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1
Lei, Hua. "Studies on the metabolic activation of glyceryl trinitrate." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0013/MQ31223.pdf.
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Ayrton, Andrew David. "Food mutagens : factors that modulate their metabolic activation." Thesis, University of Surrey, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328576.
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Anari, Mohammad Reza. "Cytochrome P450 peroxidase/peroxygenase-dependent metabolic activation of xenobiotics." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ28269.pdf.
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Preston, Kyle J. "Macronutrient Activation of Endothelium Dependent Leukocyte Trafficking: Metabolic Implications." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/361365.
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PhysiologyPh.D.
Obesity and insulin resistance are characterized by elevated pro-inflammatory proteins in the blood and immune cell accumulation in the visceral adipose tissue. Resident leukocytes release tumor necrosis factor α (TNFα) and other inflammatory cytokines which stimulate adipocyte lipolysis, recruit leukocytes to adipose tissue, promote pro-inflammatory immune cell polarization, facilitate oxidative stress, and activate intracellular kinases which dull insulin signaling cascades in metabolic tissues. Immune cell mediated dysregulation of stromal and parenchymal cells has raised suspicion that insulin resistance is an immune disorder initiated by activated white blood cells with over-nutrition. Efforts to improve pathological metabolism by reducing inflammation have yielded mixed results in humans and animal models. The role of inflammation and immune cell accumulation in the visceral fat (VF) in the progression of insulin resistance remains presently debated. There is, however, a consensus that identifying the triggers for obesity and impaired insulin signaling is of the utmost importance. The goal of this report is to identify dietary fat absorption as a key initiator of inflammatory action and insulin desensitization which may be dampened by reducing immune cell accumulation in adipose tissue. To explore how lean, healthy organisms become obese and insulin resistant, we examined the inflammatory consequences of isocaloric but variable macronutrient loads in the VF of lean mice. Mice were administered single liquid meals composed of low-fat (10% fat) or high-fat (60% fat) diet and observed by intravital microscopy to quantify leukocyte-endothelium interactions in mesenteric postcapillary venules (MPCV) 1, 2, 3, and 4 hours after oral gavage. Leukocyte rolling and leukocyte adhesion were transiently elevated within 1 hour after feeding and returned to baseline levels 4 hours later. Endothelial cell surface expression of P-selectin (Psel), a rapidly activated cell adhesion molecule (CAM), confirmed that high-fat feeding induced Psel dependent leukocyte rolling through the VF microcirculation. Furthermore, leukocyte accumulation in the VF was modestly increased by a single high-fat meal (HFM). Repetitive high-fat diet (HFD) consumption for 24 hours prolonged elevated leukocyte-endothelium interactions and promoted neutrophil accumulation in the VF. The neutrophilic enzyme myeloperoxidase (MPO), a producer of the chlorinating agent hypochlorous acid, increased in abundance and activity in the VF of HFM fed mice. Elevated leukocyte-endothelium interactions, leukocyte infiltration, and MPO activity in VF were not observed in Psel deficient (Psel-/-) mice following lipid overload. To ascertain if MPO is required for sustained endothelial activation, leukocyte-endothelium interactions and leukocyte infiltration were monitored in high-fat fed MPO deficient (MPO-/-) mice. Similar to the Psel-/- mice, MPO-/- mice were protected from the inflammatory effects of high-fat feeding. Our data supports postprandial hyperlipemia as an inducer of transient and Psel dependent inflammatory reactions that are sustained by prolonged HFD consumption. To study whether early phase inflammatory interventions granted late phase metabolic improvements, wild-type (WT), Psel deficient (Psel-/-), and MPO deficient (MPO-/-) C57BL/6 mice were given ad libitum access to LFD (10% fat) or HFD (60% fat) for 12-16 weeks. All mouse groups given HFD became obese. Prolonged HFD consumption sustained elevated leukocyte-endothelium interactions in MPCVs and was accompanied by increased local and systemic TNFα in WT mice. High-fat fed WT mice were hyperglycemic, hyperinsulinemic, glucose intolerant, and insulin resistant compared to LFD fed controls. Psel-/- mice were protected from leukocyte-endothelium interactions as well as local and systemic TNFα accumulation despite extended HFD consumption. Surprisingly, high-fat fed Psel-/- mice were equally hyperglycemic, hyperinsulinemic, glucose intolerant, and insulin resistant as the inflamed, high-fat fed WT mice. MPO-/- mice were also protected from elevated systemic TNFα and gained slightly less weight than the other high-fat fed groups. While MPO-/- mice were hyperglycemic and glucose intolerant, they did have improved insulin stimulated glucose clearance. The data presented in this report demonstrates the pro-inflammatory nature of postprandial hyperlipemia and the insulin desensitizing nature of prolonged HFD consumption. Ablation of VF immune cell accumulation by Psel deletion is not sufficient for improving insulin signaling or glycemic control, which is consistent with prior reports. Deletion of MPO, however, did result in slightly less obesity and marginally improved insulin signaling. We conclude that while immune cell accumulation in the VF contributes to the progression of insulin resistance, it is not a prerequisite for metabolic pathology development.
Temple University--Theses
5
Engelhart, David Albert. "Part~I. Metabolic activation of cyclic tertiary amines Part~II Neurotoxic activation of beta,beta'-iminodipropionitrile (IDPN)." Case Western Reserve University School of Graduate Studies / OhioLINK, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=case1057933667.
