects butterfly flight performance and metabolism differently in intensive and extensive agricultural landscapes.

PubMed

Lebeau, Julie; Wesselingh, Renate A; Van Dyck, Hans

2016-05-11

Flight is an essential biological ability of many insects, but is energetically costly. Environments under rapid human-induced change are characterized by habitat fragmentation and may impose constraints on the energy income budget of organisms. This may, in turn, affect locomotor performance and willingness to fly. We tested flight performance and metabolic rates in meadow brown butterflies (Maniola jurtina) of two contrasted agricultural landscapes: intensively managed, nectar-poor (IL) versus extensively managed, nectar-rich landscapes (EL). Young female adults were submitted to four nectar treatments (i.e. nectar quality and quantity) in outdoor flight cages. IL individuals had better flight capacities in a flight mill and had lower resting metabolic rates (RMR) than EL individuals, except under the severest treatment. Under this treatment, RMR increased in IL individuals, but decreased in EL individuals; flight performance was maintained by IL individuals, but dropped by a factor 2.5 in EL individuals. IL individuals had more canalized (i.e. less plastic) responses relative to the nectar treatments than EL individuals. Our results show significant intraspecific variation in the locomotor and metabolic response of a butterfly to different energy income regimes relative to the landscape of origin. Ecophysiological studies help to improve our mechanistic understanding of the eco-evolutionary impact of anthropogenic environments on rare and widespread species. © 2016 The Author(s).

Nectar resource limitation affects butterfly flight performance and metabolism differently in intensive and extensive agricultural landscapes

PubMed Central

Lebeau, Julie; Wesselingh, Renate A.; Van Dyck, Hans

2016-01-01

Flight is an essential biological ability of many insects, but is energetically costly. Environments under rapid human-induced change are characterized by habitat fragmentation and may impose constraints on the energy income budget of organisms. This may, in turn, affect locomotor performance and willingness to fly. We tested flight performance and metabolic rates in meadow brown butterflies (Maniola jurtina) of two contrasted agricultural landscapes: intensively managed, nectar-poor (IL) versus extensively managed, nectar-rich landscapes (EL). Young female adults were submitted to four nectar treatments (i.e. nectar quality and quantity) in outdoor flight cages. IL individuals had better flight capacities in a flight mill and had lower resting metabolic rates (RMR) than EL individuals, except under the severest treatment. Under this treatment, RMR increased in IL individuals, but decreased in EL individuals; flight performance was maintained by IL individuals, but dropped by a factor 2.5 in EL individuals. IL individuals had more canalized (i.e. less plastic) responses relative to the nectar treatments than EL individuals. Our results show significant intraspecific variation in the locomotor and metabolic response of a butterfly to different energy income regimes relative to the landscape of origin. Ecophysiological studies help to improve our mechanistic understanding of the eco-evolutionary impact of anthropogenic environments on rare and widespread species. PMID:27147100

'Detox': science or sales pitch?

PubMed

Cohen, Marc

2007-12-01

There is no question that the world is becoming increasingly toxic, with worldwide dissemination of industrial chemicals, pesticides, heavy metals and radioactive elements. Many of these toxins have demonstrated harmful effects including cancer, reproductive, metabolic, and mental health effects. It is also known that many toxins undergo bioaccumulation through the food chain and that synergistic effects can occur whereby combinations of toxins can be more potent than the sum of individual toxins.

DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR ETHYLENE GLYCOL AND ITS MAJOR METABOLITE, GLYCOLIC ACID, IN RATS AND HUMANS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Corley, Rick A.; Bartels, M J.; Carney, E W.

2005-05-19

An extensive database on the toxicity and modes of action of the major industrial chemical, ethylene glycol (EG), has been developed over the past several decades. These studies have consistently identified the kidney as a primary target organ, with rats being more sensitive than mice and males more sensitive than females following chronic exposure. Renal toxicity has been associated with the terminal metabolite, oxalic acid which can precipitate with calcium to form crystals. EG also induces developmental toxicity, although these effects appear to require high-doses or accelerated dose-rates, and have been reported only in rats and mice. The developmental toxicitymore » of EG has been attributed to the intermediate metabolite, glycolic acid (GA). The developmental toxicity of EG has been the subject of extensive research and regulatory review in recent years. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessment. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. The resulting PBPK model includes inhalation, oral, dermal, intravenous and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Several rat and human metabolism studies were used to validate the resulting PBPK model. Consistent with these studies, simulations indicated that the metabolism of EG to GA was essentially first-order (linear) up to 2500 mg/kg/day while the metabolism of GA saturated between bolus ethylene glycol doses of 200 and 1000 mg/kg/day. This saturation results in non-linear increases in blood GA concentrations, correlating with the developmental toxicity of EG. Pregnancy had no effect on maternal EG and GA kinetics over a broad dose range. The human PBPK model was validated against a large database of human clinical case reports in a companion study (Corley and McMartin, 2004) where the impacts of treatment and a comparison of internal dose surrogates for human health risk assessments were conducted.« less

Catalytic and mechanical cycles in F-ATP synthases. Fourth in the Cycles Review Series.

PubMed

Dimroth, Peter; von Ballmoos, Christoph; Meier, Thomas

2006-03-01

Cycles have a profound role in cellular life at all levels of organization. Well-known cycles in cell metabolism include the tricarboxylic acid and the urea cycle, in which a specific carrier substrate undergoes a sequence of chemical transformations and is regenerated at the end. Other examples include the interconversions of cofactors, such as NADH or ATP, which are present in the cell in limiting amounts and have to be recycled effectively for metabolism to continue. Every living cell performs a rapid turnover of ATP to ADP to fulfil various energetic demands and effectively regenerates the ATP from ADP in an energy-consuming process. The turnover of the ATP cycle is impressive; a human uses about its body weight in ATP per day. Enzymes perform catalytic reaction cycles in which they undergo several chemical and physical transformations before they are converted back to their original states. The ubiquitous F1F(o) ATP synthase is of particular interest not only because of its biological importance, but also owing to its unique rotational mechanism. Here, we give an overview of the membrane-embedded F(o) sector, particularly with respect to the recent crystal structure of the c ring from Ilyobacter tartaricus, and summarize current hypotheses for the mechanism by which rotation of the c ring is generated.

Role of genetic testing in patients undergoing percutaneous coronary intervention.

PubMed

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rivas Rios, Jose R; Kureti, Megha; Cavallari, Larisa H; Angiolillo, Dominick J

2018-02-01

Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y 12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered: The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y 12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert commentary: The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes.

Role of Genetic Testing in Patients undergoing Percutaneous Coronary Intervention

PubMed Central

Moon, Jae Youn; Franchi, Francesco; Rollini, Fabiana; Rios, Jose R. Rivas; Kureti, Megha; Cavallari, Larisa H.; Angiolillo, Dominick J.

2017-01-01

Introduction Variability in individual response profiles to antiplatelet therapy, in particular clopidogrel, is a well-established phenomenon. Genetic variations of the cytochrome P450 (CYP) 2C19 enzyme, a key determinant in clopidogrel metabolism, have been associated with clopidogrel response profiles. Moreover, the presence of a CYP2C19 loss-of-function allele is associated with an increased risk of atherothrombotic events among clopidogrel-treated patients undergoing percutaneous coronary interventions (PCI), prompting studies evaluating the use of genetic tests to identify patients who may be potential candidates for alternative platelet P2Y12 receptor inhibiting therapies (prasugrel or ticagrelor). Areas covered The present manuscript provides an overview of genetic factors associated with response profiles to platelet P2Y12 receptor inhibitors and their clinical implications, as well as the most recent developments and future considerations on the role of genetic testing in patients undergoing PCI. Expert Commentary The availability of more user-friendly genetic tests has contributed towards the development of many ongoing clinical trials and personalized medicine programs for patients undergoing PCI. Results of pilot investigations have shown promising results, which however need to be confirmed in larger-scale studies to support the routine use of genetic testing as a strategy to personalize antiplatelet therapy and improve clinical outcomes. PMID:28689434

Classification of natural products as sources of drugs according to the biopharmaceutics drug disposition classification system (BDDCS).

PubMed

Li, Ji; Larregieu, Caroline A; Benet, Leslie Z

2016-12-01

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

A Low-Oxygenated Subpopulation of Pancreatic Islets Constitutes a Functional Reserve of Endocrine Cells

PubMed Central

Olsson, Richard; Carlsson, Per-Ola

2011-01-01

OBJECTIVE The blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo. RESEARCH DESIGN AND METHODS The reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas–transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity. RESULTS In vivo, 20–25% of all islets in normal rats showed low oxygenation (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis. CONCLUSIONS The current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis. PMID:21788581

[Lymphocyte metabolism in children with extensive burns].

PubMed

Artem'ev, S A; Nazarov, I P; Kamzalakova, N I; Bulygin, G V

2009-01-01

The results of the study lead to the conclusion that the development of burn disease in children is accompanied by significant lymphocytic structural metabolic changes that determine the functional capabilities of cells and the immune system as a whole. There is an evident activation of the glutathione antioxidant system, a drastic activation of enzymes that ensure Krebs cycle reactions, as well as activation of anaerobic processes. The above changes are mainly caused by the activated sympathoadrenal system that is characteristic of stresses. The knowledge about the metabolic mechanisms responsible for the development of cellular reactions to burn shock and burn disease permits specification of the elements of the pathogenesis of these severe conditions and substantiation of the possibility of using metabolic correction in the complex treatment of children with the above pathology.

Maternal resveratrol consumption and its programming effects on metabolic health in offspring mechanisms and potential implications.

PubMed

Zheng, Sheng; Feng, Qianyun; Cheng, Jing; Zheng, Jia

2018-04-27

A growing body of evidence has clearly demonstrated that maternal nutrition can strongly determine the susceptibility to the development of metabolic diseases in offspring. With the increasing prevalence of maternal overweight, obesity, and gestational diabetes mellitus, it yields enormous burden for individual and public health. Interventions during pregnancy have been proven to be challenging, with limited efficacy and low compliance. Resveratrol, as a natural polyphenolic compound, has a wide-range of beneficial properties, including potent antiobesogenic, antiatherosclerotic, and antidiabetic effects. However, the role of maternal resveratrol intake on metabolic health in offspring has not been extensively investigated. Therefore, the aim of this study was to review the effects of maternal resveratrol supplementation on metabolic health in offspring and its potential mechanisms. © 2018 The Author(s).

Oncogene-induced senescence results in marked metabolic and bioenergetic alterations

PubMed Central

Quijano, Celia; Cao, Liu; Fergusson, Maria M; Romero, Hector; Liu, Jie; Gutkind, Sarah; Rovira, Ilsa I; Mohney, Robert P; Karoly, Edward D

2012-01-01

Oncogene-induced senescence (OIS) is characterized by permanent growth arrest and the acquisition of a secretory, pro-inflammatory state. Increasingly, OIS is viewed as an important barrier to tumorgenesis. Surprisingly, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS. Here, we have performed a metabolomic and bioenergetic analysis of Ras-induced senescence. Profiling approximately 300 different intracellular metabolites reveals that cells that have undergone OIS develop a unique metabolic signature that differs markedly from cells undergoing replicative senescence. A number of lipid metabolites appear uniquely increased in OIS cells, including a marked increase in the level of certain intracellular long chain fatty acids. Functional studies reveal that this alteration in the metabolome reflects substantial changes in overall lipid metabolism. In particular, Ras-induced senescent cells manifest a decline in lipid synthesis and a significant increase in fatty acid oxidation. Increased fatty acid oxidation results in an unexpectedly high rate of basal oxygen consumption in cells that have undergone OIS. Pharmacological or genetic inhibition of carnitine palmitoyltransferase 1, the rate-limiting step in mitochondrial fatty acid oxidation, restores a presenescent metabolic rate and, surprisingly, selectively inhibits the secretory, pro-inflammatory state that accompanies OIS. Thus, Ras-induced senescent cells demonstrate profound alterations in their metabolic and bioenergetic profiles, particularly with regards to the levels, synthesis and oxidation of free fatty acids. Furthermore, the inflammatory phenotype that accompanies OIS appears to be related to these underlying changes in cellular metabolism. PMID:22421146

Proteomic analysis of stipe explants reveals differentially expressed proteins involved in early direct somatic embryogenesis of the tree fern Cyathea delgadii Sternb.

