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Bullock, Anthony James. "Metabolic inhibition in the ureter." Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366420.
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Gibb, Fraser Wilson. "Metabolic effects of aromatase inhibition." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15838.
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Aromatase, a member of the cytochrome P450 superfamily, catalyses the conversion of androgens to estrogens; specifically, testosterone to estradiol and androstenedione to estrone. Aromatase is widely expressed across a range of tissues and deleterious metabolic effects are observed in both murine aromatase knock-out models and in rare human cases of aromatase deficiency. The effects of pharmacological inhibition of aromatase, as employed in the treatment of breast cancer, are not well characterised. This thesis addresses the hypothesis that aromatase inhibition, and consequent changes in sex steroid hormone action (higher androgen:estrogen ratio), results in disadvantageous changes in body composition and reduced insulin sensitivity. In a cohort study of 197 community-dwelling men, lower testosterone and SHBG concentrations were observed in those fulfilling criteria for metabolic syndrome, although no relationship with estrogens was observed. The strongest determinant of circulating estrogens was substrate androgen concentration. A case-control study of aromatase inhibitor treated breast cancer patients and age-matched controls (n=40) demonstrated decreased insulin sensitivity and increased body fat in those treated with aromatase inhibitors; serum leptin concentration and leptin mRNA transcript levels (in subcutaneous adipose tissue) were elevated in this group. In healthy male volunteers (n=17), 6 weeks of aromatase inhibition (1 mg anastrozole daily) resulted in reduced glucose disposal during a hyperinsulinaemic euglycaemic clamp study, with d2-glucose and d5-glycerol tracers. No effects upon hepatic insulin sensitivity, lipolysis or body composition were noted, although serum leptin concentration was reduced following aromatase inhibitor administration. In conclusion, aromatase inhibition is associated with increased insulin resistance and, in women, increased body fat. This may be relevant for patients receiving aromatase inhibitor therapy, where more careful monitoring of glucose tolerance may be warranted.
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Upreti, Rita. "Metabolic effects of 5α-reductase inhibition in humans." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/11745.
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5α-reductases (5αRs) catalyse reduction of 4-pregnene steroids, most notably the androgen testosterone to its more potent metabolite dihydrotestosterone (DHT). Well-characterised isozymes of 5αR are designated 5αR1 and 5αR2. Inhibitors of 5αR, finasteride (a 5αR2 inhibitor) and dutasteride (a dual 5αR1 and 5αR2 inhibitor), are utilised in conditions where a reduction in androgen action is desired, including benign prostatic hyperplasia. Although 5αR2 is predominantly expressed in reproductive tissues, both isozymes, but particularly 5αR1, are expressed in metabolic tissues including liver and adipose and both metabolise glucocorticoids as well as androgens; therefore inhibition of 5αR may have consequences for metabolic health. This thesis addresses the hypotheses that 5αR1 inhibition with dutasteride decreases insulin sensitivity and causes dysregulation of the HPA axis in humans. Metabolism and the HPA axis were studied in men prior to and following 3 months of dutasteride (0.5 mg daily; n=16), finasteride (5 mg daily; n=16) or control (tamsulosin MR; 0.4 mg daily; n=14). Glucose disposal during hyperinsulinaemia was the primary endpoint, measured during a hyperinsulinaemic euglycaemic clamp, with d2-glucose and d5-glycerol tracers. Peripheral insulin sensitivity for both glucose uptake and NEFA suppression decreased with dutasteride versus both finasteride and control, while hepatic insulin sensitivity was preserved. Body fat increased with dutasteride, though was not accompanied by changes in metabolic or inflammatory gene transcript abundance in subcutaneous adipose biopsies, nor any differences in abdominal adipose depots on post-treatment MRI. Subtle dysregulation of the HPA axis was evident with both 5αR inhibitors, though to a greater degree with dutasteride and changes were largely compensated for. In support of this study, this thesis also describes the development, validation and application of two novel liquid chromatography tandem mass spectrometry assays; establishing compliance by measuring serum drug levels, and demonstrating effects of 5αR inhibitors on androgen metabolism and adrenal steroidogenesis by measurement of testosterone, DHT and androstenedione. In conclusion, 5αR1 inhibition with dutasteride, but not finasteride, induces peripheral insulin resistance and increases body fat. Findings presented may have important implications for patients prescribed dutasteride for benign prostatic hyperplasia.
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何頌詩 and Chung-sze Joyce Ho. "Effects of preconditioning with metabolic inhibition or U50488H or high CA2+ on CA2+ homeostasis in ventricular myocytes subjected tosevere metabolic inhibition or high CA2+." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31226024.
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Ho, Chung-sze Joyce. "Effects of preconditioning with metabolic inhibition or U50488H or high CA2+ on CA2+ homeostasis in ventricular myocytes subjected to severe metabolic inhibition or high CA2+ /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B2359617x.
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Orr, Linda E. "Reticulocyte maturation in vitro : impaired release of vesicular activity by metabolic inhibition." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=66232.
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Wamil, Małgorzata. "Protective role of 11β-HSD1 inhibition in the metabolic syndrome and atherosclerosis." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3891.
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Obesity is associated with an increased risk of diabetes type 2, dyslipidaemia and atherosclerosis. These cardiovascular and metabolic abnormalities are exacerbated by dietary fats such as cholesterol and its metabolites. High adipose tissue glucocorticoid levels, generated by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) are also implicated in the pathogenesis of obesity, metabolic syndrome and atherosclerosis. Transgenic mice over-expressing 11β-HSD1 selectively in adipose tissue develop the metabolic syndrome whereas 11β-HSD1-/- mice have a ‘cardioprotective’ phenotype, deriving in part from improved adipose tissue function. Consistent with this, prototypical therapeutic 11β-HSD1 inhibitors ameliorate metabolic disturbances associated with obesity. 11β-HSD1 also inter-converts the atherogenic oxysterols 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7β-HC). Work presented in the first part of the thesis defines the impact of these alternative substrates on the metabolism of glucocorticoids in adipocyte cell lines (3T3-L1 and 3T3-F442A). 11β-HSD1 catalyses the reduction of 7KC in mature adipocytes leading to accumulation of 7β-HC. Oxysterol and glucocorticoid conversion by 11β-HSD1 was competitive and occurred within a physiologically-relevant IC50 range of 450nM for 7KC inhibition of glucocorticoid metabolism. Working as an inhibitor of 11β-HSD1 activity, 7KC decreased the regeneration of active glucocorticoid and limited the process of preadipocyte differentiation. 7-oxysterols did not display intrinsic activation of the glucocorticoid receptor (GR). However, when co-incubated with glucocorticoid, 7KC repressed, and 7β-HC enhanced GR transcriptional activity. The effect of 7-oxysterols resulted from the modulation of 11β-HSD1 reaction direction, at least in transfected HEK293 cells, and could be abrogated by over-expression of hexose 6-phosphate dehydrogenase, which supplies NADPH to drive the reductase activity of 11β-HSD1. 11β-HSD1 inhibition protects from atherosclerosis, yet it is unknown whether it is an effect of alterations in the metabolism of 7-oxysterols. 7KC and 7β-HC did not activate the potential cognate receptor LXRα and FXR/RXR in transactivation assays. No differential regulation of key gene targets of LXRα, FXR and RORα in the liver and fat depots of high fat fed 11β-HSD1-/- and wild type mice was observed. To further determine the molecular basis for the metabolically beneficial phenotype of 11β-HSD1-/- mice I analysed global gene expression in subcutaneous and mesenteric adipose tissues of high fat-fed (4 weeks) 11β-HSD1-/- and congenic C57BL/6J mice by microarrays, followed by pathway analysis, gene clustering and realtime-PCR validation of transcripts with >1.5-fold difference between genotypes. 11β-HSD1-/- mice gained less weight and distributed adipose tissue to subcutaneous rather than visceral depots. Broadly, high fat-fed 11β-HSD1-/- mice showed up-regulation of transcripts in subcutaneous fat (70% of 1622 differentially-expressed transcripts), but down-regulation in mesenteric adipose tissue (73% of 849 transcripts). Genes up-regulated in 11β-HSD1-/- subcutaneous adipose were associated with β-adrenergic signaling, glucose metabolism, lipid oxidation, oxidative phosphorylation, MAPK, Wnt/β-catenin, EGF, and PI3K/AKT insulin signaling pathways. Increased subcutaneous fat insulin signaling was confirmed by increased IRS-1 and Akt phosphorylation in vivo. Down-regulated genes in 11β-HSD1-/- mesenteric fat were associated with immune cells, NK-kappaB, Jak/Stat, SAPK/JNK, chemokine, toll-like-receptor and Wnt signaling pathways suggesting reduced immune cell infiltration in mesenteric adipose in high fat-fed 11β-HSD1-/- mice. 11β-HSD1 deficiency protects against metabolic disease by increasing peripheral fat insulin sensitivity and through a novel mechanism involving reduction in visceral fat immune/inflammatory cell function. Data presented in this thesis contribute to the understanding of the role of 11β-HSD1 in adipose tissues in obesity and, potentially, atherosclerosis.