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Roberts, Lee D. "Defining the metabolic effect of peroxisome proliferator-activated receptor δ activation." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/226743.
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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand activated transcription factors. There are three identified isotypes: PPAR alpha, PPAR gamma and PPAR delta, together controlling the expression of genes involved in inflammation, cell differentiation, proliferation, lipid and carbohydrate metabolism and energy homeostasis. The PPARs are potential targets for the treatment of dyslipidaemia, type II diabetes mellitus and the metabolic syndrome. This thesis uses a multi-platform metabolomics approach, 13C-isotope substrate flux analysis, respirometry and transcriptomics to determine the role PPAR delta and PPAR gamma play in metabolic control both in adipose tissue and systemically. To achieve this, the metabolic phenotype of the 3T3-L1 adipocyte cell line was defined to generate a metabolically phenotyped in vitro model of adipose tissue. The importance of fatty acid alpha-oxidation in the differentiation of adipocytes was emphasised The effects of PPAR delta and PPAR gamma activation in white adipose tissue from the ob/ob mouse model of insulin resistance, and in the phenotyped 3T3-L1 adipocyte model, were investigated. PPAR delta activation was distinguished by oxidative catabolism of fatty acids and citric acid cycle intermediates. Conversely, PPAR gamma activation was identified by the sequestration of lipids into adipose tissue. Moreover, to address the systemic influence of PPAR activation, with a focus on the Cori cycle and the interactions of the liver and skeletal muscle, the metabolic changes that occur in these tissues following PPAR delta and PPAR gamma activation in the ob/ob mouse were examined. PPAR delta activation was characterised by the mobilisation and release of triacylglycerols (TAGs) into circulation as an energy source for peripheral tissues whereas PPAR gamma activation was defined by a reduction and sequestration of circulating TAGs. This thesis has better characterised the role of the PPARs as master regulators of metabolism and emphasised their potential as therapeutic targets for metabolic diseases of global importance.
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Cammann, Clemens [Verfasser], and Jonathan [Akademischer Betreuer] Lindquist. "Metabolic reprogramming upon CD8 T cell activation / Clemens Cammann ; Betreuer: Jonathan Lindquist." Magdeburg : Universitätsbibliothek, 2016. http://d-nb.info/1113687231/34.
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Tsui, Lok Hang Carlson. "Cell intrinsic regulation of B cell activation : metabolic reprogramming and mitochondrial remodelling." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10051228/.
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B cells are fundamental components of the adaptive immune system. B-cell activation leads to the formation of effector (plasma cells) and memory (memory B cells) compartments in vivo, which together provide a potent line of defense against pathogenic infections through the production of highly specific antibodies. At the cellular level, B-cell activation triggers the rapid reorganization of the cytoskeleton. It is now recognized that the dynamic remodeling of actin and microtubules is extremely important for B cells in aspects such as receptor signalling, cell motility, as well as intracellular trafficking of membrane compartments. B-cell activation in the longer-term triggers metabolic reprogramming and remodeling of many other intracellular organelles that are required to support increased cell growth, proliferation and differentiation. However, despite previous studies have shed light into the many characteristics of B cell activation and differentiation, our understanding on how B-cell activation and fate decision is coordinated is still incomplete. To address these questions, I set out to investigate firstly the mechanism of cytoskeleton regulation and its role on B-cell activation. This involved the study on the RhoGTPase RhoF and vimentin that were largely uncharacterised in B cells. RhoF- and vimentin-deficient mouse models were used in these contexts combined with techniques including super-resolution light microscopy and electron microscopy. The results obtained suggest that while RhoF does not seem to play a major role in B-cell development and function, the dynamic reorganisation of vimentin is critical for B-cell activation. Loss of vimentin in B cells also affected intracellular trafficking, antigen presentation and in vivo antibody responses. Next, I went on to study the role of metabolic reprogramming on B-cell fate decision using the PKC-deficient model. Despite this topic has been a recent hotspot in the field of T cells, it has so far not been extensively studied in B cells. Combining advanced sequencing and detailed metabolomics analysis, I found that while PKC played multiple roles in B cell function, it is specifically required to initiate an mTORC1-dependent metabolic program to promote plasma cell differentiation. Accordingly, the loss of PKC rendered activated B cells unable to sustain this metabolic program, and as a result favouring differentiation to memory cells. All together, these results provide mechanistic insights into B-cell differentiation and highlight the central role of metabolic reprogramming on fate decision in B cells.
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Riley, Robert John. "An evaluation of the importance of metabolic activation and detoxication in drug toxicity." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316895.
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McGlashon, Jacob. "Serotonin neurons maintain central mechanisms regulating metabolic homeostasis and are vital to thermogenic activation." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/2121.
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Thermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids via uncoupling protein 1 (Ucp1), a process known as non-shivering thermogenesis. Serotonin (5-HT) neurons in the ventral medulla are known to regulate sympathetic efferent neurons in the intermediolateral nucleus (IML) necessary to maintain brown adipose tissue (BAT) activity. Previous studies show that mice lacking central 5-HT neurons are incapable of maintaining body temperature in cold, ambient conditions. Due to this direct linkage between 5-HT and thermoregulation, we hypothesized that central 5-HT neurons may be vital to the regulation of brown and beige adipocyte activity. Given that BAT consumes large amounts of substrate when active, we also hypothesized that inactivation of BAT due to deletion of the regulatory neural circuitry (5-HT neurons) would cause metabolic dysregulation.