PubMed

Domżalska, Lucyna; Kędracka-Krok, Sylwia; Jankowska, Urszula; Grzyb, Małgorzata; Sobczak, Mirosław; Rybczyński, Jan J; Mikuła, Anna

2017-05-01

Using cyto-morphological analysis of somatic embryogenesis (SE) in the tree fern Cyathea delgadii as a guide, we performed a comparative proteomic analysis in stipe explants undergoing direct SE. Plant material was cultured on hormone-free medium supplemented with 2% sucrose. Phenol extracted proteins were separated using two-dimensional gel electrophoresis (2-DE) and mass spectrometry was performed for protein identification. A total number of 114 differentially regulated proteins was identified during early SE, i.e. when the first cell divisions started and several-cell pro-embryos were formed. Proteins were assigned to seven functional categories: carbohydrate metabolism, protein metabolism, cell organization, defense and stress responses, amino acid metabolism, purine metabolism, and fatty acid metabolism. Carbohydrate and protein metabolism were found to be the most sensitive SE functions with the greatest number of alterations in the intensity of spots in gel. Differences, especially in non-enzymatic and structural protein abundance, are indicative for cell organization, including cytoskeleton rearrangement and changes in cell wall components. The highest induced changes concern those enzymes related to fatty acid metabolism. Global analysis of the proteome reveals several proteins that can represent markers for the first 16days of SE induction and expression in fern. The findings of this research improve the understanding of molecular processes involved in direct SE in C. delgadii. Copyright © 2017 Elsevier B.V. All rights reserved.

Multifaceted role of lipids in Mycobacterium leprae.

PubMed

Kaur, Gurkamaljit; Kaur, Jagdeep

2017-03-01

Mycobacterium leprae must adopt a metabolic strategy and undergo various metabolic alterations upon infection to survive inside the human body for years in a dormant state. A change in lipid homeostasis upon infection is highly pronounced in Mycobacterium leprae. Lipids play an essential role in the survival and pathogenesis of mycobacteria. Lipids are present in several forms and serve multiple roles from being a source of nutrition, providing rigidity, evading the host immune response to serving as virulence factors, etc. The synthesis and degradation of lipids is a highly regulated process and is the key to future drug designing and diagnosis for mycobacteria. In the current review, an account of the distinct roles served by lipids, the mechanism of their synthesis and degradation has been elucidated.

Metabolism of 2-chloro-1,1-difluoroethene to glyoxylic and glycolic acid in rat hepatic microsomes.

PubMed

Baker, M T; Vasquez, M T; Bates, J N; Chiang, C K

1990-01-01

The complete metabolic fate of the volatile anesthetic halothane is unclear since 2-chloro-1,1-diflurorethene (CDE), a reductive halothane metabolite, is known to readily release inorganic fluoride upon oxidation by cytochrome P-450. This study sought to clarify the metabolism of CDE by determining its metabolites and the roles of induce cytochrome P-450 forms in its metabolism. Upon incubation of [14C]CDE with rat hepatic microsomes, two major radioactive products were found which accounted for greater than 94% of the total metabolites. These compounds were determined to be the nonhalogenated compounds, glyoxylic and glycolic acids, which were formed in a ratio of approximately 1 to 2 of glyoxylic to glycolic acid. No other radioactive metabolites could be detected. Following incubation of CDE with hepatic microsomes isolated from rats treated with cytochrome P-450 inducers, measurement of fluoride release showed that phenobarbital induced CDE metabolism to the greatest degree at high CDE levels, isoniazid was the most effective inducer at low CDE concentrations, and beta-naphthoflavone was ineffective as an inducer. These results suggest that CDE biotransformation primarily involves the generation of an epoxide intermediate, which undergoes mechanisms of decay leading to total dehalogenation of the molecule, and that this metabolism is preferentially carried out by the phenobarbital- and ethanol-inducible forms of cytochrome P-450.

Cerebral monitoring during cardiopulmonary bypass in children.

PubMed

Kern, F H; Schell, R M; Greeley, W J

1993-07-01

Although cerebral monitoring during CPB remains primarily investigational, recent data support its clinical utility. In particular, it is cerebral metabolic monitoring that provides meaningful information in terms of preparing the brain for dhCPB and dhCA. Cerebral blood flow or cerebral blood flow velocity monitoring is less beneficial due to the presence of luxuriant cerebral blood flow at deep hypothermic temperatures. Conventional temperature monitoring can be improved upon by adding jugular venous oxygen saturation monitoring to satisfy the primary goal of cerebral protection--uniform cerebral cooling and metabolic suppression. Although online measures of cerebral cellular metabolism are not widely available, early experience with near infrared technology suggests that it is a feasible and reliable monitor of cerebral metabolic activity and is likely to represent an important noninvasive continuous monitor in the near future. CMRO2 recovery data have suggested that cerebral metabolic suppression is more severe the longer the period of dhCA. Cerebral protection strategies, such as intermittent cerebral perfusion have demonstrated less metabolic suppression of dhCA in animal models and are currently undergoing clinical evaluation in our institution. Finally, the postoperative period remains a high-risk period for neurologic injury because temperatures are normothermic, cardiac output is reduced, cerebral autoregulation is impaired, and management strategies, such as hyperventilation, are commonly used to increase pulmonary blood flow with little knowledge on its effects on cerebral perfusion.

Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis

PubMed Central

2014-01-01

Background The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. Results We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5′ splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Conclusion Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress adaptation in plants. It is also envisioned that alternative splicing of the clock genes plays more complex roles than previously expected. PMID:24885185

Alterations in Gut Microbiota and Immunity by Dietary Fat.

PubMed

Yang, Bo Gie; Hur, Kyu Yeon; Lee, Myung Shik

2017-11-01

Gut microbiota play critical physiological roles in energy extraction from the intestine and in the control of systemic immunity, as well as local intestinal immunity. Disturbance of gut microbiota leads to the development of several diseases, such as colitis, inflammatory bowel diseases, metabolic disorders, cancer, etc. From a metabolic point of view, the gut is a large metabolic organ and one of the first to come into contact with dietary fats. Interestingly, excessive dietary fat has been incriminated as a primary culprit of metabolic syndrome and obesity. After intake of high-fat diet or Western diet, extensive changes in gut microbiota have been observed, which may be an underlying cause of alterations in whole body metabolism and nutrient homeostasis. Here, we summarize recent data on changes in the gut microbiota and immunity associated with dietary fat, as well as their relationships with the pathogenesis of metabolic syndrome. These findings may provide insight into the understanding of the complex pathophysiology related to the development of metabolic diseases and offer an opportunity to develop novel candidates for therapeutic agents. © Copyright: Yonsei University College of Medicine 2017.

Gut microbiota functions: metabolism of nutrients and other food components.

PubMed

Rowland, Ian; Gibson, Glenn; Heinken, Almut; Scott, Karen; Swann, Jonathan; Thiele, Ines; Tuohy, Kieran

2018-02-01

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays.

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

PubMed

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

2018-01-01

An emerging paradigm in immunology suggests that metabolic reprogramming and immune cell activation and functions are intricately linked. Viral infections, such as HIV infection, as well as cancer force immune cells to undergo major metabolic challenges. Cells must divert energy resources in order to mount an effective immune response. However, the fact that immune cells adopt specific metabolic programs to provide host defense against intracellular pathogens and how this metabolic shift impacts immune cell functions and the natural course of diseases have only recently been appreciated. A clearer insight into how these processes are inter-related will affect our understanding of several fundamental aspects of HIV persistence. Even in patients with long-term use of anti-retroviral therapies, HIV infection persists and continues to cause chronic immune activation and inflammation, ongoing and cumulative damage to multiple organs systems, and a reduction in life expectancy. HIV-associated fundamental changes to the metabolic machinery of the immune system can promote a state of "inflammaging", a chronic, low-grade inflammation with specific immune changes that characterize aging, and can also contribute to the persistence of HIV in its reservoirs. In this commentary, we will bring into focus evolving concepts on how HIV modulates the metabolic machinery of immune cells in order to persist in reservoirs and how metabolic reprogramming facilitates a chronic state of inflammation that underlies the development of age-related comorbidities. We will discuss how immunometabolism is facilitating the changing paradigms in HIV cure research and outline the novel therapeutic opportunities for preventing inflammaging and premature development of age-related conditions in HIV + individuals.

Predictive factors of long-term colorectal cancer survival after ultrasound-controlled ablation of hepatic metastases.

PubMed

Hernández-Socorro, Carmen Rosa; Saavedra, Pedro; Ramírez Felipe, José; Bohn Sarmiento, Uriel; Ruiz-Santana, Sergio

2017-04-21

The risk factors associated to long-term survival were assessed in patients with liver metastases of colorectal carcinoma undergoing ablative therapies. Single-centre cohort study, retrospectively analysed and prospectively collected consecutive patients with unresectable metastatic liver disease of colorectal carcinoma treated with ablative therapies between 1996 and 2013. Factors associated with survival time were identified using Cox's proportional hazard model with time-dependent covariates. A forward variable selection based on Akaike information criterion was performed. Relative risk and 95% confidence intervals for each factor were calculated. Statistical significance was set as P<.05. Seventy-five patients with liver metastases of colorectal cancer, with a mean age of 65.6 (10.3) underwent 106 treatments. Variables selected were good quality of life (RR 0.308, 95% CI 0.150-0.632) and tumour extension (RR 3.070, 95% CI 1.776-5.308). The median overall survival was 18.5 months (95% CI 17.4-24.4). The survival prognosis in median was 13.5 vs. 23.4 months for patients with and without tumour extension, and 23.0 vs. 12.8 months for patients with good and fair or poor quality of life, respectively. Good quality of life and tumour extension were the only statistically significant predictors of long-term survival in patients of colorectal carcinoma with liver metastatic disease undergoing ablative treatment with ultrasound. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

The formulation of a nasal nanoemulsion zaleplon in situ gel for the treatment of insomnia.

PubMed

Hosny, Khaled Mohamed; Banjar, Zainy Mohammed

2013-08-01

Zaleplon is a drug used for the treatment of insomnia and is available in tablet form; however, it has two major problems. First, the drug undergoes extensive first pass metabolism, resulting in only 30% bioavailability, and second, the drug has a poor aqueous solubility, which delays the onset of action. The objective of this study is to utilise nanotechnology to formulate zaleplon into a nasal in situ nanoemulsion gel (NEG) to provide a solution for the previously mentioned problems. The solubility of zaleplon in various oils, surfactants and co-surfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanoemulsion (NE) formulations were prepared; these formulations were subjected to visual characterisation, thermodynamic stability study and droplet size and conductivity measurements. Carbopol 934 was used as an in situ gelling agent. The gel strength, pH, gelation time, in vitro release and ex vivo nasal permeation were determined. The pharmacokinetic study of the NEG was carried out in rabbits. Stable NEs were successfully developed with a droplet size range of 35 to 73 nm. A NEG composed of 15% Miglyol, 30% Labrasol and 10% PEG 200 successfully provided the maximum in vitro and ex vivo permeation and enhanced the bioavailability in the rabbits by eightfold, when compared with the marketed tablets. The nasal NEG is a promising novel formula for zaleplon that has higher nasal tissue permeability and enhanced systemic bioavailability.

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter.

PubMed

Abd-Elrasheed, Eman; Nageeb El-Helaly, Sara; El-Ashmoony, Manal M; Salah, Salwa

2018-05-01

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 2 3 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.

Effects of Intrinsic Factors on the Clinical Pharmacokinetics of Vortioxetine.

PubMed

Chen, Grace; Nomikos, George G; Affinito, John; Jacobson, William; Zhao, Zhen; Wang, Shining; Xie, Jinhui

2018-06-19

Vortioxetine is an antidepressant agent with multimodal activity that is approved for the treatment of major depressive disorder at doses of 5 to 20 mg once daily. Vortioxetine is a medium-clearance drug that undergoes extensive metabolism via several cytochrome P450 isozymes. A series of single- and multiple-dose pharmacokinetic studies were performed to evaluate the impact of intrinsic (ie, subject-related) factors, such as age, sex, race, and renal and hepatic function, on the pharmacokinetics of vortioxetine. The point estimates on the ratios and their 90% confidence intervals (CIs) for the central values of AUC (area under the concentration-time curve) and C max (maximum plasma concentration) were obtained by taking the antilog of the differences and 90%CIs in the log-transformed least-squares means. The results demonstrate that there were no clinically meaningful differences (defined as exposure difference between 50% and 2-fold change) in the exposure to vortioxetine (as assessed by AUC and C max ) between elderly and younger subjects, men and women, and blacks and whites and among subjects with varying degrees of renal or hepatic impairment. These results suggest that no dosing adjustments of vortioxetine are required for the intrinsic factors investigated in these studies. © 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Can mesenchymal cells undergo collective cell migration?