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Dry, Katherine L. "Catecholamine release from isolated chromaffin cells under conditions of anoxia or metabolic inhibition." Thesis, University of Edinburgh, 1990. http://hdl.handle.net/1842/18845.
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A significant release of catecholamines within the heart has been observed during myocardial ischaemia. Ischaemia-induced catecholamine release can be markedly inhibited by desipramine and other amine uptake blocking agents, allowing investigation of the importance of such release for arrhythmia production. The mechanism of this release appears to occur by a carrier-mediated efflux from neurones, which is not operative under normal conditions. The aim of the project has been to study this release process in chromaffin cells isolated from the bovine adrenal medulla, which are recognised as a model system for studying the sympathetic nervous system. Understanding this process of catecholamine release may lead to new methods of protecting the heart against ischaemia-induced arrhythmias. Isolated chromaffin cells could be maintained in primary culture for up to 7 days and retained all their normal secretory responses. Conditions designed to mimic ischaemia, that is, anoxia or metabolic inhibition, resulted in a significant release of catecholamines. This release was shown to be independent of extracellular calcium but, in contrast to the release observed in ischaemic hearts, it was not inhibited by uptake1 blockers. One of the main criteria for exocytosis is the co-release of other secretory granule components. Polyacrylamide gel electrophoresis and Western blotting techniques were utilised to examine this following metabolic inhbition. Significant levels of the granule proteins chromogranin A, neuropeptide Y and ATP were measured following metabolic inhibition, indicative of an exocytotic mechanism. Furthermore, there was no release of the cytosolic protein lactate dehydrogenase, indicating that there was no breakdown of the cell membrane during metabolic inhibition. Over the first 10 minutes of metabolic inhibition there was a marked uptake of 22Na+ by the cells. It is suggested that this Na+ influx triggers the catecholamine release by affecting the cytosolic Ca2+ concentration through a direct effect on intracellular stores. Intracellular Ca2+ mobilisation was measured using the calcium-sensitive fluorescent probe Fura-2. It was found that cytosolic free calcium levels were increased in response to metabolic inhibition. The conditions requird to evoke carrier-mediated efflux were also examined. Cytosolic levels of catecholarmines could be artificially raised following treatment with reserpine. Cytoplasmic catecholamine levels were measured following permeabilisation with the detergent digitonin which renders the plasma membrane leaky. Conditions designed to reverse the uptake carrier and cause carier-mediated efflux in the presence of raised cytoplasmic catecholamines such as removal of extracellular sodium, did not evoke any catecholamine overflow. These studies suggest the chromaffin cell uptake1 carrier is not reversible and may be gated in some way. This work has, therefore, raised questions concerning the suitability of chromaffin cells as a conventional model for sympathetic nerve terminals.
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Houdi, A. A. "Studies on metabolic sulphoxidation of alkyl and aryl thioethers : Role of cytochrome P-450 and FAD-containing monooxygenases." Thesis, University of Manchester, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375073.
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Reid, John M. "Role of K⺠channels during hypoxia and metabolic inhibition in the rat brain." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308872.
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Sahene, Warrick. "Pharmacological Inhibition Of Hif-1 Alpha And Its Effects On Dendritic Cell Metabolic Reprogramming." ScholarWorks @ UVM, 2020. https://scholarworks.uvm.edu/graddis/1188.
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Dendritic cells (DCs) are antigen presenting cells (APCs), a subtype of immune cells that present cellular information to T cells in the immune system. Hypoxia inducible factor 1 alpha (HIF-1 alpha) is an important transcription factor that facilitates dendritic cell metabolism by upregulating glycolysis in activated DCs. In this project, we examined the effects of HIF-1 alpha inhibition on metabolic processes of dendritic cells. Using techniques such as flow cytometry, western blotting, and extracellular flux analyzers, we used a selective inhibitor of HIF-1 alpha to test the hypothesis that HIF-1 alpha promotes glycolytic dependent processes such as glucose production, survival, and maturation. The results revealed that HIF-1 alpha impacts oxygen consumption rates in DCs, but does not affect survival, maturation rates, and glycolytic rates under the conditions studied. Dendritic cell secretion of IL-12, a proinflammatory cytokine upregulated during metabolism, decreased in a dose dependent manner under HIF-1 alpha inhibition. Understanding the effects of HIF-1 alpha can provide insight on how dendritic cells utilize their fuel source to facilitate immunological tasks and how in the future, we can optimize these sources to improve immune system functionality.
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Leppanen, Lisa. "Properties of the resting membrane potential in central myelinated axons during normoxic conditions and metabolic inhibition." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq20979.pdf.
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Leppanen, Lisa Livia. "Properties of the resting membrane potential in central myelinated axons during normoxic conditions and metabolic inhibition." Thesis, University of Ottawa (Canada), 1997. http://hdl.handle.net/10393/4413.
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Compound resting membrane potential was studied in the rat optic nerve, a representative model of myelinated CNS axons, using the grease gap recording technique which measures a reliable fraction of the true intra-axonal potential. Studies were performed during (1) normoxic conditions, (2) glycolytic inhibition, or (3) chemical anoxia at 37$\sp\circ$C, in order to characterize ions and channels promoting membrane depolarization. Ouabain, an antagonist of Na$\sp+$,K$\sp+$-ATPase, caused strong depolarization, showing that membrane potential is critically dependent on Na$\sp+$,K$\sp+$-ATPase. In addition, inhibiting energy metabolism during ouabain exposure produced further depolarization, suggesting additional ATP-dependent, ouabain-insensitive ion transport systems. Glycolysis was blocked with iodoacetate or deoxyglucose, evoking a response consisting of four distinct phases. An initial transient hyperpolarization (phase 1) preceded a rapid depolarizing response (phase 2). Phase 2 was interrupted by a second brief hyperpolarization (phase 3) which was followed by a gradual depolarization (phase 3). Chemical anoxia (cyanide) immediately depolarized the nerve, with only a small inflection introducing a final slow depolarizing response. Addition of ouabain to cyanide-treated nerves caused an additional depolarization indicating a minor glycolytic contribution to Na$\sp+$,K$\sp+$-ATPase, which seems preferentially fueled by mitochondrial ATP in optic nerve. Hyperpolarizing phases 1 and 3 induced by iodoacetate exposure and the inflection during cyanide treatment were abolished by zero-Ca$\sp{2+}$/EGTA treatment. Block of Na$\sp+$ channels with tetrodotoxin, the local anesthetics, procaine or QX-314, or replacement of Na$\sp+$ with the impermeant cation choline significantly reduced depolarization during iodoacetate or cyanide application, indicating that axonal membrane depolarization requires Na$\sp+$ influx which secondarily allows electroneutral K$\sp+$ efflux and depolarization. (Abstract shortened by UMI.)
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Baatarkhuu, Zoljargal. "Metabolic labelling of bacterial isoprenoids produced by the methylerythritol phosphate pathway : a starting point towards a new inhibitor." Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF029/document.