To test this, we generated mice in which the human diphtheria toxin (DT) receptor was selectively expressed in central 5-HT neurons under control of a Pet-1 promoter. Pet-1 is a transcription factor selectively located in mature, central 5-HT neurons. Coincidentally, some cells within pancreatic islets also express Pet-1, and contain adequate machinery to produce, release, and uptake 5-HT. Systemic treatment with DT eliminated 5-HT neurons and caused loss of thermoregulation, BAT steatosis, and a >50% decrease in Ucp1 expression in BAT and beige fat, indicative of reduced thermal production. In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold and triglycerides 6.5-fold. Intracerebroventricular (ICV) treatment with 1/30th the systemic dose of DT induced an even greater thermoregulatory impairment. The metabolic deficits following systemic DT treatment indicate that central 5-HT neurons are essential for proper metabolic regulation. However, such high levels of glucose and lipids also indicate failure of the pancreatic endocrine program following systemic treatment, likely due to moderate destruction of β-cells expressing Pet-1 and the DT receptor. Because ICV treatment caused even greater thermoregulatory and metabolic deficits, where little, if any, of the toxin would spread systemically, central 5-HT neurons are clearly essential for normal central regulation of metabolism. Interestingly, similar BAT and beige fat defects occurred in Lmx1bf/f/p mice, in which 5-HT neurons fail to develop in utero. Assessment of systemically treated animals using a euglycemic/hyperinsulinemic clamp showed extensive fasting hyperglycemia and systemic insulin resistance, coinciding with reduced glucose uptake in skeletal muscle and BAT. The hyperinsulinemic clamp failed to suppress hepatic glucose and fatty acid production, leading to the conclusion that loss of central 5-HT neurons disrupts central hepatic regulation.
In attempts to induce BAT thermogenesis and metabolism, we optogenetically stimulated 5-HT neurons in the rostral raphe pallidus and measured BAT and body temperature along with blood glucose. Unfortunately, these stimulations were incapable of increasing BAT temperature and lowering blood glucose, perhaps limiting therapeutic potential of these 5-HT neurons. We conclude that 5-HT neurons are major players in central regulation of metabolic homeostasis, in part through recruitment and activation of brown and beige adipocytes and hepatic substrate production. Data also suggest that 5-HT neurons regulate glucose homeostasis via undefined neural mechanisms independently of BAT activity and pancreatic insulin secretion. Cumulative data on central 5-HT neurons indicate they are master regulators of whole-body metabolism.
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Meng, Shu. "HYPERHOMOCYSTEINEMIA ACCELERATES THROMBOSIS THROUGH ICAM-1 DEPENDENT ENDOTHELIAL ACTIVATION AND DNA HYPOMETHYLATION." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/234268.
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PharmacologyPh.D.
Background: Hyperhomocysteinemia (HHcy) is an established risk factor for thrombotic diseases yet the underlying mechanism remain unclear. In this study we investigated the effect of HHcy on endothelial cell-platelet interaction and its role in thrombosis. Methods and Results: We used a novel mouse model of HHcy (plasma homocysteine, Hcy 80 micromolar) in which a Zn2+ inducible human cystathionine beta-synthase (CBS) transgene was introduced to circumvent the neonatal lethality of the Cbs gene deficiency (Tg-hCBS Cbs-/- mice). Hcy-lowering therapy was performed by giving ZnSO4 water to induce human CBS transgene expression in adult mice. Thrombus formation was examined by photo dye-induced cremaster microvasculature thrombosis using intravital microscopy, in which endothelium was preserved, and by FeCl3-induced carotid artery thrombosis, which denudated the endothelium. HHcy accelerated cremaster arteriolar thrombosis and decreased blood flow cessation time from 41.8 min in control mice to 30.5 min in TghCBS Cbs-/- mice. Venular blood flow cessation time was slightly decreased from 5.6 to 5.0 min. Hcy-lowering therapy reduced Hcy level from 80 micromolar to 6.8 micromolar after 2 weeks of ZnSO4 water and prolonged arteriolar blood cessation time from 30.5 to 37.8 min. Interestingly, FeCl3-induced carotid artery thrombosis did not change the occlusion time. Hcy did not potentiate the aggregation and secretion function in washed human platelets from healthy donor treated with Hcy (50, 100 micromolar) or from Tg-hCBS Cbs-/- mice. However, inter-cellular adhesion molecule 1 (ICAM-1) levels, but not vascular adhesion molecule 1 (VCAM-1), were increased in cremaster tissues from Tg-hCBS Cbs-/- mice by western blot. In cultured human umbilical vein ECs (HUVEC), Hcy (100 micromolar, 24h) promoted human platelet adhesion by 200% in static adhesion assay. Using western blot, FACS and RT-PCR, we found that Hcy increased protein and mRNA levels of ICAM-1, but not that of VCAM-1, in HUVEC. ICAM-1 blocking antibody partially reversed Hcy increased platelets adhesion to HUVEC. Hcy induced ICAM-1 expression and reduced DNA methylation on ICAM-1 promoter, which were mimicked by DNA methyltransferase inhibitor azacytidine, and histone deacetylase inhibitors sodium butyrate and trichostatin A. Hcy treatment also increased intracellular Hcy, Sadenosylhomocysteine (SAH) accumulation and decreased SAM/SAH ratio in HUVECs. Hcy decreased methyl CpG binding protein 2 (MeCP2) binding and increased acetylated histone H3 (AcH3) binding to ICAM-1 core promoter region using chromatin immunoprecipitation. Pyrosequencing of ICAM-1 core promoter and adjacent region shows a decreased DNA methylation by Hcy treatment. In high methionine diet-induce HHcy in WT and Icam-/- mice, Icam-/- mice fed with HM diet only show moderately accelerated venular and barely accelerated arteriolar occlusion time compared with WT mice with CT diet using photo dye-induced thrombosis model. Conclusion: HHcy accelerates arteriolar thrombosis and increases EC-platelet interaction via ICAM-1 induction partially through DNA hypomethylation.