PubMed Central

Theveneau, Eric

2011-01-01

Cell migration is critical for proper development of the embryo and is also used by many cell types to perform their physiological function. For instance, cell migration is essential for immune cells to monitor the body and for epithelial cells to heal a wound whereas, in cancer cells, acquisition of migratory capabilities is a critical step toward malignancy. Migratory cells are often categorized into two groups: (1) mesenchymal cells, produced by an epithelium-to-mesenchyme transition, that undergo solitary migration and (2) epithelial-like cells which migrate collectively. However, on some occasions, mesenchymal cells may travel in large, dense groups and exhibit key features of collectively migrating cells such as coordination and cooperation. Here, using data published on neural crest cells, a highly invasive mesenchymal cell population that extensively migrate throughout the embryo, we explore the idea that mesenchymal cells, including cancer cells, might be able to undergo collective cell migration under certain conditions and discuss how they could do so. PMID:22274714

Metabolic Maturation during Muscle Stem Cell Differentiation Is Achieved by miR-1/133a-Mediated Inhibition of the Dlk1-Dio3 Mega Gene Cluster.

PubMed

Wüst, Stas; Dröse, Stefan; Heidler, Juliana; Wittig, Ilka; Klockner, Ina; Franko, Andras; Bonke, Erik; Günther, Stefan; Gärtner, Ulrich; Boettger, Thomas; Braun, Thomas

2018-05-01

Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since expression of the muscle-specific miR-1/133a gene cluster correlates with increased mitochondrial activity during muscle stem cell (MuSC) differentiation, we examined the potential role of miR-1/133a in metabolic maturation of skeletal muscles in mice. We found that miR-1/133a downregulate Mef2A in differentiated myocytes, thereby suppressing the Dlk1-Dio3 gene cluster, which encodes multiple microRNAs inhibiting expression of mitochondrial genes. Loss of miR-1/133a in skeletal muscles or increased Mef2A expression causes continuous high-level expression of the Dlk1-Dio3 gene cluster, compromising mitochondrial function. Failure to terminate the stem cell-like metabolic program characterized by high-level Dlk1-Dio3 gene cluster expression initiates profound changes in muscle physiology, essentially abrogating endurance running. Our results suggest a major role of miR-1/133a in metabolic maturation of skeletal muscles but exclude major functions in muscle development and MuSC maintenance. Copyright © 2018 Elsevier Inc. All rights reserved.

Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione.

PubMed

Kürschner, Gerrit; Zhang, Qingzhou; Clima, Rosanna; Xiao, Yi; Busch, Jonas Felix; Kilic, Ergin; Jung, Klaus; Berndt, Nikolaus; Bulik, Sascha; Holzhütter, Hermann-Georg; Gasparre, Giuseppe; Attimonelli, Marcella; Babu, Mohan; Meierhofer, David

2017-12-01

Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD + , NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor.

Renal oncocytoma characterized by the defective complex I of the respiratory chain boosts the synthesis of the ROS scavenger glutathione

PubMed Central

Clima, Rosanna; Xiao, Yi; Busch, Jonas Felix; Kilic, Ergin; Jung, Klaus; Berndt, Nikolaus; Bulik, Sascha; Holzhütter, Hermann-Georg; Gasparre, Giuseppe; Attimonelli, Marcella; Babu, Mohan; Meierhofer, David

2017-01-01

Renal oncocytomas are rare benign tumors of the kidney and characterized by a deficient complex I (CI) enzyme activity of the oxidative phosphorylation (OXPHOS) system caused by mitochondrial DNA (mtDNA) mutations. Yet, little is known about the underlying molecular mechanisms and alterations of metabolic pathways in this tumor. We compared renal oncocytomas with adjacent matched normal kidney tissues on a global scale by multi-omics approaches, including whole exome sequencing (WES), proteomics, metabolomics, and metabolic pathway simulation. The abundance of proteins localized to mitochondria increased more than 2-fold, the only exception was a strong decrease in the abundance for CI subunits that revealed several pathogenic heteroplasmic mtDNA mutations by WES. We also observed renal oncocytomas to dysregulate main metabolic pathways, shunting away from gluconeogenesis and lipid metabolism. Nevertheless, the abundance of energy carrier molecules such as NAD+, NADH, NADP, ATP, and ADP were significantly higher in renal oncocytomas. Finally, a substantial 5000-fold increase of the reactive oxygen species scavenger glutathione can be regarded as a new hallmark of renal oncocytoma. Our findings demonstrate that renal oncocytomas undergo a metabolic switch to eliminate ATP consuming processes to ensure a sufficient energy supply for the tumor. PMID:29285300

Fatty Aldehyde and Fatty Alcohol Metabolism: Review and Importance for Epidermal Structure and Function

PubMed Central

Rizzo, William B.

2014-01-01

Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. PMID:24036493

Incision extension is the optimal method of difficult gallbladder extraction at laparoscopic cholecystectomy.

PubMed

Bordelon, B M; Hobday, K A; Hunter, J G

1992-01-01

An unsolved problem of laparoscopic cholecystectomy is the optimal method of removing the gallbladder with thick walls and a large stone burden. Proposed solutions include fascial dilatation, stone crushing, and ultrasonic, high-speed rotary, or laser lithotripsy. Our observation was that extension of the fascial incision to remove the impacted gallbladder was time efficient and did not increase postoperative pain. We reviewed the narcotic requirements of 107 consecutive patients undergoing laparoscopic cholecystectomy. Fifty-two patients required extension of the umbilical incision, and 55 patients did not have their fascial incision enlarged. Parenteral meperidine use was 39.5 +/- 63.6 mg in the patients requiring fascial incision extension and 66.3 +/- 79.2 mg in those not requiring fascial incision extension (mean +/- standard deviation). Oral narcotic requirements were 1.1 +/- 1.5 doses vs 1.3 +/- 1.7 doses in patients with and without incision extension, respectively. The wide range of narcotic use in both groups makes these apparent differences not statistically significant. We conclude that protracted attempts at stone crushing or expensive stone fragmentation devices are unnecessary for the extraction of a difficult gallbladder during laparoscopic cholecystectomy.

Branched-chain amino acids to tyrosine ratio value as a potential prognostic factor for hepatocellular carcinoma.

PubMed

Ishikawa, Toru

2012-05-07

The prognosis of hepatocellular carcinoma (HCC) depends on tumor extension as well as hepatic function. Hepatic functional reserve is recognized as a factor affecting survival in the treatment of HCC; the Child-Pugh classification system is the most extensively used method for assessing hepatic functional reserve in patients with chronic liver disease, using serum albumin level to achieve accurate assessment of the status of protein metabolism. However, insufficient attention has been given to the status of amino acid (AA) metabolism in chronic liver disease and HCC. Fischer's ratio is the molar ratio of branched-chain AAs (BCAAs: leucine, valine, isoleucine) to aromatic AAs (phenylalanine, tyrosine) and is important for assessing liver metabolism, hepatic functional reserve and the severity of liver dysfunction. Although this ratio is difficult to determine in clinical situations, BCAAs/tyrosine molar concentration ratio (BTR) has been proposed as a simpler substitute. BTR correlates with various liver function examinations, including markers of hepatic fibrosis, hepatic blood flow and hepatocyte function, and can thus be considered as reflecting the degree of hepatic impairment. This manuscript examines the literature to clarify whether BTR can serve as a prognostic factor for treatment of HCC.

Relationship of CYP2D6, CYP3A, POR, and ABCB1 genotypes with galantamine plasma concentrations.

PubMed

Noetzli, Muriel; Guidi, Monia; Ebbing, Karsten; Eyer, Stephan; Zumbach, Serge; Giannakopoulos, Panteleimon; von Gunten, Armin; Csajka, Chantal; Eap, Chin B

2013-04-01

The frequently prescribed antidementia drug galantamine is extensively metabolized by the enzymes cytochrome P450 (CYP) 2D6 and CYP3A and is a substrate of the P-glycoprotein. We aimed to study the relationship between genetic variants influencing the activity of these enzymes and transporters with galantamine steady state plasma concentrations. In this naturalistic cross-sectional study, 27 older patients treated with galantamine were included. The patients were genotyped for common polymorphisms in CYP2D6, CYP3A4/5, POR, and ABCB1, and galantamine steady state plasma concentrations were determined. The CYP2D6 genotype seemed to be an important determinant of galantamine pharmacokinetics, with CYP2D6 poor metabolizers presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6 extensive metabolizers (median 2.9 versus 2.0 ng/mL · mg, P = 0.025, and 1.8 ng/mL · mg, P = 0.004), respectively. The CYP2D6 genotype significantly influenced galantamine plasma concentrations. The influence of CYP2D6 polymorphisms on the treatment efficacy and tolerability should be further investigated.

Coupling Between Metabolism and Compartmentalization: Vesicle Growth in the Presence of Dipeptides

NASA Astrophysics Data System (ADS)

Wei, C.; Pohorille, A.

2017-07-01

Extensive molecular dynamics simulations demonstrate low energy pathway for fast fusion of vesicle mediated by membrane-bound hydrophobic dipeptides and facilitated flip-flop transport of fatty acid molecule for transmembrane proton transfer.

Insulin and wound healing.

PubMed

Hrynyk, Michael; Neufeld, Ronald J

2014-12-01

Skin is a dynamic and complex organ that relies on the interaction of different cell types, biomacromolecules and signaling molecules. Injury triggers a cascade of events designed to quickly restore skin integrity. Depending on the size and severity of the wound, extensive physiological and metabolic changes can occur, resulting in impaired wound healing and increased morbidity resulting in higher rates of death. While wound dressings provide a temporary barrier, they are inherently incapable of significantly restoring metabolic upsets, post-burn insulin resistance, and impaired wound healing in patients with extensive burns. Exogenous insulin application has therefore been investigated as a potential therapeutic intervention for nearly a century to improve wound recovery. This review will highlight the important achievements that demonstrate insulin's ability to stimulate cellular migration and burn wound recovery, as well as providing a perspective on future therapeutic applications and research directions. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Variable-Internal-Stores models of microbial growth and metabolism with dynamic allocation of cellular resources.

PubMed

Nev, Olga A; van den Berg, Hugo A

2017-01-01

Variable-Internal-Stores models of microbial metabolism and growth have proven to be invaluable in accounting for changes in cellular composition as microbial cells adapt to varying conditions of nutrient availability. Here, such a model is extended with explicit allocation of molecular building blocks among various types of catalytic machinery. Such an extension allows a reconstruction of the regulatory rules employed by the cell as it adapts its physiology to changing environmental conditions. Moreover, the extension proposed here creates a link between classic models of microbial growth and analyses based on detailed transcriptomics and proteomics data sets. We ascertain the compatibility between the extended Variable-Internal-Stores model and the classic models, demonstrate its behaviour by means of simulations, and provide a detailed treatment of the uniqueness and the stability of its equilibrium point as a function of the availabilities of the various nutrients.

Extensive Functional Evaluations to Monitor Aerobic Training in Becker Muscular Dystrophy: A Case Report.

PubMed

Tramonti, Caterina; Rossi, Bruno; Chisari, Carmelo

2016-06-13

Low-intensity aerobic training seems to have positive effects on muscle strength, endurance and fatigue in Becker Muscular Dystrophy (BMD) patients. We describe the case of a 33-year old BMD man, who performed a four-week aerobic training. Extensive functional evaluations were executed to monitor the efficacy of the rehabilitative treatment. Results evidenced an increased force exertion and an improvement in muscle contraction during sustained exercise. An improvement of walk velocity, together with agility, endurance capacity and oxygen consumption during exercise was observed. Moreover, an enhanced metabolic efficiency was evidenced, as shown by reduced lactate blood levels after training. Interestingly, CK showed higher levels after the training protocol, revealing possible muscle damage. In conclusion, aerobic training may represent an effective method improving exercise performance, functional status and metabolic efficiency. Anyway, a careful functional assessment should be taken into account as a useful approach in the management of the disease's rehabilitative treatment.