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Les isoprénoïdes, présents dans tous les organismes vivants, sont synthétisés selon deux processus: la voie du Mevalonate et la voie Méthylérythritol phosphate (MEP). Cette dernière, absente chez l’humain, est très étudiée car elle représente une cible pour le développement de nouveaux antimicrobiens. Le ME-N3, un analogue du méthylérythritol portant un azoture, a été synthétisé et exploité dans des expériences de marquage métabolique de la voie MEP en utilisant un couplage bioorthogonale suivi d’une analyse par LC/MS. De façon intéressante, nous avons découvert que le MEP-N3, un analogue du MEP, inhibe l'enzyme IspD d’ E. coli (3ème enzyme de la voie MEP). Les études cinétiques ont révélé que le MEP-N3 possède la meilleure activité inhibitrice sur IspD d’ E.coli en comparaison avec les inhibiteurs connus, et que le mécanisme d'inhibition est de type mixte. Une étude détaillée du mécanisme de la réaction catalysée par IspD a été réalisée pour la première fois, en utilisant une analyse cinétique à deux substratsIsoprenoids, present in all living organisms, are synthesised according to two routes: the Mevalonate and the Methylerythritol phosphate (MEP) pathways. The MEP pathway, absent in humans, is extensively investigated as it is a target for the development of new antimicrobials. ME-N3 an azide tagged analogue of methylerythritol was synthesised and utilised for metabolic labelling studies of the MEP pathway using bioorthogonal ligation followed by LC-MS analysis. Interestingly, we found that MEP-N3, an analogue of MEP, inhibits E.coli IspD (3rd enzyme of the MEP pathway). Further inhibition kinetic studies revealed that MEP-N3 possesses the highest inhibitory activity on E.coli ispD when compared to known inhibitors. In addition, the mechanism of inhibition of E.coli ispD by MEP-N3 was found to be best described using a mixed type model. Moreover, determination of the IspD reaction mechanism has been carried out for the first time, by virtue of a bisubstrate steady state kinetic analysis
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Chou, Chih-Chien. "Inhibition of Epithelial-to-Mesenchymal Transition by Anti-tumor Agents in Cancer Cells." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396875461.
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LaVoie, Holly Anne. "Reproductive and Metabolic Characteristics in Peromyscus leucopus noveboracensis from Laboratory Populations and Females during Release from Reproductive Inhibition." W&M ScholarWorks, 1989. https://scholarworks.wm.edu/etd/1539625509.
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Mukai, Eri. "The effect of metabolic inhibition on ATP-sensitive K[+] channel block by sulfonylurea and cibenzoline in pancreatic β-cells." Kyoto University, 2001. http://hdl.handle.net/2433/150530.
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Gramolini, Anthony Orlando. "The effect of modulating ATP-sensitive potassium channels in frog skeletal muscle, in vitro, during fatigue and metabolic inhibition." Thesis, University of Ottawa (Canada), 1996. http://hdl.handle.net/10393/9473.
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The ATP-sensitive potassium (K$\sp+\rm\sb{(ATP)}$) channel is a K$\sp+$ channel which is activated as the energy state of a muscle decreases. It has been hypothesized that once activated, K$\sp+\rm\sb{(ATP)}$ channels decrease the excitability of the cell and cause decreased contractility, such as during fatigue, in order to prevent energy levels from falling to dangerously low levels. The purpose of this study was to test this hypothesis and to determine under which conditions K$\sp+\rm\sb{(ATP)}$ channels can contribute to a decrease in force during a metabolic stress in the sartorius muscle of the frog, Rana pipiens. In the first series of experiments, sartorius muscle fibres were fatigued with 100 msec long tetanic contractions every second for three minutes, a condition known to activate ATP-sensitive potassium channels. So if K$\sp+\rm\sb{(ATP)}$ channels contribute to a decrease in force during fatigue, an activation of K$\sp+\rm\sb{(ATP)}$ channels with channel openers should further decrease membrane excitability and contractility. In a second series of experiments, muscles were subjected to metabolic inhibition which is known to activate a large number of K$\sp+\rm\sb{(ATP)}$ channels in order to better understand the relationship between K$\sp+\rm\sb{(ATP)}$ channel activity, the bioenergetic state, and force. The goal was to determine if K$\sp+\rm\sb{(ATP)}$ channels can contribute to a decrease in force under a bioenergetic state that is within physiological limits. (Abstract shortened by UMI.)
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Fulton, Stephanie E. "The lateral hypothalamus and energy balance, facilitation and inhibition of perifornical self-stimulation by long- and short-term metabolic signals." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ39058.pdf.
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Maharao, Neha V. "Inhibition of Oxidative and Conjugative Metabolism of Buprenorphine Using Generally Recognized As Safe (GRAS) Compounds or Components of Dietary Supplements." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4752.
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This dissertation aimed at developing an inhibitor strategy to improve the oral bioavailability (Foral) and systemic exposure (AUC∞) of buprenorphine (BUP) as well as reduce the variability associated with them. Twenty-seven generally recognized as safe (GRAS) compounds or dietary substances were evaluated for their potential to inhibit the oxidative and conjugative metabolism of BUP, using pooled human intestinal and liver microsomes. In both the organs, oxidation appeared to be the major metabolic pathway with a 6 fold (intestine) and 4 fold (liver) higher intrinsic clearance than glucuronidation. Buprenorphine was predicted to show low and variable Foral, AUC∞, and a large total clearance. The biorelevant solubilities of 5 preferred inhibitors were incorporated in the final model. An inhibitor dosing strategy was identified to increase Foral and reduce the variability in oral BUP AUC∞. These results demonstrate the feasibility of the approach of using GRAS or dietary compounds to inhibit the presystemic metabolism of buprenorphine and thus improve its oral bioavailability. This inhibitor strategy has promising applicability to a variety of drugs suffering from low and variable oral bioavailability due to extensive presystemic oxidative and conjugative metabolism.
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Dool, Carly Jade 1985. "Pharmacologic inhibition of insulin receptor tyrosine kinase activity has antineoplastic effects similar to alloxan-induced insulin deficiency with less acute metabolic toxicity." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111555.
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Recent population studies provide evidence that individuals with high circulating insulin levels have a poor prognosis and/or increased risk of cancer development; however, laboratory studies concerning the role of insulin in breast cancer biology are sparse. We compared the growth of 4T1 murine breast cancer allografts in control mice, alloxan-induced hypoinsulinemic mice, and mice treated with the insulin/insulin-like growth factor-1 receptor tyrosine kinase inhibitor BMS-536924. Both interventions significantly decreased tumor growth versus control and decreased pathway activation downstream of the insulin receptor as reflected by Aktser473 phosphorylation status in the neoplastic tissue. Alloxan-treated mice exhibited signs of insulin deficiency, while BMS-536924-treated animals showed only minor metabolic derangements. Skeletal muscle displayed reduced pAktser473 in alloxan-treated mice. In contrast, BMS-536924 treatment increased pAktser473 in muscle. This raises the possibility that the relative lack of metabolic toxicity of BMS-536924 involves varying tissue levels of the drug. These results support the view that host insulin physiology is a potentially modifiable determinant of breast cancer behaviour.
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Maarman, Gerald Jerome. "The effect of CPT-1 inhibition on myocardial function and resistance to ischemia/reperfusion injury in a rodent model of the metabolic syndrome." Thesis, Stellenbosch : University of Stellenbosch, 2010. http://hdl.handle.net/10019.1/5354.
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Thesis (MScMedSc (Dept. of Biomedical Sciences. Medical Physiology))University of Stellenbosch, 2010.ENGLISH ABSTRACT: Background: Obesity is associated with dyslipidemia, insulin resistance and glucose intolerance and together these components characterise the metabolic syndrome (Dandona et al. 2005). In the state of obesity, there are high levels of circulating free fatty acids and increased rates of fatty oxidation which inhibit glucose oxidation. This: (i) reduce the heart‘s contractile ability, (ii) exacerbates ischemic/reperfusion injury and (iii) decreases cardiac mechanical function during reperfusion (Kantor et al. 2000; Liu et al. 2002; Taegtmeyer, 2000). Aim: The aim of our study was to investigate the effect of inhibiting fatty acid oxidation, with oxfenicine (4-Hydroxy-L-phenylglycine), on (i) cardiac mechanical function, (ii) mitochondrial respiration, (iii) myocardial tolerance to ischemia/reperfusion injury, (iv) CPT-I expression, MCAD expression, IRS-1 activation, total GLUT- 4 expression and (v) the RISK pathway (ERK42/44 and PKB/Akt). Methods: Male Wistar rats were fed a control rat chow diet or a high calorie diet (HCD) for 16 weeks. The HCD caused diet induced obesity (DIO). The animals were randomly divided into 4 groups [Control, DIO, Control + oxfen and DIO + oxfen]. The drug was administered for the last 8 weeks of feeding (200mg/kg/day). Animals were sacrificed and the hearts were perfused on the Langendorff perfusion system. After being subjected to regional ischemia and two hours of reperfusion, infarct size was determined. A separate series of animals were fed and/or treated and hearts were collected after 25 minutes global ischemia followed by 30 min reperfusion for determination of GLUT- 4, CPT-1, IRS -1, MCAD, ERK (42/44) and PKB/Akt expression/phosphorylation using Western blot analysis. A third series of hearts were excised and used for the isolation of mitochondria. Results: In the DIO rats, chronic oxfenicine treatment improved cardiac mechanical function by improving mitochondrial respiration. Oxfenicine inhibited CPT-1 expression but had no effect on MCAD or GLUT- 4 expression. Oxfenicine decreased IRS-1 iv expression, but not IRS-1 activation. Oxfenicine also improved myocardial tolerance to ischemia/reperfusion without activation of the RISK pathway (ERK & PKB). In the control rats, chronic oxfenicine treatment worsened cardiac mechanical function by adversely affecting mitochondrial respiration. Oxfenicine also worsened myocardial tolerance to ischemia/reperfusion in the control rats without changes in the RISK pathway (ERK & PKB). Oxfenicine had no effect on CPT-1, MCAD or GLUT- 4 expression. Oxfenicine increased IRS-1 expression, but not IRS-1 activity. Conclusion: Chronic oxfenicine treatment improved cardiac mechanical function and myocardial resistance to ischemia/reperfusion injury in obese animals, but worsened it in control animals. The improved cardiac mechanical function and tolerance to ischemia/reperfusion injury may be due to improvement in mitochondrial respiration.