Temple University--Theses
12
Shah, Ume-Kulsoom. "Genotoxic responses at low doses for chemicals requiring metabolic activation using different human cell lines." Thesis, Swansea University, 2014. https://cronfa.swan.ac.uk/Record/cronfa43055.
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ro-carcinogens e.g. B[a]P and PhIP require metabolic activation to exert genotoxicity. Both B[a]P and PhIP are known to cause different types of cancers, however, very little is known about the dose response of these two chemicals at low concentrations. This study was conducted to determine the effect of low doses of B[a]P and PhIP and their exposure time on cell lines with varying levels of metabolic activity. Micronucleus and HPRT assays were conducted to determine the effect of low doses of B[a]P on micronuclei induction and mutation frequency following 4 or 24 h exposure. MCL-5 and HepG2 cell lines showed higher induction of micronuclei irrespective of B[a]P dose and exposure time. Micronuclei induction was least in AHH-1 while TK-6 cells showed no micronuclei induction. HPRT assay also showed higher mutation frequency in MCL-5 as compared to AHH-1 at both time exposures. Analysis of mutation spectra of MCL-5 and AHH-1 HPRT mutants revealed that the type of mutations observed in B[a]P treated cells were different to those observed in untreated control B[a]P-induced mutations were predominantly G → T transversions. Real time PCR assays revealed higher induction of CYP1A1 and CY1A2 enzymes in response to B[a]P in MCL-5 and HepG2 cell lines. Studies on PhIP showed significantly higher cytotoxicity, genotoxicity and mutation frequency in the MCL-5 and HepG2 cell lines than AHH-1 cells. Micronucleus assays (24h) revealed 1.56 and 1.9-.fold increase in micronuclei induction in MCL-5 and HepG2, respectively as compared to control. A similar trend was observed in 4h PhIP exposure study, where MCL-5 and HepG2 had 1.83 and 1.92-.fold increase respectively. These findings are in line with the metabolic potential of the cell lines. Real-time PCR assays showed that over all, expression of CYP1A1 and CY1A2 was higher in HepG2 than MCL-5 following PhIP exposure for 24h. PhIP was observed to induce a significantly higher mutation frequency in MCL-5 cell lines than untreated control. Mutation type also varied among PhIP treated and untreated control of MCL-5. PhIP treated MCL-5 cells showed predominantly G → T transversions. These studies showed that cells with higher metabolic activity are relatively more capable of activating B[a]P and PhIP and therefore show higher genotoxicity in response to dose and exposure of these pro-carcinogens. Considering the results of this study, potential risk of B[a]P and PhIP induced cancers has been discussed.
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Lansdown, Andrew John. "Anthropometric and metabolic correlates of sympathetic nervous system activation in women with polycystic ovary syndrome." Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/100609/.
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Background: Polycystic ovary syndrome (PCOS) is associated with increased metabolic risk and hypertension, which may relate to enhanced sympathetic nervous system (SNS) activation. The cerebral pathways involved in this process are not known. Aims: (1) To compare blood pressure and SNS activation in response to isometric forearm contraction (IFC) between PCOS and control groups. (2) To identify and compare the neuronal signatures of this response. (3) To investigate metabolic and anthropometric correlates of SNS activation. Methods: 20 PCOS (age 29.8 yrs, BMI 26.1 kg/ m²) and 20 matched controls (age 29.7 yrs, BMI 26.1 kg/ m²; p=NS) were studied. Out-of-scanner tests: measurement of mean blood pressure (MAP) and heart rate (HR) responses to 30% IFC for 180 seconds; baseline and post-task catecholamines, and microneurography (MSNA) in a subgroup of 8 PCOS and 8 controls. In-scanner: Blood oxygen level dependent (BOLD) fMRI using an identical block paradigm design for IFC, BOLD signalcorrelating to MAP responses (threshold Z > 2.3, corrected cluster threshold p=0.05). Results: IFC elicited an increase in HR and MAP in PCOS and controls but these did not differ between groups (p=0.16[HR] and p=0.06[MAP]). Adrenaline increased significantly post-IFC in PCOS (0.68 to 1.23ng/mL p < 0.001) but not in controls (0.77 to 0.99ng/mL p=0.14). MSNA burst frequency increased by 68% in the PCOS group compared to 11.9% in controls (p=0.002). Brain activation indexed by the BOLD signal in response to IFC was significantly greater in the PCOS group compared to the control group in the right orbitofrontal cortex (p < 0.0001), left angular gyrus and lateral occipital cortex (p=0.04). When the BOLD signal was separately corrected for insulin sensitivity, BOLD signal in the right orbitofrontal cortex was no longer significant. Conclusions: PCOS is associated with enhanced SNS activation and increased regional brain activation in response to IFC. The right orbitofrontal cortex BOLD signal change in the PCOS group is associated with insulin sensitivity.