Single-molecule study of the DNA denaturation phase transition in the force-torsion space.

PubMed

Salerno, D; Tempestini, A; Mai, I; Brogioli, D; Ziano, R; Cassina, V; Mantegazza, F

2012-09-14

We use the "magnetic tweezers" technique to show the structural transitions that the DNA undergoes in the force-torsion space. In particular, we focus on the regions corresponding to negative supercoiling. These regions are characterized by the formation of the so-called denaturation bubbles, which play an essential role in the replication and transcription of DNA. We experimentally map the region of the force-torsion space where the denaturation takes place. We observe that large fluctuations in DNA extension occur at one of the boundaries of this region, i.e., when the formation of denaturation bubbles and of plectonemes compete. To describe the experiments, we introduce a suitable extension of the classical model. The model correctly describes the position of the denaturation regions, the transition boundaries, and the measured values of the DNA extension fluctuations.

Single-Molecule Study of the DNA Denaturation Phase Transition in the Force-Torsion Space

NASA Astrophysics Data System (ADS)

Salerno, D.; Tempestini, A.; Mai, I.; Brogioli, D.; Ziano, R.; Cassina, V.; Mantegazza, F.

2012-09-01

We use the “magnetic tweezers” technique to show the structural transitions that the DNA undergoes in the force-torsion space. In particular, we focus on the regions corresponding to negative supercoiling. These regions are characterized by the formation of the so-called denaturation bubbles, which play an essential role in the replication and transcription of DNA. We experimentally map the region of the force-torsion space where the denaturation takes place. We observe that large fluctuations in DNA extension occur at one of the boundaries of this region, i.e., when the formation of denaturation bubbles and of plectonemes compete. To describe the experiments, we introduce a suitable extension of the classical model. The model correctly describes the position of the denaturation regions, the transition boundaries, and the measured values of the DNA extension fluctuations.

The Changing Lifeworld of Young People: Risk, Resume-Padding, and Civic Engagement. Circle Working Paper 40

ERIC Educational Resources Information Center

Friedland, Lewis A.; Morimoto, Shauna

2005-01-01

This research assumes a relatively stable lifeworld for young people. For example, it assumes that the meaning of volunteering or service is sufficiently similar across multiple contexts to remain a valid and stable indicator. By extension, it also assumes that the lifeworld of young people today is not undergoing a period of rapid, and perhaps…

Multi-analysis strategy for metabolism of Andrographis paniculata in rat using liquid chromatography/quadrupole time-of-flight mass spectrometry.

PubMed

Li, Wenlan; Sun, Xiangming; Xu, Ying; Wang, Xuezhi; Bai, Jing; Ji, Yubin

2015-07-01

Compared with chemical drugs, it is a huge challenge to identify active ingredients of multicomponent traditional Chinese medicine (TCM). For most TCMs, metabolism investigation of absorbed constituents is a feasible way to clarify the active material basis. Although Andrographis paniculata (AP) has been extensively researched by domestic and foreign scholars, its metabolism has seldom been fully addressed to date. In this paper, high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was applied to analysis and characterization of AP metabolism in rat urine and feces samples after oral administration of ethanol extract. The differences in metabolites and metabolic pathways between the two biological samples were further compared. The chemical structures of 20 components were tentatively identified from drug-treated biological samples, including six prototype components and 14 metabolites, which underwent such main metabolic pathways as hydrolyzation, hydrogenation, dehydroxylation, deoxygenation, methylation, glucuronidation, sulfonation and sulfation. Two co-existing components were found in urine and feces samples, suggesting that some ingredients' metabolic processes were not unique. This study provides a comprehensive report on the metabolism of AP in rats, which will be helpful for understanding its mechanism. Copyright © 2014 John Wiley & Sons, Ltd.

THE EFFECTS OF TYPE II BINDING ON METABOLIC STABILITY AND BINDING AFFINITY IN CYTOCHROME P450 CYP3A4

PubMed Central

Peng, Chi-Chi; Pearson, Josh T.; Rock, Dan A.; Joswig-Jones, Carolyn A.; Jones, Jeffrey P.

2010-01-01

One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound’s metabolic stability can be increased by incorporation of a sp2 nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme iron (termed type II binding). However, questions regarding binding affinity, metabolic stability, and how metabolism of type II binders occurs remain unanswered. Herein, we use pyridinyl quinoline-4-carboxamide analogs to answer these questions. We show that type II binding can have a profound influence on binding affinity for CYP3A4, and the difference in binding affinity can be as high as 1,200 fold. We also find that type II binding compounds can be extensively metabolized, which is not consistent with the dead-end complex kinetic model assumed for type II binders. Two alternate kinetic mechanisms are presented to explain the results. The first involves a rapid equilibrium between the type II bound substrate and a metabolically oriented binding mode. The second involves direct reduction of the nitrogen-coordinated heme followed by oxygen binding. PMID:20346909

The dysmetabolic syndrome: epidemiology and etiology.

PubMed

Sauerwein, H P

2006-01-01

The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. It also refers to a clustering of specific cardiovascular disease risk factors whose underlying pathophysiology is thought to be related to insulin resistance with an excessive flux of fatty acids implicated. Opinions have varied as to whether the metabolic syndrome should be defined to indicate mainly insulin resistance, the metabolic consequences of obesity, risk of cardiovascular disease, or simply a collection of statistically related factors. Based on these different viewpoints 4 definition sets of the metabolic syndrome are formulated. The pros and cons of each of them are extensively discussed. A major role in the etiology of the metabolic syndrome is ascribed to the occurrence of insulin resistance. Data are provided that insulin resistance can worsen the expression of this syndrome, but cannot have a primary role. Therefore, insulin resistance is not the main player of the metabolic syndrome, but central obesity is. Free fatty acid induced insulin resistance is found and induced by central obesity. The metabolic syndrome is a cluster of abnormalities in which each of them deserves its own (maximal) treatment to diminish the risk for cardiovascular disease.

Maternal Pseudo-Bartter Syndrome Associated with Severe Perinatal Brain Injury.

PubMed

Vora, Shrenik; Ibrahim, Thowfique; Rajadurai, Victor Samuel

2017-09-15

Maternal electrolyte imbalance is rarely reported as causative factor of severe perinatal brain injury. This case outlines a unique maternal and neonatal pseudo-Bartter syndrome presented with metabolic alkalosis and hypochloremia due to maternal severe vomiting. Neonatal MRI brain revealed extensive brain hemorrhages with porencephalic cysts. Subsequent investigation workup points towards maternal severe metabolic alkalosis as its cause. Careful medical attention should be paid to pregnant women with excessive vomiting to ensure a healthy outcome for both the mother and the baby.

Is hypercortisolism in anorexia nervosa detectable using hair samples?

PubMed

Ritschel, Franziska; Clas, Sabine; Geisler, Daniel; Haas, Verena; Seidel, Maria; Steding, Julius; Roessner, Veit; Kirschbaum, Clemens; Ehrlich, Stefan

2018-03-01

Anorexia nervosa (AN) is a severe mental disorder accompanied by extensive metabolic and endocrine abnormalities. It has been associated with hypercortisolism using short-term measurement methods such as 24 h-urine, saliva, and blood. The aim of this study was to examine whether the proposed hypercortisolism in acutely underweight AN (acAN) is also reflected in a long-term measure: hair cortisol (HCC). To gain further insight, we compared hair cortisol to a well-established classical cortisol measure (24 h-urine; UCC) longitudinally in acAN. Hair samples were collected and analyzed using a LC-MS/MS-based method to provide a monthly cortisol value. We compared HCC in samples of 40 acAN with 40 pairwise age-matched healthy controls (HC) as well as 23 long-term recovered AN participants (recAN) with 23 pairwise age-matched HC (cross-sectional design). In the second part, UCC collected weekly during 14 weeks of weight-restoration therapy in 16 acAN was compared with the (time-corresponding) HCC using linear mixed models and bivariate correlations (longitudinal design). No group differences in HCC occurred comparing acAN and recAN to HC (cross-sectional study). The longitudinal analysis revealed a decrease of UCC but not HCC with weight gain. Furthermore, there was no overall significant association between UCC and HCC. Only in the last four weeks of weight-restoration therapy we found a significant moderate correlation between UCC and HCC. HCC did not reflect the expected hypercortisolism in acAN and did not decrease during short-term weight-restoration. Time-corresponding measurements of UCC and HCC were not consistently associated in our longitudinal analysis of acAN undergoing inpatient treatment. Given the drastic metabolic disturbances in acutely underweight AN our findings could be interpreted as disturbed cortisol incorporation or altered activity of 11-β-HSD-enzymes in the hair follicle. Copyright © 2017. Published by Elsevier Ltd.

A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

PubMed

Paine, Mary F; Widmer, Wilbur W; Hart, Heather L; Pusek, Susan N; Beavers, Kimberly L; Criss, Anne B; Brown, Sherri S; Thomas, Brian F; Watkins, Paul B

2006-05-01

Grapefruit juice (GFJ) enhances the systemic exposure of numerous CYP3A4 drug substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. Furanocoumarins have been identified as major CYP3A4 inhibitors contained in the juice, but their contribution to the GFJ effect in vivo remains unclear. To ascertain whether furanocoumarins mediate the GFJ-felodipine interaction, a furanocoumarin-free GFJ was created and tested against orange juice and the original GFJ with respect to the oral pharmacokinetics of felodipine. With the use of food-grade solvents and absorption resins, furanocoumarins were removed (approximately 99%) from whole GFJ, whereas other major ingredients (flavonoids) were retained. In an open, 3-way, randomized crossover design, 18 healthy volunteers ingested felodipine (10 mg) with 1 of the 3 juices (240 mL). Blood was collected over 24 h. At least 1 wk elapsed between juice treatments. The median and range of the area under the curve and the maximum concentration of felodipine were significantly (P < 0.001) greater with consumption of GFJ [110 (range: 58-270) nmol . h/L and 21 (7.6-50) nmol/L, respectively] than with that of orange juice [54 (29-150) nmol . h/L and 7.6 (3.4-13.9) nmol/L, respectively] or furanocoumarin-free GFJ [48 (23-120) nmol . h/L and 8.3 (3.0-16.6) nmol/L, respectively]. GFJ, orange juice, and furanocoumarin-free GFJ did not differ significantly (P > 0.09) in median time to reach maximum plasma concentration [2.5 (1.5-6), 2.8 (1.5-4), and 2.5 (2-6) h, respectively] or terminal half-life [6.6 (4.2-13.6), 7.8 (4.4-13.2), and 6.8 (2.6-14.4) h, respectively]. Furanocoumarins are the active ingredients in GFJ responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first-pass metabolism.

Enantioselective distribution of albendazole metabolites in cerebrospinal fluid of patients with neurocysticercosis

PubMed Central

Takayanagui, O M; Bonato, P S; Dreossi, S A C; Lanchote, V L

2002-01-01

Aims Albendazole (ABZ) is effective in the treatment of neurocysticercosis. ABZ undergoes extensive metabolism to (+) and (−)-albendazole sulphoxide (ASOX), which are further metabolized to albendazole sulphone (ASON). We have investigated the distribution of (+)-ASOX (−)-ASOX, and ASON in cerebrospinal fluid (CSF) of patients with neurocysticercosis. Methods Twelve patients with a diagnosis of active brain parenchymal neurocysticercosis treated with albendazole for 8 days (15 mg kg−1 day−1) were investigated. On day 8, serial blood samples were collected during the dose interval (0–12 h) and one CSF sample was taken from each patient by lumbar puncture at different time points up to 12 h after the last albendazole dose. Albendazole metabolites were determined in CSF and plasma samples by h.p.l.c. using a Chiralpak AD column and fluorescence detection. Population curves for CSF albendazole metabolite concentration vs time were constructed. Results The mean plasma/CSF ratios were 2.6 (95% CI: 1.9, 3.3) for (+)-ASOX and 2.7 (95% CI: 1.8, 3.7) for (−)-ASOX, with the two-tailed P value of 0.9873 being non-significant. These data indicate that the transport of ASOX through the blood–brain barrier is not enantioselective, but rather depends on passive diffusion. The present results suggest the accumulation of the (+)-ASOX metabolite in the CSF of patients with neurocysticercosis. The CSF AUC(+)/AUC(−) ratio was 3.4 for patients receiving albendazole every 12 h. The elimination half-life of both ASOX enantiomers in CSF was 2.5 h. ASOX was the predominant metabolite in the CSF compared with ASON; the CSF AUCASOX/AUCASON ratio was approximately 20 and the elimination half-life of ASON in CSF was 2.6 h. Conclusions We have demonstrated accumulation of the (+)-ASOX metabolite in CSF, which was about three times greater than the (−) antipode. ASOX concentrations were approximately 20 times higher than those observed for the ASON metabolite. PMID:12207631

Metabolic syndrome after laparoscopic bariatric surgery.