AFRIKAANSE OPSOMMING: Agtergrond: Vetsug word geassosieer met dislipidemie, insulien weerstandigheid en glukose intoleransie, wat saam die metaboliese sindroom karakteriseer (Dandona et al. 2005). Met vetsug is daar ‗n hoë sirkulasie van vetsure, sowel as verhoogde vertsuur oksidasie wat gevolglik glukose oksidasie onderdruk. Dit: (i) verlaag die hart se vermoë om saam te trek, (ii) vererger isgemiese/herperfusie skade en (iv) verlaag kardiale effektiwiteit gedurende herperfusie (Kantor et al. 2000; Liu et al. 2002; Taegtmeyer, 2000). Doel: Die doel van die studie was om die effekte van vetsuur onderdrukking m.b.v. oksfenisien (4-Hidroksie-L-fenielglisien) op (i) meganiese hart funksie, (ii) mitokondriale respirasie, (iii) miokardiale toleransie teen isgemiese/herperfusie skade, (iv) CPT-I uitdrukking, MCAD uitdrukking, IRS-1 aktiwiteit, totale GLUT-4 uitdrukking en (v) die RISK pad (ERK42/44 en PKB/Akt) te ondersoek. Metodes: Manlike Wistar rotte was gevoer met ‗n kontrole rot dieet of ‗n hoë kalorie dieet (HKD) vir 16 weke. Die HKD lei tot dieet-geïnduseerde vetsug (DGV). Die diere was lukraak verdeel in 4 groepe [kontrole, DGV, kontrole + oksfen en DGV + oksfen]. Die behandeling met die middel was toegedien vir die laaste 8 weke van die voeding protokol (200mg/kg/dag). Die diere was geslag en die harte was geperfuseer op die Langendorff perfusie sisteem. Na blootstelling aan streeks- of globale isgemie en 2 ure herperfusie was infark groottes bepaal. ‗n Aparte reeks diere was gevoer en/of behandel en die harte was versamel na 25 minute globale isgemie gevolg deur 30 minute herperfusie vir die bepaling van GLUT-4, CPT 1, IRS -1, MCAD, ERK (42/44) en PKB/Akt uitdrukking/aktivering d.m.v. Western blot analise. ‗n Derde reeks diere was gebruik vir die isolasie van mitokondria. Resultate: In die DGV diere, het kroniese oksfenisien behandeling meganiese hart funksie verbeter d.m.v. die verbetering van mitokondriale respirasie. Oksfenisien het CPT-1 uitdrukking verlaag terwyl GLUT- 4 en MCAD uitdrukking nie geaffekteer was vi nie. Oksfenisien het IRS-1 uitdrukking verlaag, maar nie IRS-1 aktiwiteit nie. Oksfenisien het ook miokardiale weerstand teen isgemiese/herperfusie verbeter met sonder aktivering van die RISK pad (ERK & PKB). In die kontrole diere, het kroniese oksfenisien behandeling die meganiese hart funksie versleg d.m.v. negatiewe effekte op mitokondriale respirasie. Oksfenisien het die miokardiale weerstand teen isgemiese/herperfusie van die kontrole rotte versleg sonder veranderinge in die RISK pad (ERK & PKB). Oksfenisien het geen effek gehad op CPT-1, MCAD en GLUT-4 uitdrukking nie. Oksfenisien het IRS-1 uitdrukking verhoog, maar nie IRS-1 aktiwiteit nie. Samevatting: Kroniese oksfenisien behandeling het die meganiese hart funksie en miokardiale weerstand teen isgemiese/herperfusie skade in die vet diere verbeter, maar versleg in die kontrole diere. Hierdie verbetering van meganiese hart funksie en weerstand teen isgemiese/herperfusie skade kon dalk wees a.g.v. ‗n verbetering in mitokondriale respirasie.
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Zreikat, Hala. "EFFECT OF RENIN ANGIOTENSIN SYSTEM INHIBITION ON CARDIOVASCULAR SEQUELAE IN ELDERLY HYPERTENSIVE PATIENTS WITH INSULIN RESISTANCE." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/2009.
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Background: Insulin resistance may play a pathogenic role in cardiovascular disease (CVD). Resistance to insulin has been associated with obesity, hypertension, and abnormal glucose and lipid metabolism. The constellation of these features among insulin resistant subjects has been called the metabolic syndrome. Prevalence of the metabolic syndrome increases with age and is most common in the elderly. Different criteria have been proposed to define the metabolic syndrome (ATP, WHO, AACE, EGIR). Current management of metabolic syndrome focuses on the specific risk factors that the patient may have without targeting the underlying insulin resistance. Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) are widely used antihypertensive medications that may improve insulin sensitivity. We hypothesize that they can be used to reduce the long term cardiovascular complications in elderly hypertensive subjects with evidence of insulin resistance. In this study, we determined the effect of ACEI/ARB on the long term development of CVD in hypertensive non-diabetic elderly patients with the metabolic syndrome, as well as in patients with insulin resistance. Methods: Our research project utilizes the Cardiovascular Health Study (CHS) dataset. This dataset is a community based observational study where elderly participants were randomly selected and followed up for 11 years and the time to any cardiovascular event was recorded. In our project, we included hypertensive, non-diabetic individuals, with evidence of metabolic syndrome or insulin resistance, but had not experienced cardiovascular events at baseline. Cox regression model was used to evaluate the effect of ACEI/ARB on the time to the first cardiovascular event compared to the other antihypertensive medications adjusting for possible confounders such as age, race, gender, smoking status, triglycerides, LDL levels, systolic blood pressure, development of diabetes, congestive heart failure (CHF) and the number of anti-hypertensives. Results: In elderly hypertensive non-diabetic subjects with the metabolic syndrome according to the ATP and the WHO criteria, the hazard ratio for CVD associated with the use of ACEI/ARB was 0.65 or 0.68 (with 95 % C.I. of [0.45, 0.98], and [0.48, 0.96]) respectively when compared to the group exposed to the other anti-hypertensives. When the metabolic syndrome was defined according to the AACE and EGIR, the use of ACE/ARB was associated with hazard ratios for CVD equal to 0.74 and 0.899, respectively (with 95 % C.I. of [0.54, 1.09] and [0.61, 1.34]) compared to the use of the other anti-hypertensives. Hypertensive non-diabetic elderly subjects who were insulin resistant as evidenced by a HOMA-IR in the upper quartile, had a hazard ratio for CVD of 0.78 (95 % C.I. [0.56, 1.09]) associated with the use of ACEI/ARB compared to the use of other anti-hypertensives. Conclusions: The effect of ACEI/ARB on the development of cardiovascular events differs according to the definition of the metabolic syndrome. Elderly hypertensive patients with the metabolic syndrome, defined by ATP and WHO, seem to have lower risk of CVD with ACEI/ARB compared to the other antihypertensive medications. However, this association is not significant in elderly hypertensive patients in the upper quartile of HOMA and in patients with the metabolic syndrome as defined by AACE and EGIR criteria.