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Followay, Brittany. "EFFECTS OF CYCLING EXERCISE AND COLD EXPOSURE ON NEUROMUSCULAR ACTIVATION AND FATIGUE,AND METABOLIC RESPONSES." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1531736690094866.
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Kimura, Rino. "Studies on the attenuation effects of intestinal PPARα activation on postprandial hyperlipidemia." Kyoto University, 2014. http://hdl.handle.net/2433/188757.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第18319号
農博第2044号
新制||農||1021(附属図書館)
学位論文||H26||N4826(農学部図書室)
31177
京都大学大学院農学研究科食品生物科学専攻
(主査)教授 河田 照雄, 教授 伏木 亨, 教授 金本 龍平
学位規則第4条第1項該当
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Nault, Rance. "Energetic Costs of AhR Activation in Rainbow Trout (Oncorhynchus mykiss) Hepatocytes." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20229.
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Aquatic organisms in response to toxic insults from environmental pollutants activate defence systems including the aryl hydrocarbon receptor (AhR) in an attempt to metabolize and excrete these toxicants and their metabolites. These detoxification mechanisms however may come with certain energetic costs. I hypothesize that the activation of the AhR by β-Naphthoflavone (β-NF), a model AhR agonist, results in increased energetic costs requiring metabolic reorganization in rainbow trout hepatocytes. While the results obtained suggest that there are no significant energetic costs of AhR activation, analysis of enzyme activities suggests possible metabolic reorganization. This study also showed significant changes in cellular processes in hepatocytes over the incubation periods which previously were not reported. Furthermore, for the first time in fish hepatocytes, metabolic flux analysis (MFA) was used to examine intra-cellular metabolism, the applicability of which is discussed.
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Layne, Andrew S., Sami Nasrallah, Mark A. South, Mary E. A. Howell, Melanie P. McCurry, Michael W. Ramsey, Michael H. Stone, and Charles A. Stuart. "Impaired Muscle AMPK Activation in the Metabolic Syndrome May Attenuate Improved Insulin Action after Exercise Training." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etsu-works/4126.
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Context: Strength training induces muscle remodeling and may improve insulin responsiveness.
Objective: This study will quantify the impact of resistance training on insulin sensitivity in subjects with the metabolic syndrome and correlate this with activation of intramuscular pathways mediating mitochondrial biogenesis and muscle fiber hypertrophy.
Design: Tens ubjects with the metabolic syndrome(MS) and nine sedentary controls underwent 8 wk of supervised resistance exercise training with pre-and post-training anthropometric and muscle biochemical assessments.
Setting: Resistance exercise training took place in a sports laboratory on a college campus.
Main Outcome Measures: Pre- and posttraining insulin responsiveness was quantified using a euglycemic clamp. Changes in expression of muscle 5-AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways were quantified using immunoblots.
Results: Strength and stamina increased in both groups. Insulin sensitivity increased in controls (steady-state glucose infusion rate 7.0 2.0 mg/kg min pretraining training vs. 8.7 3.1 mg/kg min posttraining; P 0.01) but did not improve in MS subjects (3.3 1.3 pre vs. 3.1 1.0 post).Muscleglucosetransporter4increased67%incontrolsand36%intheMSsubjects.Control subjects increased muscle phospho-AMPK (43%), peroxisome proliferator-activated receptor coactivator1 (57%),andATPsynthase(60%),morethanMSsubjects(8,28,and21%,respectively). In contrast, muscle phospho-mTOR increased most in the MS group (57 vs. 32%).
Conclusion: Failure of resistance training to improve insulin responsiveness in MS subjects was coincident with diminished phosphorylation of muscle AMPK, but increased phosphorylation of mTOR, suggesting activation of the mTOR pathway could be involved in inhibition of exercise training-related increases in AMPK and its activation and downstream events
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Mestre-Farrera, Aida 1992. "Metabolic stress and tumor progression : a role for glutamine in fibroblast migration." Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/668751.
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Tumors are complex tissues composed by multiple cell types, such as cancer associated fibroblasts (CAFs), that facilitate the invasive behavior of tumor cells. When we examined their nutrient requirements, we observed that CAFs rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to glutaminase inhibition. Glutamine-dependence in CAFs promotes their migration and invasion towards this amino acid when challenged with a gradient of glutamine. Moreover, fibroblasts support the collective invasion of epithelial tumor cells towards glutamine, a process that is governed by TGF-β/Snail1-dependent fibroblast activation. Fibroblasts migrating towards glutamine present a polarized distribution of Akt2, that is modulated by the E3 ubiquitin ligase TRAF6 in response to TGF-β stimulation and glutamine availability. In addition, the depletion of this Akt isoform prevents the effect of these cells on epithelial tumor invasion. Therefore, these results demonstrate that the high dependence on glutamine of CAFs promotes nutrient-driven tumor invasion.Els tumors son teixits complexos compostos per diversos tipus cel·lulars, així com els fibroblasts associats a tumors (CAFs), que fomenten un comportament invasiu en cèl·lules canceroses. A l’examinar els requeriments nutricionals d’aquestes cèl·lules, vàrem observar que els CAFs són molt més dependents a glutamina que les cèl·lules tumorals epitelials. En conseqüència, els CAFs són més sensibles a la inhibició de l’enzim glutaminasa. La seva dependència a glutamina promou tant la migració com la invasió dels CAFs cap a aquest aminoàcid. A més, els fibroblasts promouen la invasió col·lectiva de cèl·lules tumorals epitelials cap a un gradient de glutamina, en un procés governat per l’activació de fibroblast depenent de TGF-β i Snail1. Al migrar cap a glutamina, els fibroblasts presenten una distribució polaritzada d’Akt2, que està regulada per la ubiqüitina-lligasa TRAF6 en resposta a TGF-β i la disponibilitat de glutamina. La depleció d’Akt2 prevé l’efecte dels CAFs en la invasió de cèl·lules canceroses. Així doncs, aquests resultats demostren que l’alta dependència a glutamina promou la invasió tumoral estimulada per nutrients.