PubMed

Nugent, Clare; Bai, Chunhong; Elariny, Hazem; Gopalakrishnan, Priya; Quigley, Caitlin; Garone, Michael; Afendy, Mariam; Chan, Oscar; Wheeler, Angela; Afendy, Arian; Younossi, Zobair M

2008-10-01

Metabolic syndrome (MS) is common among morbidly obese patients undergoing bariatric surgery. The aim of this study was to assess the impact and predictors of bariatric surgery on the resolution of MS. Subjects included 286 patients [age 44.0 +/- 11.5, female 78.2%, BMI 48.7 +/- 9.4, waist circumference 139 +/- 20 cm, AST 23.5 +/- 14.9, ALT 30.0 +/- 20.1, type 2 diabetes mellitus (DM) 30.1% and MS 39.2%] who underwent bariatric surgery. Of the entire cohort, 27.3% underwent malabsorptive surgery, 55.9% underwent restrictive surgery, and 16.8% had combination restrictive-malabsorptive surgery. Mean weight loss was 33.7 +/- 20.1 kg after restrictive surgery (follow up period 298 +/- 271 days), 39.4 +/- 22.9 kg after malabsorptive surgery (follow-up period 306 +/- 290 days), and 28.3 +/- 14.1 kg after combination surgery (follow-up period 281 +/- 239 days). Regardless of the type of bariatric surgery, significant improvements were noted in MS (p values from <0.0001-0.01) as well as its components such as DM (p values from <0.0001-0.0005), waist circumference (p values <0.0001), BMI (p values <0.0001), fasting serum triglycerides (p values <0.0001 to 0.001), and fasting serum glucose (p values <0.0001). Additionally, a significant improvement in AST/ALT ratio (p value = 0.0002) was noted in those undergoing restrictive surgery. Multivariate analysis showed that patients who underwent malabsorptive bariatric procedures experienced a significantly greater percent excess weight loss than patients who underwent restrictive procedures (p value = 0.0451). Percent excess weight loss increased with longer postoperative follow-up (p value <0.0001). Weight loss after bariatric surgery is associated with a significant improvement in MS and other metabolic factors.

Predictive factors of silent reflux in subjects with erosive esophagitis.

PubMed

Lei, Wei-Yi; Yu, Hao-Chun; Wen, Shu-Hui; Liu, Tso-Tsai; Yi, Chih-Hsun; Wang, Chia-Chi; Hsu, Ching-Sheng; Chen, Chien-Hwa; Chen, Chien-Lin; Pace, Fabio

2015-01-01

Asymptomatic erosive esophagitis by definition is a condition lacking any reflux symptom. We aimed to investigate the prevalence of asymptomatic erosive esophagitis in a general population undergoing periodic health checkup. Consecutive subjects undergoing a medical checkup were enrolled for evaluation of reflux disease with upper endoscopy and a validated reflux questionnaire. The presence and severity of erosive esophagitis were evaluated. In all subjects, demographic characteristics and biochemical data were recorded, and sleep and psychological characteristics were assessed by means of self-administered Pittsburgh Sleep Quality Index score, Taiwanese Depression Questionnaire score, and State-Trait Anxiety Inventory score. Of 2568 subjects eligible for this study, erosive esophagitis was found in 676 subjects (26.3%), in whom the proportions of asymptomatic and symptomatic erosive esophagitis were 59.2% (400 subjects) and 40.8% (276 subjects) respectively. At a univariate analysis, it was found that asymptomatic erosive esophagitis subjects were more frequently of female gender, of older age, with a lower level of education. They also showed less alcohol and tea consumption, less depression, less anxiety, lower serum level of triglyceride, and lower prevalence of metabolic syndrome. Multivariate analysis revealed that female sex (OR = 1.645, p = 0.0146) was a positive predictive factor for asymptomatic erosive esophagitis, whereas higher level of education (OR = 0.564, p = 0.044), higher Taiwanese Depression Questionnaire score (OR = 0.922, p < 0.001), and the presence of metabolic syndrome (OR = 0.625, p = 0.0379) were negative predictive factors. Asymptomatic erosive esophagitis is a common feature in otherwise healthy subjects and is independently associated with female gender, lower education level, less depression, and lower prevalence of metabolic syndrome. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Extensive Turnover of Compatible Solutes in Cyanobacteria Revealed by Deuterium Oxide (D 2 O) Stable Isotope Probing

DOE PAGES

Baran, Richard; Lau, Rebecca; Bowen, Benjamin P.; ...

2017-01-18

In diverse environments on a global scale cyanobacteria are important primary producers of organic matter. Moreover, while mechanisms of CO 2 fixation are well understood, the distribution of the flow of fixed organic carbon within individual cells and complex microbial communities is less well characterized. To obtain a general overview of metabolism, we describe the use of deuterium oxide (D 2O) to measure deuterium incorporation into the intracellular metabolites of two physiologically diverse cyanobacteria: a terrestrial filamentous strain (Microcoleus vaginatus PCC 9802) and a euryhaline unicellular strain (Synechococcus sp. PCC 7002). D 2O was added to the growth medium duringmore » different phases of the diel cycle. Incorporation of deuterium into metabolites at nonlabile positions, an indicator of metabolite turnover, was assessed using liquid chromatography mass spectrometry. Expectedly, large differences in turnover among metabolites were observed. Some metabolites, such as fatty acids, did not show significant turnover over 12–24 h time periods but did turn over during longer time periods. Unexpectedly, metabolites commonly regarded to act as compatible solutes, including glutamate, glucosylglycerol, and a dihexose, showed extensive turnover compared to most other metabolites already after 12 h, but only during the light phase in the cycle. We observed extensive turnover and found it surprising considering the conventional view on compatible solutes as biosynthetic end points given the relatively slow growth and constant osmotic conditions. Our suggests the possibility of a metabolic sink for some compatible solutes (e.g., into glycogen) that allows for rapid modulation of intracellular osmolarity. To investigate this, uniformly 13C-labeled Synechococcus sp. PCC 7002 were exposed to 12C glucosylglycerol. Following metabolite extraction, amylase treatment of methanol-insoluble polymers revealed 12C labeling of glycogen. Overall, our work shows that D 2O probing is a powerful method for analysis of cyanobacterial metabolism including discovery of novel metabolic processes.« less

[Comparative effectiveness of the antisecretory action of rabeprazole and esomeprazole in people with rapid metabolism of proton pump inhibitors].

PubMed

Morozov, S V; Tsodikova, O M; Isakov, V A; Gushchin, A E; Shipulin, G A

2003-01-01

To compare antisecretory effects of Rabeprazole and Esomeprazole in proton pump inhibitors extensive metabolizers in an open, randomized, two-way crossover study. Sixteen GERD H. pylori-positive patients (8 men, mean age 49.6 and 8 women, mean age 49.3) with the homozygous extensive metabolizer genotype of CYP2C19 determined by polymerase chain reaction-restriction fragment length polymorphism analysis received Rabeprazole 20 mg or Esomeprazole 20 mg daily on days 1-6, with a 14-day wash-out period. Intragastric pH was recorded continuously on days 0, 1, 5 and 7. On days 1 and 5 no differences were found between Rabeprazole 20 mg and Esomeprazole 20 mg in 24-hours median pH (day 1: 5.9 versus 5.0; day 5: 6.45 versus 6.3) or in percent of time with pH 4 (day 1: 57.8% versus 50.5%; day 5: 81.4% versus 81.2%). On day 1, mean percent of time pH 4 were significantly greater after Esomeprazole 20 mg 52.6% (95% CI: 23.6-68.2) than Rabeprazole 20 mg 33.0% (95% CI: 15.3-48.2) during 0-6 h (p = 0.02). On day 7 (24 later the last dose), 24-hours median pH was higher after Esomeprazole 20 mg than Rabeprazole 20 mg (2.7 versus 5.05; p = 0.02). Rabeprazole 20 mg and Esomeprazole 20 mg are equally effective in increasing gastric pH in H. pylori-positive PPI extensive metabolizers on days 1 and 5. Esomeprazole 20 mg is more effective than Rabeprazole 20 mg in maintaining pH 4 during the first 6 hours on the first day and increasing of intragastric pH on the day 24 hours later the last dose.

ELAV Links Paused Pol II to Alternative Polyadenylation in the Drosophila Nervous System

PubMed Central

Oktaba, Katarzyna; Zhang, Wei; Lotz, Thea Sabrina; Jun, David Jayhyun; Lemke, Sandra Beatrice; Ng, Samuel Pak; Esposito, Emilia; Levine, Michael; Hilgers, Valérie

2014-01-01

SUMMARY Alternative polyadenylation (APA) has been implicated in a variety of developmental and disease processes. A particularly dramatic form of APA occurs in the developing nervous system of flies and mammals, whereby various developmental genes undergo coordinate 3′ UTR extension. In Drosophila, the RNA-binding protein ELAV inhibits RNA processing at proximal polyadenylation sites, thereby fostering the formation of exceptionally long 3′ UTRs. Here, we present evidence that paused Pol II promotes recruitment of ELAV to extended genes. Replacing promoters of extended genes with heterologous promoters blocks normal 3′ extension in the nervous system, while extension-associated promoters can induce 3′ extension in ectopic tissues expressing ELAV. Computational analyses suggest that promoter regions of extended genes tend to contain paused Pol II and associated cis-regulatory elements such as GAGA. ChIP-Seq assays identify ELAV in the promoter regions of extended genes. Our study provides evidence for a regulatory link between promoter-proximal pausing and APA. PMID:25544561

Gender-related similarities and differences in the body distribution of grape seed flavanols in rats.

PubMed

Margalef, Maria; Pons, Zara; Iglesias-Carres, Lisard; Arola, Lluís; Muguerza, Begoña; Arola-Arnal, Anna

2016-04-01

Dietary flavanols produce beneficial health effects, and once absorbed, they are recognized as xenobiotics and undergo phase-II enzymatic detoxification. Flavanols health-promoting properties are mainly attributed to their metabolic products. This work aimed to elucidate whether rats of the opposite sex exhibited differences in the metabolism and distribution of ingested flavanols. Acute doses of grape seed polyphenols were administered to male and female rats. After 1, 2 and 4 h, plasma, liver, mesenteric white adipose tissue (MWAT), brain and hypothalamus flavanol metabolites were quantified by HPLC-MS/MS. Results indicated important sex-related quantitative differences in plasma and brain. Moreover, remarkable sex-related differences in the distributions and types of flavanol metabolites were also observed between liver and brain. This study demonstrated that sex differentially influences the metabolism and distribution of flavanols throughout the bodies of rats, which may affect the physiological bioactivities of flavanols between males and females. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages.

PubMed

Mills, Evanna L; Kelly, Beth; Logan, Angela; Costa, Ana S H; Varma, Mukund; Bryant, Clare E; Tourlomousis, Panagiotis; Däbritz, J Henry M; Gottlieb, Eyal; Latorre, Isabel; Corr, Sinéad C; McManus, Gavin; Ryan, Dylan; Jacobs, Howard T; Szibor, Marten; Xavier, Ramnik J; Braun, Thomas; Frezza, Christian; Murphy, Michael P; O'Neill, Luke A

2016-10-06

Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Chlorinated Hydrocarbon Degradation in Plants: Mechanisms and Enhancement of Phytoremediation of Groundwater Contamination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Strand, Stuart E.