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Liu, Rui. "Effects of Selected Natural Health Products on Drug Metabolism: Implications for Pharmacovigilance." Thesis, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19818.
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Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.
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Scott, D. A. "Folate metabolism in Leishmania." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375461.
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Katouah, Hanadi. "Inhibition of macrophage metabolism by oxLDL." Thesis, University of Canterbury. School of Biological Sciences, 2012. http://hdl.handle.net/10092/7395.
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Intracellular oxidative stress is induced by oxidised low density lipoprotein (oxLDL) in macrophages. In the atherosclerotic lesions, this oxLDL dependent oxidative stress appears to cause macrophage cell death, a key process in the development of the necrotic core within the complex plaque. Macrophages are activated by γ-interferon to synthesise and release a potent antioxidant, 7,8-dihydroneopterin (7,8-NP), which has been previously shown to protect human monocyte-like U937 cells and human monocyte-derived macrophage (HMDM) cells from oxLDL cytotoxicity. This study examined whether oxLDL causes the loss of cellular metabolic function and whether 7,8-dihydroneopterin can prevent this loss of metabolic activity in U937 cells and HMDM cells.
OxLDL prepared by copper oxidation caused cell death in both U937 and HMDM cells at concentrations of 0.5 and 2.0 mg/ml, respectively. Cell morphology showed the oxLDL caused a necrotic like death in both cells as indicated by cell swelling and lysis. The decrease in cell viability was only observed after the loss of intracellular glutathione (GSH) which occurred in the first 3 hours in U937 cells following oxLDL addition. The loss of GSH appeared to be due to the production of intracellular oxidants generated in response to the presence of the oxLDL.
Within 3 hours of oxLDL addition to both cell types, there was a rapid and progressive shutdown of cell metabolism indicated by a significant decrease in the enzymatic activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and a fall in lactate production and intracellular ATP levels. GAPDH activity was found to be inactivated rather than being lost from the cell. Gel electrophoresis with specific staining for oxidised proteins showed that the GAPDH had been oxidatively inactivated in the cells when oxLDL was present. Unlike GAPDH, lactate dehydrogenase (LDH) was not inactivated by the oxidation but was lost from the cells due to cell lysis. The observed rate of glycolysis failure was similar in both cell types except the HMDM cells did not lose lactate, LDH activity and cell viability until 6 hours compared to 3 hours with the U937 cells.
The rate of oxygen consumption (VO2) was measured in U937 cells by taking cells at set time points and placing them in the respirometers to measure the VO2. U937 cells were found to increase their VO2 with incubation but this increase was inhibited in the presence of oxLDL within 3 hours.
The addition of the 7,8 dihydroneopterin above 100 μM to both the U937 and HMDM cells significantly inhibited the oxLDL-induced loss of cell viability. GAPDH activity loss was also inhibited while lactate production was maintained. The 7,8-dihydroneopterin also prevented the decrease in the VO2 in oxLDL-treated U937 cells.
OxLDL was labelled with fluorescent DiI to measure the uptake of oxLDL by HMDM cells. The incorporation of DiI into oxLDL was found to make it non-cytotoxic, possibly due to DiI’s antioxidant properties. Studies were therefore conducted using either a mixture of oxLDL and DiI labelled oxLDL (DiI-oxLDL) at non-protective concentrations or low concentration of DiI-oxLDL alone. These studies showed that 7,8-dihydroneopterin downregulated the oxLDL uptake in oxLDL-treated HMDM cells. Surprisingly the uptake rates also suggested that there was no relationship between oxLDL uptake and cell death assuming oxLDL and DiI-oxLDL are taken up by the same mechanism.
This research showed that oxLDL-induced oxidative stress in macrophage cells causes a rapid oxidative loss of GAPDH activity which leads to the loss of glycolytic activity and a fall in ATP levels. The failure of cell metabolism appears to be a key event in the death mechanism triggered by the oxLDL. The radical scavenging activity of 7,8-dihydroneopterin appears to prevent the oxidative stress as indicated by the protection of the GSH pool. Without the oxidative stress, GAPDH remains functioning, glycolytic activity is maintained and both the U937 cells and HMDM cells did not die. This suggests that within the atherosclerotic plaque, 7,8-dihydroneopterin may act to stabilise the metabolism of macrophage cells in the presence of oxLDL and downregulate the oxLDL uptake.
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Li, Mengyao. "USING SEMIPHYSIOLOGICALLY-BASED PHARMACOKINETIC (SEMI-PBPK) MODELING TO EXPLORE THE IMPACT OF DIFFERENCES BETWEEN THE INTRAVENOUS (IV) AND ORAL (PO) ROUTE OF ADMINISTRATION ON THE MAGNITUDE AND TIME COURSE OF CYP3A-MEDIATED METABOLIC DRUG-DRUG INTERACTIONS (DDI) USING MIDAZOLAM (MDZ) AS PROTOTYPICAL SUBSTRATE AND FLUCONAZOLE (FLZ) AND ERYTHROMYCIN (ERY) AS PROTOTYPICAL INHIBITORS." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4402.
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The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.
Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ PK profiles were compared with observed data from available clinical PK and DDI studies, by visual predictive check and exposure metrics comparison. DDI magnitude and time course for CYP3AI (IV vs. PO) followed by MDZ (IV vs. PO) at various time points were predicted by the validated semi-PBPK-DDI models. Two hypothetical CYP3A substrates and four CYP3AI (derived from MDZ, FLZ and ERY, with GW metabolism removed, hepatic metabolism reduced, or oral bioavailability (Foral) and/or elimination half-life (t1/2) modified) were also simulated to generalize conclusions.
The final semi-PBPK-DDI models predict well the PK profiles for IV/PO MDZ in absence/presence of IV/PO CYP3AI, with deviations between model-predicted and observed exposure metrics within 30%. Prospective simulations demonstrate that:
1) CYP3A substrates, e.g., MDZ, are consistently more sensitive to metabolic inhibition after PO than after IV administration, due to pre-systemic hepatic and/or GW metabolism. For substrates without GW metabolism and limited hepatic metabolism, only a marginal route difference for substrate administration is observed.
2) For high-Foral CYP3AIs, e.g., FLZ, no inhibitor IV-PO route DDI differences are expected, unless they are given simultaneously with PO MDZ.
3) For low-Foral CYP3AIs, e.g., ERY, greater inhibition is expected after IV than after PO administration for IV MDZ, but is difficult to predict for PO MDZ.
4) In addition to Foral and plasma t1/2 of CYP3AIs, the DDI onset, peak and duration are determined by their oral absorption rate and by the resulting hepatic and/or GW concentration profiles relative to Ki for noncompetitive CYP3AIs, but by CYP3A kinetics (synthesis, degradation rate) for MBI CYP3AIs.
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Tjia, J. F. "Inhibition of drug metabolism in vitro and in vivo." Thesis, University of Leeds, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382142.
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Jones, S. V. P. "The characteristics of endplate ion channel block produced by disopyramide and two erythrina alkaloids." Thesis, University of Strathclyde, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372105.
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Kerzic, Patrick James. "Inhibition of NF-[kappa]B by the benzene metabolite hydroquinone /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2006.
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Thesis (Ph.D. in Toxicology) -- University of Colorado at Denver and Health Sciences Center, 2006.Typescript. Includes bibliographical references (leaves 121-141). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Lakhal, Samira. "Tryptophan transport & metabolism mechanism of immunosuppression and therapeutic inhibition." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442596.
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Milne, Gavin D. S. "Inhibition studies of kynurenine 3-monooxygenase." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4101.
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Kynurenine 3-monooxygenase (K3MO) lies on the kynurenine pathway, the major pathway for the catabolism of L-tryptophan. It converts kynurenine to 3-hydroxy kynurenine. Inhibition of K3MO is important in several neurological diseases and there is evidence that inhibition of K3MO could also be targeted for the prevention of multiple organ failure, secondary to acute pancreatitis. A structure activity relationship based upon the 1,2,4-oxadiazoles motif was carried out which revealed amide 207 as an inhibitor of P. fluorescens K3MO. Further structure activity relationships were developed based upon 207. This revealed 3,4-dichloro substitution in 235 and 245 as optimum for inhibition. Co-crystalisation of these inhibitors with P. fluorescens K3MO revealed their interactions with the enzyme. It also highlighted new, potential interactions between the inhibitors and K3MO. This led to the synthesis of 271 and 272, which were also potent inhibitors of K3MO. These amides were successfully co-crystalised with P. fluorescens K3MO. Further development of the amides followed, with amide 282 providing the most potent inhibitor of P. fluorescens K3MO to date (Kᵢ = 29.1 nM).