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Gunawardhana, Lhanoo. "The role of metabolic activation and oxidant injury in the hepatotoxicity of 1,2-dichlorobenzene in the rat." Diss., The University of Arizona, 1992. http://hdl.handle.net/10150/186039.
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1,2-Dichlorobenzene (1,2-DCB) is a potent hepatotoxicant in the Fischer-344 (F344) rat. Phenobarbital (PB), a known inducer of cytochrome P-450, enhanced the metabolism and covalent binding of 1,2-DCB in F344 rat liver microsomes. Identification of 2,3-dichlorophenol, 3,4-dichlorophenol and dichlorobenzene dihydrodiol indicated the formation of dichlorobenzene epoxides in PB induced microsomes. Moreover, modulation of microsomal metabolism and covalent binding using glutathione, trichloropropene oxide, ascorbic acid and superoxide dismutase implicated quinones as the major covalent binding species of 1,2-DCB. These findings indicate that 1,2-DCB is activated by cytochrome P-450 to reactive intermediates that may initiate hepatocellular injury. The hepatotoxicity of 1,2-DCB was also studied in normal F344 rats administered methyl palmitate (MP) to inhibit Kupffer cell function or superoxide dismutase (conjugated to polyethylene glycol, i.e. PEG-SOD) to scavenge superoxide anions. Both agents markedly reduced the severity of 1,2-DCB induced liver injury in normal rats. However, MP and PEG-SOD did not inhibit the PB potentiated hepatotoxicity of 1,2-DCB. In summary, the data presented in this dissertation strongly support a role for Kupffer cell derived superoxide anions in the hepatotoxicity of 1,2-DCB in normal F344 rats. Since Sprague-Dawley (SD) rats are less susceptible to the hepatotoxicity of 1,2-DCB than F344 rats, markers of oxidant injury were assessed in both strains of rats following administration of 1,2-DCB. 1,2-DCB treatment did not deplete hepatic vitamin E in F344 or SD rats. However, 1,2-DCB treated F344 rats exhibited greater ethane exhalation than SD rats, at a time when differences in GSH depletion between the two strains were most prominent and prior to the initial appearance of toxicity in F344 rats. The results further confirmed the involvement of oxidative injury in the hepatotoxicity of 1,2-DCB. It is concluded that two key events are involved in the hepatotoxicity of 1,2-DCB (1) metabolism of 1,2-DCB by cytochrome P-450 to reactive intermediates that initiate cell injury (2) oxidative injury induced by Kupffer cell derived active oxygen species, that contributes to the progression of the injury.
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Zhang, Wenyan. "Identification and Characterization of Genes Involved in Regulation of Ascorbate Metabolic Pathway(s) in Arabidopsis thaliana." Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/26211.
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Vitamin C (ascorbic acid, AsA), an important primary metabolite of plants, functions as an antioxidant, an enzyme cofactor, and a cell-signaling modulator in a wide array of crucial physiological processes including biosynthesis of the cell wall, secondary metabolites and phytohormones, stress resistance, photoprotection, cell division, senescence, and growth. To identify genes that may regulate vitamin C levels in plants, about 3000 activation-tagged Arabidopsis lines were treated with ozone, which is a power oxidizing agent. Two mutants were selected for identification of potential genes involved in the regulation of vitamin C synthesis. A putative F-box gene, VCF1, and a purple acid phosphatase, AtPAP15, were identified for further characterization.
Two homozygous SALK T-DNA knockouts in the open reading frame (ORF) of VCF1 exhibited high tolerance to ozone when treated with 450 ppb for 3 hours and the AsA levels of these mutants were 2 to 3 fold higher than wild-type (wt) plants. Developmental studies, using RT-PCR, indicated that foliar expression of the VCF1 gene increased with plant age from 1 to 5 weeks, whereas AsA decreased during this same period. The expression of VCF1 was higher under a low-light condition in which AsA was reduced considerably. The AsA levels in two VCF1 overexpressing lines were only 50 to 70% of wt plants. These results suggested that the putative F-box gene functions as a negative regulator of leaf ascorbate content.