2002-06-01

Several varieties of transgenic poplar containing cytochrome P-450 2E1 have been constructed and are undergoing tests. Strategies for improving public acceptance and safety of transgenic poplar for chlorinated hydrocarbon phytoremediation are being developed. We have discovered a unique rhizobium species that lives within the stems of poplar and we are investigating whether this bacterium contributes nitrogen fixed from the air to the plant and whether this endophyte could be used to introduce genes into poplar. Studies of the production of chloride ion from TCE have shown that our present P-450 constructs did not produce chloride more rapidly than wild typemore » plants. Follow-up studies will determine if there are other rate limiting downstream steps in TCE metabolism in plants. Studies of the metabolism of carbon tetrachloride in poplar cells have provided evidence that the native plant metabolism is due to the activity of oxidative enzymes similar to the mammalian cytochrome P-450 2E1.« less

The physical health of Indigenous and non-Indigenous patients participating in residential rehabilitation programs: a comparison study.

PubMed

Meehan, Tom; Jones, Donna; Stedman, Terry; Johnson, Dean; Suetani, Shuichi; Foreman, Emma

2017-04-01

To examine the differences in the physical health of Indigenous and non-Indigenous patients with severe mental illness (SMI) undergoing psychiatric rehabilitation. An audit of the physical health of patients ( n = 361) in all publicly funded residential rehabilitation programs in Queensland was carried out in late 2014. Data collection focused on clinical and lifestyle factors associated with physical health. The prevalence of smoking, substance use and type 2 diabetes in Indigenous patients was significantly higher than rates found in non-Indigenous patients. Metabolic syndrome was also significantly higher in indigenous patients, with 66% of Indigenous patients compared to 46% of non-Indigenous patients meeting criteria for metabolic syndrome. Patients with SMI in residential rehabilitation programs have poor physical health. Our findings underscore the need for clinicians to develop and evaluate interventions aimed at improving the metabolic profile of those with SMI in residential rehabilitation programs. Historical factors and cultural traditions need to be considered when designing lifestyle interventions for Indigenous patients.

Transcriptome analysis illuminates the nature of the intracellular interaction in a vertebrate-algal symbiosis

PubMed Central

Burns, John A; Zhang, Huanjia; Hill, Elizabeth; Kim, Eunsoo; Kerney, Ryan

2017-01-01

During embryonic development, cells of the green alga Oophila amblystomatis enter cells of the salamander Ambystoma maculatum forming an endosymbiosis. Here, using de novo dual-RNA seq, we compared the host salamander cells that harbored intracellular algae to those without algae and the algae inside the animal cells to those in the egg capsule. This two-by-two-way analysis revealed that intracellular algae exhibit hallmarks of cellular stress and undergo a striking metabolic shift from oxidative metabolism to fermentation. Culturing experiments with the alga showed that host glutamine may be utilized by the algal endosymbiont as a primary nitrogen source. Transcriptional changes in salamander cells suggest an innate immune response to the alga, with potential attenuation of NF-κB, and metabolic alterations indicative of modulation of insulin sensitivity. In stark contrast to its algal endosymbiont, the salamander cells did not exhibit major stress responses, suggesting that the host cell experience is neutral or beneficial. DOI: http://dx.doi.org/10.7554/eLife.22054.001 PMID:28462779

Fenetylline: new results on pharmacology, metabolism and kinetics.

PubMed

Nickel, B; Niebch, G; Peter, G; von Schlichtegroll, A; Tibes, U

1986-06-01

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.

Identification of the Human SULT Enzymes Involved in the Metabolism of Rotigotine.

PubMed

Jia, Chaojun; Luo, Lijun; Kurogi, Katsuhisa; Yu, Juming; Zhou, Chunyang; Liu, Ming-Cheh

2016-06-01

Sulfation has been reported to be a major pathway for the metabolism and inactivation of rotigotine in vivo. The current study aimed to identify the human cytosolic sulfotransferase (SULT) enzyme(s) capable of mediating the sulfation of rotigotine. Of the 13 known human SULTs examined, 6 of them (SULT1A1, 1A2, 1A3, 1B1, 1C4, 1E1) displayed significant sulfating activities toward rotigotine. pH dependence and kinetic parameters of the sulfation of rotigotine by relevant human SULTs were determined. Of the 6 human organ samples tested, small intestine and liver cytosols displayed considerably higher rotigotine-sulfating activity than did brain, lung, and kidney. Moreover, sulfation of rotigotine was shown to occur in HepG2 human hepatoma cells and Caco-2 human colon adenocarcinoma cells under metabolic conditions. Collectively, the results obtained provided a molecular basis underlying the previous finding of the excretion of sulfated rotigotine by patients undergoing treatment with rotigotine. © 2015, The American College of Clinical Pharmacology.

Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders.

PubMed

Trauner, Michael; Halilbasic, Emina; Claudel, Thierry; Steinacher, Daniel; Fuchs, Claudia; Moustafa, Tarek; Pollheimer, Marion; Krones, Elisabeth; Kienbacher, Christian; Traussnigg, Stefan; Kazemi-Shirazi, Lili; Munda, Petra; Hofer, Harald; Fickert, Peter; Paumgartner, Gustav

2015-01-01

24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling 'ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on 'Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders. 2015 S. Karger AG, Basel.

Quantum Gravity in Cyclic (ekpyrotic) and Multiple (anthropic) Universes with Strings And/or Loops

NASA Astrophysics Data System (ADS)

Chung, T. J.

2008-09-01

This paper addresses a hypothetical extension of ekpyrotic and anthropic principles, implying cyclic and multiple universes, respectively. Under these hypotheses, from time immemorial (t = -∞), a universe undergoes a big bang from a singularity, initially expanding and eventually contracting to another singularity (big crunch). This is to prepare for the next big bang, repeating these cycles toward eternity (t = +∞), every 30 billion years apart. Infinity in time backward and forward (t = ±∞) is paralleled with infinity in space (Xi = ±∞), allowing multiple universes to prevail, each undergoing big bangs and big crunches similarly as our own universe. It is postulated that either string theory and /or loop quantum gravity might be able to substantiate these hypotheses.

Replacement of Atlantis', OV-104's, right orbital maneuvering system pod

NASA Technical Reports Server (NTRS)

1988-01-01

Atlantis', Orbiter Vehicle (OV) 104's, right orbital maneuvering system (OMS) pod (RP01) is placed in a checkout cell at Kennedy Space Center's (KSC's) Hypergolic Maintenance Facility (HMF). Technicians steady OMS mounted on ground handling cart as third technician, standing on ladder, secures support frame. At the HMF, a group of specially-equipped buildings in the KSC Industrial Area, the OMS pods are undergoing extensive processing, including removal of certain components that will undergo modification at vendor facilities prior to the Shuttle's return to flight. The OMS pods are bolted to the aft fuselage of the orbiter and contain the engines and thrusters used to maneuver the spaceship in orbit. View provided by KSC with alternate number KSC-87PC-93.

KSC-98pc1162

NASA Image and Video Library

1998-09-27

KENNEDY SPACE CENTER, FLA. -- The Shuttle Carrier Aircraft rolls to a stop with its piggyback cargo orbiter Atlantis at the Shuttle Landing Facility. In the background is the Vehicle Assembly Building. Atlantis returns home after a 10-month stay in the Palmdale, CA, orbiter processing facility undergoing extensive inspections and modifications. They included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. The flight from Palmdale included a fueling stop in Ft. Hood, TX, and overnight stay at Ft. Campbell, KY. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

KSC-98pc1163

NASA Image and Video Library

1998-09-27

KENNEDY SPACE CENTER, FLA. -- Stairs are rolled to the forward opening of the Shuttle Carrier Aircraft with its piggyback cargo, the orbiter Atlantis after it rolls to a stop at the Shuttle Landing Facility. Atlantis returns home after a 10-month stay in the Palmdale, CA, orbiter processing facility undergoing extensive inspections and modifications. They included several upgrades enabling it to support International Space Station missions, such as adding an external airlock for ISS docking missions and installing thinner, lighter thermal protection blankets for weight reduction which will allow it to haul heavier cargo. The flight from Palmdale included a fueling stop in Ft. Hood, TX, and overnight stay at Ft. Campbell, KY. Atlantis will undergo preparations in the Orbiter Processing Facility at KSC for its planned flight in June 1999

Lifelong alpha-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage.

PubMed

Selman, Colin; McLaren, Jane S; Mayer, Claus; Duncan, Jackie S; Collins, Andrew R; Duthie, Garry G; Redman, Paula; Speakman, John R

2008-02-01

The effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 +/- 2 degrees C and supplemented their diet with alpha-tocopherol from 4 months of age. Supplementation significantly increased (p = 0.042) median life span by 15% (785 days, n = 44) relative to unsupplemented controls (682 days, n = 43) and also increased maximum life span (oldest 10%, p = 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that alpha-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of alpha-tocopherol. We propose that the life span extension observed following alpha-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following alpha-tocopherol supplementation.

Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

PubMed

Brown, Jacob T; Bishop, Jeffrey R

2015-01-01

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

Marine Omega-3 Phospholipids: Metabolism and Biological Activities

PubMed Central

Burri, Lena; Hoem, Nils; Banni, Sebastiano; Berge, Kjetil

2012-01-01

The biological activities of omega-3 fatty acids (n-3 FAs) have been under extensive study for several decades. However, not much attention has been paid to differences of dietary forms, such as triglycerides (TGs) versus ethyl esters or phospholipids (PLs). New innovative marine raw materials, like krill and fish by-products, present n-3 FAs mainly in the PL form. With their increasing availability, new evidence has emerged on n-3 PL biological activities and differences to n-3 TGs. In this review, we describe the recently discovered nutritional properties of n-3 PLs on different parameters of metabolic syndrome and highlight their different metabolic bioavailability in comparison to other dietary forms of n-3 FAs. PMID:23203133

Metabolic brain networks in aging and preclinical Alzheimer's disease.

PubMed

Arnemann, Katelyn L; Stöber, Franziska; Narayan, Sharada; Rabinovici, Gil D; Jagust, William J

2018-01-01

Metabolic brain networks can provide insight into the network processes underlying progression from healthy aging to Alzheimer's disease. We explore the effect of two Alzheimer's disease risk factors, amyloid-β and ApoE ε4 genotype, on metabolic brain networks in cognitively normal older adults (N = 64, ages 69-89) compared to young adults (N = 17, ages 20-30) and patients with Alzheimer's disease (N = 22, ages 69-89). Subjects underwent MRI and PET imaging of metabolism (FDG) and amyloid-β (PIB). Normal older adults were divided into four subgroups based on amyloid-β and ApoE genotype. Metabolic brain networks were constructed cross-sectionally by computing pairwise correlations of metabolism across subjects within each group for 80 regions of interest. We found widespread elevated metabolic correlations and desegregation of metabolic brain networks in normal aging compared to youth and Alzheimer's disease, suggesting that normal aging leads to widespread loss of independent metabolic function across the brain. Amyloid-β and the combination of ApoE ε4 led to less extensive elevated metabolic correlations compared to other normal older adults, as well as a metabolic brain network more similar to youth and Alzheimer's disease. This could reflect early progression towards Alzheimer's disease in these individuals. Altered metabolic brain networks of older adults and those at the highest risk for progression to Alzheimer's disease open up novel lines of inquiry into the metabolic and network processes that underlie normal aging and Alzheimer's disease.