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Scott-Taggart, Catherine Patricia. "Inhibition of glutamine production increases glutamate metabolism via the GABA shunt." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ27542.pdf.
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Briggs, William Thomas Edward. "Metabolomic insights into the pharmacological and genetic inhibition of cyclooxygenase-2." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/275854.
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Metabolomic Insights into the Pharmacological and Genetic Inhibition of Cyclooxygenase-2 William T. E. Briggs The cyclooxygenase (COX)-2 inhibitors, or “coxibs,” are excellent anti-inflammatory agents, but their reputation has been tarnished by the adverse cardiovascular (CV) events, including heart failure (HF), with which they are associated. Whilst the risk of HF represents the greatest adverse CV event signal seen with these compounds, it is also perhaps the least well understood and has often been explained away as a consequence of the thrombotic risk with which the coxibs are also associated. One recent hypothesis, put forward by Ahmetaj-Shala et al., suggests that asymmetric dimethylarginine (ADMA) may serve as a mechanistic bridge between COX-2 inhibition and HF. However, the ADMA-COX-2 hypothesis was developed based on findings in a constitutive mouse model of COX-2 knock-out (KO), which is compromised by severe developmental cardio-renal pathology, and pharmacological studies which may not accurately reflect coxib use in clinical practice. Various studies have explored the metabolic changes induced by coxib treatment. However, these studies have been limited in scope and have tended to focus on specific pathways or certain tissues/bio-fluids. This has left large regions of the metabolome, in the context of coxib-treatment, unexplored. Given that metabolic remodelling is a key feature of HF, changes in these metabolites may hold the key to understanding the pathogenesis of coxib-induced HF. L-Carnitine shuttles activated long-chain fatty acids (FAs) across the inner mitochondrial membrane to the mitochondrial matrix, where they are oxidised by β-oxidation. This is especially important in the heart, which derives the majority of its energy from the metabolism of FAs. Changes in carnitine metabolism are also seen in HF. It is therefore biologically plausible that derangements in carnitine metabolism may contribute to the pathogenesis of coxib-induced HF. This thesis employs a combination of targeted and untargeted metabolomic techniques, stable isotope labelling and quantitative reverse transcription polymerase chain reaction (RT-qPCR) to i) profile the metabolic changes induced by celecoxib and rofecoxib, in the mouse; ii) specifically interrogate the effect of celecoxib, rofecoxib and global COX-2 gene deletion on carnitine synthesis, metabolism and shuttling, and iii) explore the advantages and disadvantages of the inducible post-natal global (IPNG) COX-2 KO (COX-2-/-) mouse, an alternative to the constitutive COX-2-/- mouse used by Ahmetaj-Shala et al. The results of this thesis demonstrate that i) celecoxib and rofecoxib have similar metabolomic consequences in the mouse; ii) carnitine metabolism may be affected by celecoxib, rofecoxib and dietary composition, via a peroxisome proliferator-activated receptor-alpha (PPAR-α) mediated effect on hepatic carnitine synthesis and iii) the IPNG COX-2-/- mouse neither exhibits the severe developmental cardio-renal pathology nor the altered ADMA metabolism observed in the constitutive COX-2-/- mouse. These findings contradict those of Ahmetaj-Shala et al., oppose the ADMA-COX-2 hypothesis and highlight a potential role for carnitine metabolism and diet in coxib induced HF.
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Ball, Simon Edward. "Inhibition and characterisation of oestrogen 2-hydroxylase in rat and man in vitro." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329411.
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Macauley, Mavin Ekundayo Obafemi. "Metabolic effects of dipeptyl peptidase 4 inhibitor in type 2 diabetes." Thesis, University of Newcastle upon Tyne, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701160.
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Insulin resistance and abnormal insulin secretion are central to type 2 diabetes. The relationships have been established between lipid accumulation in the liver and muscle and insulin resistance, and that of lipid accumulation in the pancreas and β cell dysfunction. Therefore it is vital to assess the effect of therapies on intra-organ lipid concentration. DPP-4 inhibitor vildagliptin is a new therapeutic agent in type 2 diabetes. Its known primary mechanism of action is to delay GLP-1 and GIP degradation, and enhance their endogenous concentration. GLP-1 and GIP increase the sensitivity of the α- and β-cells to glucose concentration. Although DPP-4 inhibitors have been found to decrease postprandial triglyceride levels and lipolysis, the effect on intra-organ lipid concentration is unknown. Glycogen storage in the liver and muscle in type 2 diabetes is subnormal, nonetheless, the extent of glycogen storage abnormality after a whole day of normal eating has not been previously examined. Although abnormal β cell function has been recognised as a feature of type 2 diabetes, the whole pancreas has not been extensively studied previously. To test the hypothesis that DPP-4 inhibitors modulate intra-organ lipid accumulation, 44 well-controlled type 2 diabetes subjects treated only with metformin were randomised in a double-blinded manner to receive either vildagliptin or placebo for 6 months. In order to assess the extent of change, in intra-organ lipid content, and abnormal glycogen storage, and to provide comparative data for pancreas morphology, 14 normal glucose tolerant subjects matched for weight, BMI, sex and age were studied. A clinically significant decrease in liver triglyceride content after 6 months treatment with vildagliptin was observed. Additionally, the studies demonstrate that the pancreas volume in type 2 diabetes was smaller compared to match controls, and that muscle did not contribute to glycogen storage during normal daily eating in type 2 diabetes.
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Sánchez, Saavedra Javier Augusto. "Inhibition of the plasma contact system on end-point immobilized heparin and human endothelium /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19980513sanc.
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Jackson, Matthew Irick. "Biochemical targets of Nitroxyl (HNO) and the inhibition of hydrogen peroxide metabolism." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1596647481&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Wehelie, Rahma. "Mycoplasma pyrimidine deoxynucleotide biosynthesis : molecular characterization of a new family flavin-dependent thymidylate synthase /." Uppsala : Dept. of Molecular Biosciences, Swedish University of Agricultural Sciences, 2006. http://epsilon.slu.se/200676.pdf.
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Taavitsainen, P. (Päivi). "Cytochrome P450 isoform-specific in vitro methods to predict drug metabolism and interactions." Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514259009.
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Abstract
Cytochromes P450 (P450, CYP) are a superfamily of enzymes that participate
especially in the oxidative metabolism of various xenobiotics and endogenous
compounds.
The major goal of this study was to characterise suitable methods for routine
preclinical in vitro testing of new chemical entities (NCE)
and to test the methods for the affinity screening of selected drugs.
In vitro methods used involve the utilisation of human
liver microsomes for studies with P450-selective reference inhibitors,
inhibitory antibodies and cDNA-expressed enzymes in cytochrome P450-catalysed
activities and for studying the reactions of selegiline and entacapone.
In this project, the CYP-catalysed oxidative in vitro
biotransformation of selegiline into its primary metabolites desmethylselegiline
and l-methamphetamine and the transformation of entacapone
into its in vitro metabolite
N-desethylentacapone were studied. The affinities of
selegiline, desmethylselegiline, l-methamphetamine,
entacapone, candesartan, eprosartan, irbesartan, losartan and valsartan to P450
enzymes were also elucidated, and the selectivity of tranylcypromine as a
CYP2A6-selective reference inhibitor was characterised.
The most important findings were that the methodology developed during this work
is suitable for preclinical in vitro testing of NCEs and
that the results obtained for the studied compounds are in line with the
available in vivo data.
By the in vitro testing methodology, it is possible to
target the in vivo interaction studies to the relevant
groups of compounds. The in vitro methods presented in this
thesis could also make the early phases of drug development more cost-effective.
Further, the number of animals used for in vivo testing in
preclinical metabolism and interaction studies can be markedly reduced by
effectively using this methodology.
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Patel, Meghana. "Inhibitor of kappa B kinase epsilon (IKKε), the metabolic syndrome and atherosclerosis." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648358.
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Keating, Jeffrey Desmond. "Characterization of an ethanologenic yeast inhibiting atypical galactose metabolism." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/410.