Overexpression of AtPAP15 with the CaMV 35S promoter resulted in up to 3-fold higher AsA levels than wt plants, where two independent SALK T-DNA insertion mutants in AtPAP15 had 50% less AsA than wt plants. Enzyme activity of bacterially expressed GST:AtPAP15 was greatest with phytate as a substrate indicating that AtPAP15 is a phytase. Phytase catalyzes hydrolysis of phytate (myo-inositol hexakisphosphate) to yield myo-inositol and free phosphate. Thus, AtPAP15 may regulate AsA levels by controlling the input of myo-inositol into this branch of AsA biosynthesis in Arabidopsis. AtPAP15 was expressed in all tested organs in wt plants and suggests that the enzyme may have functions other than phytate degradation during seed germination.Ph. D.
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Vaughan, Tamisha Y. "Novel Mechanisms Underlying the Inflammatory Effects of Leptin and Low Dose Endotoxin." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/28013.
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Obesity over the last several has become a major health concern in our country as well as the world. Obesity is also one of the risk factors which lead to several inflammatory complications such as diabetes, artherosclerosis, etc. Two leading factors involved in the causes of inflammatory complications include leptin and low dose endotoxin lipopolysaccharide (LPS). However, the mechanism underlying the involvement of these two mediators is not clearly understood. The purpose of this study is to understand the mechanism underlying inflammatory complications caused by leptin and low dose endotoxin most recently coined metabolic endotoxemia. Interleukin-Receptor Associated Kinase 1 (IRAK-1) is an intracellular signaling component shown to activate NFκB which leads to the induction of proinflammatory mediators. Deletion of IRAK-1 in mice has beneficial effects in alleviating inflammatory complications and human variations in IRAK-1 gene are correlated with higher risks for inflammatory diseases. Therefore, we hypothesized that IRAK-1 is critically involved for the induction of proinflammatory mediators induced by leptin and low dose LPS. IL-6 mRNA levels were measured in THP-1 (human monocytic cells) and wild type and IRAK-deficient bone marrow derived macrophages (BMDM) challenged with different combinations of leptin and LPS. Data shows that leptin alone will not induce inflammatory mediators. However, increased induction of IL-6 was observed in a synergistic manner involving both LPS and leptin in an IRAK-1 dependent manner causing a robust inflammatory response. With regard to the effect of low dose LPS, we observed that human monocytic cells treated with low concentrations of LPS showed a mild yet sustained induction of proinflammatory cytokines, which is contrast to the robust and transient induction of cytokines by a high dose LPS. To further determine the molecular mechanisms, we measured several key signaling molecules that include IRAK-1, IKKepsilon, and C/EBPdelta. Our study revealed a novel mechanism that appears to be distinct from the traditional NFï «B pathway responsible for the effect of low dose LPS.Ph. D.
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Cox, Julie. "Evaluation of Strategies to Improve In Vitro Mutagenicity Assessment: Alternative Sources of S9 Exogenous Metabolic Activation and the Development of an In Vitro Assay Based on MutaMouse Primary Hepatocytes." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39340.
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In vitro genetic toxicity tests using cultured bacterial or mammalian cells provide a cost- and time-effective alternative to animal tests. Unfortunately, existing in vitro assays are not always reliable. This is in part due to the limited metabolic capacity of the cells used, which is often critical to accurately assess chemical genotoxicity. This limited metabolic capacity necessitates the use of exogenous sources of mammalian metabolic enzymes that can simulate in vivo mammalian metabolic activation reactions. In response to this, and other limitations, alongside the worldwide trend to reduce animal testing, there is an acute need to consider various strategies to improve in vitro mutagenicity assessment. This thesis first examined the utility of exogenous metabolic activation systems based on human hepatic S9, relative to conventional induced rat liver S9, for routine genetic toxicity assessment. This was accomplished by critically evaluating existing literature, as well as new experimental data. The results revealed the limitations of human liver S9 for assessment of chemical mutagenicity. More specifically, the analyses concluded that, due to the increased risk of false negative results, human liver S9 should not be used as a replacement for induced rat liver S9. To address the limitations of conventional mammalian cell genetic toxicity assays that require exogenous hepatic S9, the thesis next evaluated the utility of an in vitro mutagenicity assay based on metabolically-competent primary hepatocytes (PHs) derived from the transgenic MutaMouse. Cultured MutaMouse PHs were thoroughly characterized, and found to temporarily retain the phenotypic attributes of hepatocytes in vivo; they express hepatocyte-specific proteins, exhibit the karyotype of typical hepatocytes, and maintain metabolic activity for at least the first 24 hours after isolation. Preliminary validation of the in vitro MutaMouse PH gene mutation assay, using a panel of thirteen mutagenic and non-mutagenic chemicals, demonstrated excellent sensitivity and specificity. Moreover, inclusion of substances requiring a diverse array of metabolic activation pathways revealed comprehensive metabolic competence. Finally, the thesis further investigated the applicability domain of the in vitro MutaMouse PH assay by challenging the assay with selected azo compounds. Comparison of these results with those obtained using the in vivo MutaMouse TGR (transgenic rodent) assay revealed that MutaMouse PHs can carry out some forms of reductive metabolism. Overall, this thesis demonstrated that a gene mutation assay based on MutaMouse PHs holds great promise for routine assessments of chemical mutagenicity.
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Tsuda, Satoshi. "Metabolic effects of coffee components on rat skeletal muscle in the resting and contracting states ―Evidence for 5’AMP-activated protein kinase activation, glucose metabolism enhancement, and ergogenic effect―." Kyoto University, 2020. http://hdl.handle.net/2433/253369.