PanDaTox: A tool for accelerated metabolic engineering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amitai, Gil; Sorek, Rotem

2012-07-18

Metabolic engineering is often facilitated by cloning of genes encoding enzymes from various heterologous organisms into E. coli. Such engineering efforts are frequently hampered by foreign genes that are toxic to the E. coli host. We have developed PanDaTox (www.weizmann.ac.il/pandatox), a web-based resource that provides experimental toxicity information for more than 1.5 million genes from hundreds of different microbial genomes. The toxicity predictions, which were extensively experimentally verified, are based on serial cloning of genes into E. coli as part of the Sanger whole genome shotgun sequencing process. PanDaTox can accelerate metabolic engineering projects by allowing researchers to exclude toxicmore » genes from the engineering plan and verify the clonability of selected genes before the actual metabolic engineering experiments are conducted.« less

Quantitative Analysis of Cellular Metabolic Dissipative, Self-Organized Structures

PubMed Central

de la Fuente, Ildefonso Martínez

2010-01-01

One of the most important goals of the postgenomic era is understanding the metabolic dynamic processes and the functional structures generated by them. Extensive studies during the last three decades have shown that the dissipative self-organization of the functional enzymatic associations, the catalytic reactions produced during the metabolite channeling, the microcompartmentalization of these metabolic processes and the emergence of dissipative networks are the fundamental elements of the dynamical organization of cell metabolism. Here we present an overview of how mathematical models can be used to address the properties of dissipative metabolic structures at different organizational levels, both for individual enzymatic associations and for enzymatic networks. Recent analyses performed with dissipative metabolic networks have shown that unicellular organisms display a singular global enzymatic structure common to all living cellular organisms, which seems to be an intrinsic property of the functional metabolism as a whole. Mathematical models firmly based on experiments and their corresponding computational approaches are needed to fully grasp the molecular mechanisms of metabolic dynamical processes. They are necessary to enable the quantitative and qualitative analysis of the cellular catalytic reactions and also to help comprehend the conditions under which the structural dynamical phenomena and biological rhythms arise. Understanding the molecular mechanisms responsible for the metabolic dissipative structures is crucial for unraveling the dynamics of cellular life. PMID:20957111

The cellular basis of the convergence and extension of the Xenopus neural plate.

PubMed

Keller, R; Shih, J; Sater, A

1992-03-01

There is great interest in the patterning and morphogenesis of the vertebrate nervous system, but the morphogenetic movements involved in early neural development and their underlying cellular mechanisms are poorly understood. This paper describes the cellular basis of the early neural morphogenesis of Xenopus laevis. The results have important implications for neural induction. Mapping the fate map of the midneurula (Eagleson and Harris: J. Neurobiol. 21:427-440, 1990) back to the early gastrula with time-lapse video recording demonstrates that the prospective hindbrain and spinal cord are initially very wide and very short, and thus at the beginning of gastrulation all their precursor cells lie within a few cell diameters of the inducing mesoderm. In the midgastrula, the prospective hindbrain and spinal cord undergo very strong convergence and extension movements in two phases: In the first phase they primarily undergo thinning in the radial direction and lengthening (extension) in the animal-vegetal direction, and the second phase is characterized primarily by mediolateral narrowing (convergence) and anterior-posterior lengthening (extension). These movements also occur in sandwich explants of the gastrula, thus demonstrating the local autonomy of the forces producing them. Tracing cell movements with fluorescein dextran-labeled cells in embryos or explants shows that the initial thinning and extension occurs by radial intercalation of deep cells to form fewer layers of greater area, all of which is expressed as increased length. The subsequent convergence and extension occurs by mediolateral intercalation of deep cells to form a longer, narrower array. These results establish that a similar if not identical sequence of radial and mediolateral cell intercalations underlie convergence and extension of the neural and the mesoderm tissues (Wilson and Keller: Development, 112:289-300, 1991). Moreover, these results establish that radial and mediolateral intercalation are the principal neural cell behaviors induced by the planar signals emanating from the dorsal involuting marginal zone (the Spemann organizer) in the early gastrula (Keller et al: Develop. Dynamics, 193: 218-234, 1992). Radial and mediolateral intercalation are induced among the 5 to 7 rows of cells comprising the prospective hindbrain and spinal cord, thus producing the massive convergence and extension movements that narrow and elongate these regions of the nervous system in the late gastrula. A more general significance of these results is that neural induction is best analyzed and understood in terms of the dynamics of the morphogenetic processes involved.

Recent developments of cyclotron produced radionuclides for nuclear cardiology

NASA Astrophysics Data System (ADS)

Kulkarni, P. V.; Jansen, D. E.; Corbett, J. R.

1987-04-01

For over a decade myocardial perfusion imaging with thallium-201, a cyclotron product, has been routinely used in clinical medicine. Recent advances have allowed the efficient production of very high purity (> 99.8%) iodine-123. New metabolically active 123I labeled radiopharmaceuticals, including alkyl and phenyl fatty acids, and norepinephrine analogs, have been developed and are undergoing clinical trials. Fab' fragments of monoclonal antibodies to cardiac myosin have been labeled with indium-111 ( 111In) and are undergoing clinical evaluation for imaging myocardial infarcts. Monoclonal antibodies to platelets, fibrin, and the thrombolytic agent, tissue plasminogen activator (TPA), have recently been labeled with 111In. Together these developments in radiotracers and instrumentation should have a significant impact on the future of cardiovascular nuclear medicine. This manuscript will discuss developments in single photon emitting radiotracers for myocardial imaging.

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

PubMed Central

Koeth, Robert A.; Wang, Zeneng; Levison, Bruce S.; Buffa, Jennifer A.; Org, Elin; Sheehy, Brendan T.; Britt, Earl B.; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D.; DiDonato, Joseph A.; Chen, Jun; Li, Hongzhe; Wu, Gary D.; Lewis, James D.; Warrier, Manya; Brown, J. Mark; Krauss, Ronald M.; Tang, W. H. Wilson; Bushman, Frederic D.; Lusis, Aldons J.; Hazen, Stanley L.

2013-01-01

Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk. PMID:23563705

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

PubMed

Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

2017-06-01

Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

An overview of bilastine metabolism during preclinical investigations.

PubMed

Lucero, María Luisa; Gonzalo, Ana; Mumford, Rory; Betanzos, Mónica; Alejandro, Ana

2012-06-01

Knowledge of the biotransformation of oral H₁ antihistamines is clinically important because it can define their pharmacokinetic profile through possible effects on absorption (i.e., first-pass metabolism) and elimination. Further, clinically significant interactions with inhibitors of cytochrome P450 (CYP) have previously been reported for drugs of this therapeutic group, such as terfenadine and astemizole, indicating the possibility of drug-drug interactions involving agents that share the same metabolic pathway. The aim of this article was to review the preclinical testing of a new antihistamine (i.e., bilastine) in terms of its biotransformation in various animal species, including humans, and to evaluate its potential for possible drug-drug interactions involving the CYP system. A wide array of preclinical experiments were reviewed, all of which demonstrated that bilastine undergoes minimal metabolism in all species tested to date, including humans. Further, bilastine did not interact significantly, either as an inhibitor or inducer, with the CYP enzyme system, suggesting a low propensity for involvement in drug-drug interactions. These characteristics demonstrate the potential for bilastine to be a good choice for allergic patients receiving treatment for other concomitant diseases, including those with renal or hepatic dysfunction.

Distinct Metabolic Requirements of Exhausted and Functional Virus-Specific CD8 T Cells in the Same Host.

PubMed

Schurich, Anna; Pallett, Laura J; Jajbhay, Danyal; Wijngaarden, Jessica; Otano, Itziar; Gill, Upkar S; Hansi, Navjyot; Kennedy, Patrick T; Nastouli, Eleni; Gilson, Richard; Frezza, Christian; Henson, Sian M; Maini, Mala K

2016-08-02

T cells undergo profound metabolic changes to meet the increased energy demands of maintaining an antiviral response. We postulated that differences in metabolic reprogramming would shape the efficacy of CD8 T cells mounted against persistent viral infections. We found that the poorly functional PD-1(hi) T cell response against hepatitis B virus (HBV) had upregulated the glucose transporter, Glut1, an effect recapitulated by oxygen deprivation to mimic the intrahepatic environment. Glut1(hi) HBV-specific T cells were dependent on glucose supplies, unlike the more functional cytomegalovirus (CMV)-specific T cells that could utilize oxidative phosphorylation in the absence of glucose. The inability of HBV-specific T cells to switch to oxidative phosphorylation was accompanied by increased mitochondrial size and lower mitochondrial potential, indicative of mitochondrial dysfunction. Interleukin (IL)-12, which recovers HBV-specific T cell effector function, increased their mitochondrial potential and reduced their dependence on glycolysis. Our findings suggest that mitochondrial defects limit the metabolic plasticity of exhausted HBV-specific T cells. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.

PubMed

Caterino, Marianna; Chandler, Randy J; Sloan, Jennifer L; Dorko, Kenneth; Cusmano-Ozog, Kristina; Ingenito, Laura; Strom, Stephen C; Imperlini, Esther; Scolamiero, Emanuela; Venditti, Charles P; Ruoppolo, Margherita

2016-02-01

Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.

Intestinal disposition of quercetin and its phase-II metabolites after oral administration in healthy volunteers.

PubMed

Chalet, Clément; Rubbens, Jari; Tack, Jan; Duchateau, Guus S; Augustijns, Patrick

2018-05-15

Quercetin is one of the main dietary flavonoids and undergoes a substantial intestinal phase-II metabolism. Quercetin conjugates have been detected in plasma and in urine, but their presence in the small intestine has not been assessed. This study aimed to investigate the intestinal metabolism and metabolite excretion of quercetin by the human small intestinal wall after oral dosing. Six healthy volunteers were given a capsule of 500 mg of quercetin with 240 ml of water. Duodenal fluids were collected using the intraluminal sampling technique for 4 h and analysed by LC-MS/MS. Phase-II metabolites of quercetin were detected and quantified in aspirated intestinal fluids. Metabolites appeared almost immediately after administration, indicating an intestinal metabolism and apical excretion into the lumen. Quercetin-3'-O-glucuronide was found to be the main intestinal metabolite. Our results could not conclude on the enterohepatic recycling of quercetin or its metabolites, although several individual profiles showed distinctive peaks. This study highlights the intestinal metabolism and excretion of quercetin and its conjugates in humans and gives insights into the relevant concentrations which should be used to investigate potential food-drug interactions in vitro. © 2018 Royal Pharmaceutical Society.

Therapeutic modulation of cannabinoid lipid signaling: metabolic profiling of a novel antinociceptive cannabinoid-2 receptor agonist

PubMed Central

Wood, JodiAnne T.; Smith, Dustin M.; Janero, David R.; Zvonok, Alexander M.; Makriyannis, Alexandros

2012-01-01

Aims AM-1241, a novel, racemic cannabinoid-2 receptor (CB2) ligand, is the primary experimental agonist used to characterize the role of CB2-mediated lipid signaling in health and disease, including substance abuse disorders. In vivo pharmacological effects have been used as indirect proxies for AM-1241 biotransformation processes that could modulate activity. We report the initial pre-clinical characterization of AM-1241 biotransformation and in vivo distribution. Main methods AM-1241 metabolism was characterized in a variety of predictive in vitro systems (Caco-2 cells, mouse, rat and human microsomes) and in the mouse in vivo. Liquid chromatography and mass spectrometry techniques were used to quantify AM-1241 tissue distribution and metabolic conversion. Key findings AM-1241 bound extensively to plasma protein/albumin. A pharmacological AM-1241 dose (25 mg/kg, i.v.) was administered to mice for direct determination of its plasma half-life (37 min), following which AM-1241 was quantified in brain, spleen, liver, and kidney. After p.o. administration, AM-1241 was detected in plasma, spleen, and kidney; its oral bioavailability was ~21%. From Caco-2 permeability studies and microsomal-based hepatic clearance estimates, in vivo AM-1241 absorption was moderate. Hepatic microsomal metabolism of AM-1241 in vitro generated hydroxylation and demethylation metabolites. Species-dependent differences were discovered in AM-1241’s predicted hepatic clearance. Our data demonstrate that AM-1241 has the following characteristics: a) short plasma half-life; b) limited oral bioavailability; c) extensive plasma/albumin binding; d) metabolic substrate for hepatic hydroxylation and demethylation; e) moderate hepatic clearance. Significance These results should help inform the design, optimization, and pre-clinical profiling of CB2 ligands as pharmacological tools and medicines. PMID:22749867

Comparison of the In Vivo Biotransformation of Two Emerging Estrogenic Contaminants, BP2 and BPS, in Zebrafish Embryos and Adults

PubMed Central

Le Fol, Vincent; Brion, François; Hillenweck, Anne; Perdu, Elisabeth; Bruel, Sandrine; Aït-Aïssa, Selim; Cravedi, Jean-Pierre; Zalko, Daniel

2017-01-01

Zebrafish embryo assays are increasingly used in the toxicological assessment of endocrine disruptors. Among other advantages, these models are 3R-compliant and are fit for screening purposes. Biotransformation processes are well-recognized as a critical factor influencing toxic response, but major gaps of knowledge exist regarding the characterization of functional metabolic capacities expressed in zebrafish. Comparative metabolic studies between embryos and adults are even scarcer. Using 3H-labeled chemicals, we examined the fate of two estrogenic emerging contaminants, benzophenone-2 (BP2) and bisphenol S (BPS), in 4-day embryos and adult zebrafish. BPS and BP2 were exclusively metabolized through phase II pathways, with no major qualitative difference between larvae and adults except the occurrence of a BP2-di-glucuronide in adults. Quantitatively, the biotransformation of both molecules was more extensive in adults. For BPS, glucuronidation was the predominant pathway in adults and larvae. For BP2, glucuronidation was the major pathway in larvae, but sulfation predominated in adults, with ca. 40% conversion of parent BP2 and an extensive release of several conjugates into water. Further larvae/adults quantitative differences were demonstrated for both molecules, with higher residue concentrations measured in larvae. The study contributes novel data regarding the metabolism of BPS and BP2 in a fish model and shows that phase II conjugation pathways are already functional in 4-dpf-old zebrafish. Comparative analysis of BP2 and BPS metabolic profiles in zebrafish larvae and adults further supports the use of zebrafish embryo as a relevant model in which toxicity and estrogenic activity can be assessed, while taking into account the absorption and fate of tested substances. PMID:28346357

Comparison of the In Vivo Biotransformation of Two Emerging Estrogenic Contaminants, BP2 and BPS, in Zebrafish Embryos and Adults.