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In the near future, biomass-derived energy is predicted to substantially complement that generated from petroleum. However, certain types of biomass employed as substrates in the microorganism-mediated production of renewable fuelethanol contain significant amounts of the recalcitrant hexose sugar galactose. The consumption of galactose in hexose sugar-fermenting yeasts is often delayed with respect to other sugars, such as glucose and mannose, because of an intrinsic preference for carbon sources requiring less energy in the preparatory reactions preceding glycolysis. This work comprised the search for, and characterization of anethanologenic yeast capable of efficiently assimilating galactose.
Screening experiments conducted with wild-type Saccharomyces cerevisiae strains identified one isolate (Y-1528) exhibiting exceptionally fast galactose fermentation. The absence of conventional glucose repression, including a preference for galactose as carbon source and notable delays in the utilization of glucose and mannose, was demonstrated in mixed sugar fermentations. Endogenous extracellular glucose was observed during double sugar fermentations of galactose and mannose. This glucose was traced to supplied galactose by radioisotope labeling, suggesting involvement of UDP-galactose 4-epimerase in the responsible reaction mechanism(s).Sub-cellular fractionation was employed in an attempt to ascertain enzyme localization in Y-1528.
Fermentations of lignocellulosic substrate mixtures by Y-1528 illustrated better performance than that accomplished by a reference yeast strain, and again showed a preference for galactose. Mixed cultures of Y-1528 and the same reference strain demonstrated accelerated hexose sugar consumption, and no detrimental effects from competition, during synthetic and lignocellulosic substrate fermentations. Glucose repression was absent in mixed culture fermentations.
Fermentations of synthetic sugar mixtures augmented with lignocellulosic inhibitory compounds showed Y-1528 to have better performance than a reference yeast strain, despite a global detrimental effect relative to inhibitor-free fermentations. Cell recycle batch fermentations of spent sulfite liquor illustrated the toxic effect of the hardwood variant, as well as a net loss of performance from all strains tested.
Y-1528 was taxonomically confirmed as S. cerevisiae. UDP-galactose 4-epimerase chromatographic purification was unsuccessful, but a partial sequence of the enzyme, showing complete identity with type sequence, was obtained by electrophoretic separation, liquid chromatography, and mass spectrometry. A significantly mutated UDP-galactose 4-epimerase gene was successfully sequenced.
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Javeshghani, Shiva. "Effects of metformin and Ataxia Telangiectasia mutated kinase inhibition on cellular energy metabolism." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110539.
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The use of the biguanide metformin for the management of type 2 diabetes has been associated with reduced cancer burden and mortality by several population studies. Our previous work has demonstrated that metformin has growth inhibitory effects in vitro that are related to AMPK phosphorylation, leading to mTOR inhibition. Prior evidence linked the activation of AMPK to a decline in ATP as a result of the inhibitory effects of metformin on complex 1 of the mitochondria. In view of this finding, we studied the inhibitory effects of metformin on proliferation as a function of carbon source in several transformed cell lines. Our results demonstrated that the consequences of exposure to metformin vary as a function of carbon source. The greatest inhibition by metformin resulted in the presence of glutamine and absence of glucose. This finding together with prior evidence linking myc expression to "glutamine addiction", led us to examine the effects of varying myc level on metformin sensitivity. Our results revealed the overexpression of this oncogene to be associated with sensitization to the antiproliferative effects of metformin. This suggests that for a subset of neoplasms in which myc is overexpressed, biguanides may provide significant antiproliferative activity.In view of preliminary evidence suggesting defective mitochondrial function in patients with Ataxia-Telangiectasia, we examined whether the ATM inhibitor KU55933 resulted in similar antiproliferative effects to those of metformin. Our results indicated that similar to metformin, KU-55933 exposure resulted in inhibition of proliferation. Furthermore, analogous to the effects of metformin on metabolism, the compound also increased AMPK activation, glucose uptake, and lactate production, while reducing mitochondrial membrane potential and coupled respiration. Our observations suggest a role for ATM in mitochondrial function, and reveal that both KU-55933 and metformin perturb the TCA cycle and oxidative phosphoryaltion.L'utilisation de la metformine, un biguanide, pour la gestion de diabète de type 2, a été associée à une réduction du risque de cancer et de mortalité due au cancer par plusieurs études de population. Nos travaux antérieurs ont démontré que la metformine a des effets inhibiteurs de la croissance cellulaire in vitro qui sont liés à la phosphorylation d'AMPK, conduisant à une inhibition de mTOR. De plus, des études précédentes ont montré que l'activation de l'AMPK est liée à une baisse de l'ATP suite aux effets inhibiteurs de la metformine sur le complexe 1 de la mitochondrie. Compte tenu de ces résultats, nous avons étudié les effets inhibiteurs de la metformine sur la prolifération en fonction de la source de carbone dans plusieurs lignées cellulaires transformées. Nos résultats ont démontré que les conséquences de l'exposition à la metformine varient en fonction de la source de carbone. La plus grande inhibition par la metformine se produit en présence de glutamine et en l'absence de glucose. Ces résultats, conjointement avec des observations antérieures liant l'expression de myc à la «dépendance à la glutamine», nous a conduits à examiner les effets de la variation des niveaux de myc sur la sensibilité à la metformine. Nos résultats ont révélé que la surexpression de cet oncogène est associée à une sensibilisation aux effets anti-prolifératifs de la metformine. Cela suggère que pour un sous-ensemble des néoplasmes dans lequel myc est surexprimé, les biguanides peuvent apporter une importante activité anti-proliférative. Compte tenu des preuves préliminaires suggérant une fonction mitochondriale défectueuse chez les patients atteints d'ataxie télangiectasie, nous avons examiné si l'inhibiteur de l'ATM KU55933 produit des effets antiprolifératifs similaires à ceux de la metformine. Nos résultats indiquent que comme la metformine, l'exposition à KU-55933 a entraîné une inhibition de la prolifération cellulaire. En outre, KU-55933 provoque des effets analogues à ceux de la metformine sur le métabolisme : soit une augmentation de l'activation de l'AMPK, de l'absorption du glucose et de la production de lactate, tout en réduisant le potentiel de membrane mitochondriale et la respiration couplée. Nos observations suggèrent un rôle pour l'ATM dans la fonction mitochondriale et révèle que KU-55933 et la metformine peuvent perturber le cycle de Krebs et la phosphorylation oxydative.
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Trousil, Sebastian. "Choline kinase inhibition as a treatment strategy of cancers with deregulated lipid metabolism." Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25146.
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Aberrant choline metabolism is a characteristic shared by many human cancers. It is predominantly caused by elevated expression of choline kinase alpha, which catalyses the phosphorylation of choline to phosphocholine, an essential precursor of membrane lipids. In this thesis, a novel choline kinase inhibitor has been developed and its therapeutic potential evaluated. Furthermore the probe was used to elaborate choline kinase biology. A lead compound, ICL-CCIC-0019 (IC50 of 0.27 ± 0.06 μM), was identified through a focused library screen. ICL-CCIC-0019 was competitive with choline and non-competitive with ATP. In a selectivity screen of 131 human kinases, ICL-CCIC-0019 inhibited only 5 kinases more than 20% at a concentration of 10 μM (< 35% in all 131 kinases). ICL- CCIC-0019 potently inhibited cell growth in a panel of 60 cancer cell lines (NCI-60 screen) with a median GI50 of 1.12 μM (range: 0.00389-16.2 μM). Importantly, proliferation of normal cells was only minimally affected (MCF-10A, ST-T1b and CCD-18Co; GI50 30-120 μM). In HCT116 cells, ICL-CCIC-0019 potently inhibited the formation of phosphocholine (EC50 0.67 ± 0.28 μM), which consequently decreased the formation of phosphatidylcholine. The compound arrested cells in the G1 phase of the cell cycle, and induced endoplasmic reticulum stress and apoptosis. A single injection of ICL-CCIC-0019 at 10 mg/kg decreased tumour uptake of the choline kinase specific PET tracer [18F]fluoromethyl-[1,2-2H4]-choline at 24 hours (AUC0-60-23%). Treatment of HCT116 colon cancer cell xenograft bearing mice with 5 mg/kg ICL-CCIC-0019 i.p. resulted in strong tumour growth inhibition. Human breast cancer cell lines oncogenically transformed by HER2 exhibit increased levels of phosphocholine and are therefore more likely respond to CHKA inhibition. To identify such patients more readily, a novel, non-invasive, PET-imaging-based HER2- targeting diagnostic tool, [18F]GE-226, was developed. [18F]GE-226 (KD = 76 pM) uptake was 11 to 67-fold higher in 10 HER2 positive versus negative cell lines in vitro. Tumour uptake correlated with HER2 expression in 5 different tumour models (r2 = 0.78), and a fluorophore-labelled tracer analogue co-localised with HER2 expression. Tracer uptake was not influenced by short-term or continuous treatment with trastuzumab, but reflected HER2 degradation by short-term HSP90 inhibition. Taken together, these data further validate CHKA as a drug target and warrant the further development of ICL-CCIC-0019, potentially in the setting of HER2 positive cancers.