PubMed

Le Fol, Vincent; Brion, François; Hillenweck, Anne; Perdu, Elisabeth; Bruel, Sandrine; Aït-Aïssa, Selim; Cravedi, Jean-Pierre; Zalko, Daniel

2017-03-25

Zebrafish embryo assays are increasingly used in the toxicological assessment of endocrine disruptors. Among other advantages, these models are 3R-compliant and are fit for screening purposes. Biotransformation processes are well-recognized as a critical factor influencing toxic response, but major gaps of knowledge exist regarding the characterization of functional metabolic capacities expressed in zebrafish. Comparative metabolic studies between embryos and adults are even scarcer. Using ³H-labeled chemicals, we examined the fate of two estrogenic emerging contaminants, benzophenone-2 (BP2) and bisphenol S (BPS), in 4-day embryos and adult zebrafish. BPS and BP2 were exclusively metabolized through phase II pathways, with no major qualitative difference between larvae and adults except the occurrence of a BP2-di-glucuronide in adults. Quantitatively, the biotransformation of both molecules was more extensive in adults. For BPS, glucuronidation was the predominant pathway in adults and larvae. For BP2, glucuronidation was the major pathway in larvae, but sulfation predominated in adults, with ca. 40% conversion of parent BP2 and an extensive release of several conjugates into water. Further larvae/adults quantitative differences were demonstrated for both molecules, with higher residue concentrations measured in larvae. The study contributes novel data regarding the metabolism of BPS and BP2 in a fish model and shows that phase II conjugation pathways are already functional in 4-dpf-old zebrafish. Comparative analysis of BP2 and BPS metabolic profiles in zebrafish larvae and adults further supports the use of zebrafish embryo as a relevant model in which toxicity and estrogenic activity can be assessed, while taking into account the absorption and fate of tested substances.

Gibberellin-Stimulation of Rhizome Elongation and Differential GA-Responsive Proteomic Changes in Two Grass Species

PubMed Central

Ma, Xiqing; Huang, Bingru

2016-01-01

Rapid and extensive rhizome development is a desirable trait for perennial grass growth and adaptation to environmental stresses. The objective of this study was to determine proteomic changes and associated metabolic pathways of gibberellin (GA) -regulation of rhizome elongation in two perennial grass species differing in rhizome development. Plants of a short-rhizome bunch-type tall fescue (TF; Festuca arundinacea; ‘BR’) and an extensive rhizomatous Kentucky bluegrass (KB; Poa pratensis; ‘Baron’) were treated with 10 μM GA3 in hydroponic culture in growth chambers. The average rhizome length in KB was significantly longer than that in TF regardless of GA3 treatment, and increased significantly with GA3 treatment, to a greater extent than that in TF. Comparative proteomic analysis using two-dimensional electrophoresis and mass spectrometry was performed to further investigate proteins and associated metabolic pathways imparting increased rhizome elongation by GA. A total of 37 and 38 differentially expressed proteins in response to GA3 treatment were identified in TF and KB plants, respectively, which were mainly involved in photosynthesis, energy and amino acid metabolism, protein synthesis, defense and cell development processes. Accelerated rhizome elongation in KB by GA could be mainly associated with the increased abundance of proteins involved in energy metabolism (glyceraldehyde-3-phosphate dehydrogenase, fructose-bisphosphate aldolase, and ATP synthase), amino acid metabolism (S-adenosylmethionine and adenosylhomocysteinase), protein synthesis (HSP90, elongation factor Tu and eukaryotic translation initiation factor 5A), cell-wall development (cell dividion cycle protein, alpha tubulin-2A and actin), and signal transduction (calreticulin). These proteins could be used as candidate proteins for further analysis of molecular mechanisms controlling rhizome growth. PMID:27446135

Uncertainty quantification in flux balance analysis of spatially lumped and distributed models of neuron-astrocyte metabolism.

PubMed

Calvetti, Daniela; Cheng, Yougan; Somersalo, Erkki

2016-12-01

Identifying feasible steady state solutions of a brain energy metabolism model is an inverse problem that allows infinitely many solutions. The characterization of the non-uniqueness, or the uncertainty quantification of the flux balance analysis, is tantamount to identifying the degrees of freedom of the solution. The degrees of freedom of multi-compartment mathematical models for energy metabolism of a neuron-astrocyte complex may offer a key to understand the different ways in which the energetic needs of the brain are met. In this paper we study the uncertainty in the solution, using techniques of linear algebra to identify the degrees of freedom in a lumped model, and Markov chain Monte Carlo methods in its extension to a spatially distributed case. The interpretation of the degrees of freedom in metabolic terms, more specifically, glucose and oxygen partitioning, is then leveraged to derive constraints on the free parameters to guarantee that the model is energetically feasible. We demonstrate how the model can be used to estimate the stoichiometric energy needs of the cells as well as the household energy based on the measured oxidative cerebral metabolic rate of glucose and glutamate cycling. Moreover, our analysis shows that in the lumped model the net direction of lactate dehydrogenase (LDH) in the cells can be deduced from the glucose partitioning between the compartments. The extension of the lumped model to a spatially distributed multi-compartment setting that includes diffusion fluxes from capillary to tissue increases the number of degrees of freedom, requiring the use of statistical sampling techniques. The analysis of the distributed model reveals that some of the conclusions valid for the spatially lumped model, e.g., concerning the LDH activity and glucose partitioning, may no longer hold.

The Discriminatory Value of CYP2D6 Genotyping in Predicting the Dextromethorphan/Dextrorphan Phenotype in Women with Breast Cancer

PubMed Central

Trojan, Andreas; Vergopoulos, Athanasios; Breitenstein, Urs; Seifert, Burkhardt; Rageth, Christoph; Joechle, Wolfgang

2012-01-01

Background The growth inhibitory effect of tamoxifen is used for the treatment of breast cancer. Tamoxifen efficacy is mediated by its biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoenzyme, to the active metabolite endoxifen. We investigated the relationship of CYP2D6 genotypes to the metabolism of dextromethorphan (DM), which is frequently used as a surrogate marker for the formation of endoxifen. Methods The CYP2D6 genotype was determined by polymerase chain reaction (PCR) in previously untreated patients with hormone receptor-positive invasive breast cancer considered to receive antihormonal therapy. The DM/dextrorphan (DX) urinary excretion ratios were obtained in a subset of patients by high-pressure liquid chromatography (HPLC)-mediated urine analysis after intake of 25 mg DM. The relationships of genotype and corresponding phenotype were statistically analyzed for association. Results From 151 patients predicted based on their genotype data for the ‘traditional’ CYP2D6 phenotype classes poor, intermediate, extensive and ultrarapid, 83 patients were examined for their DM/DX urinary ratios. The genotype-based poor metabolizer status correlated with the DM/DX ratios, whereas the intermediate, extensive and ultrarapid genotypes could not be distinguished based on their phenotype. Citalopram intake did not significantly influence the phenotype. Conclusions The DM metabolism can be reliably used to assess the CYP2D6 enzyme activity. The correlation with the genotype can be incomplete and the metabolic ratios do not seem to be compromised by citalopram. DM phenotyping may provide a standardized tool to better assess the CYP2D6 metabolic capacity. PMID:22553469

Metaproteomics: Harnessing the power of high performance mass spectrometry to identify the suite of proteins that control metabolic activities in microbial communities

PubMed Central

Hettich, Robert L.; Pan, Chongle; Chourey, Karuna; Giannone, Richard J.

2013-01-01

Summary The availability of extensive genome information for many different microbes, including unculturable species in mixed communities from environmental samples, has enabled systems-biology interrogation by providing a means to access genomic, transcriptomic, and proteomic information. To this end, metaproteomics exploits the power of high performance mass spectrometry for extensive characterization of the complete suite of proteins expressed by a microbial community in an environmental sample. PMID:23469896

Metabolic screening in patients with polycystic ovary syndrome is largely underutilized among obstetrician-gynecologists.

PubMed

Dhesi, Amy S; Murtough, Katie L; Lim, Jonathan K; Schulkin, Jay; McGovern, Peter G; Power, Michael L; Morelli, Sara S

2016-11-01

Women with polycystic ovary syndrome have substantially higher rates of insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and metabolic syndrome when compared with women without the disease. Given the high prevalence of these comorbidities, guidelines issued by the American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all women with polycystic ovary syndrome undergo screening for impaired glucose tolerance and dyslipidemia with a 2 hour 75 g oral glucose tolerance test and fasting lipid profile upon diagnosis and also undergo repeat screening every 2-5 years and every 2 years, respectively. Although a hemoglobin A1C and/or fasting glucose are widely used screening tests for diabetes, both the American College of Obstetricians and Gynecologists and the Endocrine Society preferentially recommend the 2 hour oral glucose tolerance test in women with polycystic ovary syndrome as a superior indicator of impaired glucose tolerance/diabetes mellitus. However, we found that gynecologists underutilize current recommendations for metabolic screening in women with polycystic ovary syndrome. In an online survey study targeting American College of Obstetricians and Gynecologists fellows and junior fellows, 22.3% of respondents would not order any screening test at the initial visit for at least 50% of their patients with polycystic ovary syndrome. The most common tests used to screen for impaired glucose tolerance in women with polycystic ovary syndrome were hemoglobin A1C (51.0%) and fasting glucose (42.7%). Whereas 54.1% would order a fasting lipid profile in at least 50% of their polycystic ovary syndrome patients, only 7% of respondents order a 2 hour oral glucose tolerance test. We therefore call for increased efforts to encourage obstetrician-gynecologists to address metabolic abnormalities in their patients with polycystic ovary syndrome. Such efforts should include education of physicians early in their careers, at the medical student and resident level. Efforts should also include implementation of continuing medical education activities, both locally and at the national level, to improve understanding of the metabolic implications of polycystic ovary syndrome. Electronic medical record systems should be utilized to generate prompts for appropriate screening tests in patients with a diagnosis of polycystic ovary syndrome. Because obstetrician-gynecologists may be the only physicians seen by many polycystic ovary syndrome patients, particularly those in their young reproductive years, such interventions could effectively promote optimal preventative health care and early diagnosis of metabolic comorbidities in these at-risk women. Copyright © 2016 Elsevier Inc. All rights reserved.

Feline idiopathic hepatic lipidosis.

PubMed

Dimski, D S; Taboada, J

1995-03-01

Feline IHL is a severe hepatopathy that can be treated by aggressive nutritional support. Until the underlying mechanisms of protein and lipid metabolism are understood in both healthy and ill cats, dietary therapy remains supportive. It is likely that the pathogenesis of IHL in cats is multifactorial, involving both increased fatty acid mobilization to the liver and a defect in oxidation of fatty acids or removal of VLDL. It is also possible that individual variation may play a role in the development of this disease in cats undergoing starvation. Continued studies will focus on the unique pathways of hepatic metabolism in the cat, and how these pathways are altered, leading to hepatic lipid accumulation and clinical disease. Hopefully, these studies can be applied to the prevention or treatment of IHL in cats.