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Smith, Shelly Ann. "Effect of carbonic anhydrase inhibition on muscle metabolism during exercise studied by ³¹P-MRS." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ30742.pdf.
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Kessler, Dino. "Wirkung der Pityriarubine - neue Tryptophan-Metabolite von Malassezia furfur - auf humane Granulozyten." Giessen VVB Laufersweiler, 2007. http://d-nb.info/98877335X/34.
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Ward, Nathan Patrick. "Therapeutic Modulation of Cancer Metabolism with Dichloroacetate and Metformin." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6778.
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The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin’s reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in the VM-M3 model of GBM. We demonstrated that metformin potentiated DCA-induced superoxide production and that this was required for enhanced cytotoxicity towards VM-M3 cells with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. We also show that DCA and metformin reduce tumor burden and prolong survival in VM-M3 tumor-burdened mice as individual therapies. In contrast to our in vitro work, we did not observe synergy between DCA and metformin in vivo. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells. This work supports further investigation and optimization of a DCA/metformin combination as a potential pro-oxidant combinatorial therapy for GBM.
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Billard, 1959 Jean-Marie. "Olive inférieure et inhibition cérébelleuse." Paris 6, 1986. http://www.theses.fr/1986PA066044.
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Etude du rôle de l'olive inferieure dans l'inhibition cérébelleuse chez le rat, après destruction sélective de l'O. I. Cette destruction élimine l'action de suppression tonique qu'exercent les fibres grimpantes sur les décharges simples des Purkinje. On observe : a) un accroissement de l'inhibition cérébelleuse dans les premiers jours, ainsi qu'une disfacilitation rubrale et une dépression des activités motrices; b) ces effets régressent jusqu'à 1 mois; c) passe 1 mois le déficit moteur persiste.
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Fuhr, Luise Anna. "The Circadian Clock Modulates Tumour Progression and Drug Response in Colorectal Cancer Cells through Metabolic Phenotype Rewiring." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/20850.
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Die zirkadiane Uhr ist ein endogenes Zeitmesssystem, das die Anpassung physiologischer Prozesse an die geophysikalische Zeit ermöglicht. Die zirkadiane Uhr besteht aus einem zentralen Schrittmacher und peripheren Uhren in jeder Zelle. Bei Säugern ist eine bestimmte Anzahl von Uhr-Genen in regulatorischen Schleifen miteinander verbunden, wodurch Oszillationen in der Expression der Uhr-Gene sowie in zahlreichen Zielgenen erzeugt werden. Zielgene der zirkadianen Uhr sind unter anderem an zellulären Prozessen beteiligt, die eine Rolle bei der Tumorentstehung und -progression spielen. Funktionsstörungen der zirkadianen Uhr stehen im Zusammenhang mit verschiedenen Krankheitsbildern, unter anderem Krebs. Ziel dieses Projekts war es, die Rolle der zirkadianen Uhr bei der Tumorentstehung und entwicklung zu untersuchen. Der Fokus lag dabei auf tumorspezifischen Stoffwechselwegen. Die Rolle einer deregulierten zirkadianen Uhr wurde in einem in vitro Zellmodel untersucht. Die SW480 Zelllinie wurde aus einem Primärtumor isoliert und die SW620 Zelllinie aus einer Lymphknotenmetastase desselben Patienten. Die untersuchten Zelllinien zeigten deutliche Unterschiede in Bezug auf ihre Uhr Phänotypen mit globalen Konsequenzen auf oszillierende Gene und Stoffwechselwege. Die Runterregulation des Uhrgens Bmal1 führte in SW480 Zellen zu einem metastatischen Phänotyp, der stark dem von SW620 Wildtypzellen ähnelte. Darüber hinaus führte die Runterregulation von Bmal1 zu einer Veränderung des metabolischen Phänotyps und zu einer modifizierten Antwort auf die Behandlung mit einem Glykolyseinhibitor. Die in diesem Projekt erzielten Ergebnisse unterstützen die postulierte Rolle von Bmal1 als Tumorsuppressor und verdeutlichen das reziproke Wechselspiel zwischen der zirkadianen Uhr und dem Stoffwechsel von Krebszellen und zeigen mögliche Auswirkungen einer deregulierten Uhr auf den Zellmetabolismus während der Tumorentwicklung.The circadian clock is an internal timing system that allows the entrainment of physiological and behavioural processes to the geophysical time with a periodicity of about 24 hours. It consists of a central pacemaker and peripheral clocks in every cell. In mammals, a distinct set of genes is interconnected in regulatory feedback loops, thereby generating oscillations in gene expression in the core-clock itself as well as in many target genes. Clock target genes are, among others, involved in cellular processes connected to tumour development and progression, including metabolic pathways, drug response pathways and the cell cycle. Malfunctions of the circadian clock are associated with different pathologies including cancer. The aim of this project was to study the role of the circadian clock in tumour development and progression with a focus on cancer metabolism and treatment response. The role of a deregulated clock was investigated in SW480 cells derived from a primary tumour and SW620 cells derived from a lymph node metastasis of the same patient. The investigated cell lines showed clear differences with respect to their clock phenotypes with consequences on global oscillating gene expression and alterations in metabolic pathways. A knockdown of the core-clock gene Bmal1 in SW480 cells induced a metastatic phenotype similar to SW620 wild type cells, as indicated by faster proliferation, lower apoptosis rate and a highly energetic metabolic phenotype. Furthermore, Bmal1-KD induced metabolic phenotype rewiring as seen by altered glycolytic activity and mitochondrial respiration and modified treatment response to metabolism-targeting anticancer treatment. The results obtained in this project reinforce the postulated role of Bmal1 as a tumour suppressor and elucidate a reciprocal interplay between the circadian clock and cancer metabolism with implications in metabolic phenotype rewiring during tumour progression.
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Echecopar-Sabogal, Jose, Lorenzo D’Angelo-Piaggio, Diego M. Chanamé-Baca, and Cesar Ugarte-Gil. "Association between the use of protease inhibitors in highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: A systematic review and meta-analysis." SAGE Publications Ltd, 2018. http://hdl.handle.net/10757/624660.
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El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.This systematic review and meta-analysis tries to determine whether there is an association between the use of protease inhibitors (PIs) and the incidence of diabetes mellitus (DM) and/or metabolic syndrome (MS) in HIV-infected patients. A systematic literature search was performed using MEDLINE/PubMed, CENTRAL, LILACS, and EMBASE. Included articles were observational studies published on or prior to November 2015 that met specific inclusion criteria. Pooled relative risks (RRs) and hazard ratios (HRs) were calculated. Nine articles met the inclusion criteria, describing 13,742 HIV patients. Use of PIs was associated with the development of MS (RR: 2.11; 95% CI 1.28–3.48; p-value 0.003). No association between the use of PIs and development of DM was found: the HR for the incidence of DM among patients using PIs was 1.23 (95% CI 0.66–2.30; p-value: 0.51) and the RR was 1.25 (95% CI 0.99–1.58; p-value 0.06). Use of PIs in HIV-infected patients is associated with an increased risk of MS. No evidence of an increased risk of DM was found. However, because MS is a precursor to DM, it is possible that studies with a longer follow-up duration are needed in order to detect an association between PI use and onset of DM.
First, we would like to thank our families for all their support. Second, we would like to thank the Universidad Peruana de Ciencias Aplicadas, the Health Sciences Department, and the School of Medicine for their support and for all the tools they have provided throughout this process. Finally, we want to thanks to Dr Gwenyth O. Lee and Dr Daniela E. Kirwan for their comments.
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