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Kyoto University (京都大学)0048
新制・課程博士
博士(人間・環境学)
甲第22533号
人博第936号
新制||人||223(附属図書館)
2019||人博||936(吉田南総合図書館)
京都大学大学院人間・環境学研究科共生人間学専攻
(主査)教授 林 達也, 教授 石原 昭彦, 教授 久代 恵介
学位規則第4条第1項該当
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Bellamri, Medjda. "Activation métabolique et génotoxicité des Amines Hétérocycliques Aromatiques (AHA) chez l’Homme." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B033/document.
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Les amines hétérocycliques aromatiques (AHA) sont des contaminants de l'environnement et de l'alimentation, majoritairement formés lors de la cuisson de viande et poisson ainsi que dans la fumée de cigarette et les gaz d'échappements. Les AHA sont mutagènes chez la bactérie, cancérogènes multi-sites chez le rongeur et sont classées comme cancérogènes possibles ou probables chez l'Homme par l'IARC. Il est aujourd'hui indispensable de caractériser des biomarqueurs d'exposition dérivés des AHA (adduits à l'ADN et métabolites) pour améliorer l'estimation du risque chez l'Homme. Des résultats de l'équipe ont démontré que le 2-amino-9H-pyrido[2,3-b]indole (AαC) forme des niveaux d'adduits à l'ADN élevés dans les hépatocytes humains. Ces niveaux sont plus élevés que ceux formés par les autres AHA. L'objectif de cette thèse est de mieux comprendre le potentiel génotoxique d'AαC chez l'Homme. Nos travaux ont démontré que les adduits à l'ADN dérivés d'AαC sont persistants dans les hépatocytes humains et formés à des doses aussi faibles que 1nM. De plus, le CYP1A2 a été confirmé comme enzyme majoritaire dans la bioactivation d'AαC dans le foie humain. Nous avons également caractérisé les métabolites majeurs dérivés d'AαC dans les hépatocytes humains. Cette étude a permis d'établir pour la première fois une corrélation entre l'activité catalytique du CYP1A2, la formation d'AαC-HN2-O-Gl et la formation des adduits à l'ADN dérivés d'AαC. Le métabolite AαC-HN2-O-Gl étant réactif vis-à-vis de l'ADN in vitro, nos travaux confortent l'hypothèse que la voie des UDP-Glucuronosyltransférases (UGTs) est une nouvelle voie de bioactivation d'AαC dans le foie humain. De plus, nous avons montré que les adduits à l'ADN dérivés des AHA sont formés dans les lymphocytes T humains activés et en particulier les adduits en position C8 de la guanine dérivés d'AαC. Au total, ces travaux ont permis l'identification de métabolites stables et des adduits à l'ADN, potentiels biomarqueurs d'exposition à AαC, qui sont indispensables pour une meilleure estimation du risque génotoxique d'AαC chez l'HommeHeterocyclic aromatic amines (HAA) are environmental and food contaminants, mainly formed during meat and fish cooking, but also in cigarette smoke and exhaust gaz. HAA are mutagenic in bacteria, carcinogenic in rodents and are classified as possible or probable human carcinogens by IARC. Today it is essential to characterize exposure biomarkers i.e. DNA adducts and metabolites, to assess the human risk associated with HAA. The research team has previously demonstrated that 2-amino-9H-pyrido[2,3-b]indole (AαC) form high levels of DNA adducts in human hepatocytes. These levels are greater that those derived from other HAAs. Thus, the aim of this thesis was to better understand the genotoxic potential of AαC in human. We demonstrated that in human hepatocytes, DNA adducts derived from AαC are persistent and formed at doses as low as 1nM. Moreover, we confirmed that CYP1A2 is the major enzyme implicated in the bioactivation of AαC in human liver. We have also characterized the major metabolites derived from AαC formed in human hepatocytes. This study allows, for the first time, the establishment of a correlation between the catalytic activity of CYP1A2, AαC-HN2-O-Gl formation and AαC derived DNA adducts formation. AαC-HN2-O-Gl being reactive toward DNA in vitro, our work reinforces the hypothesis that the UDP-glucuronosyltransferase (UGTs) pathway is a new bioactivation pathway for AαC in human liver. Moreover, we demonstrated the formation of HAA derived DNA adducts, especially those derived from AαC at position C8 of guanine, in activated human T lymphocytes. Taken together, our data lead to the identification of stable metabolites as well as DNA adducts which are potentials AαC exposure biomarkers in human. These biomarkers are essential for a better assessment of the genotoxic risk of AαC in human
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Busquet, François. "Development of a new screening assay to identify proteratogenic compounds using Zebrafish Danio rerio embryo combined with an exogenous mammalian metabolic activation system (mDarT)." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1228302283465-60848.
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The assessment of teratogenic effects of chemicals is generally performed using in vivo teratogenicity assays e.g., in rats or rabbits. Following the 3R principles, the development of alternative methods is encouraged to reduce the number of animal tests. From this perspective, we have developed an in vitro assay (mDarT) using the zebrafish Danio rerio embryo teratogenicity assay (DarT) combined with an exogenous mammalian metabolic activation system (MAS), able to biotransform proteratogenic compounds. Cyclophosphamide, ethanol, benzo[a]pyrene and thalidomide were used as test materials to assess the efficiency of this assay. Briefly, the zebrafish embryos were co-cultured at 2 hpf (hours post fertilization) with the test material at varying concentrations, mammalian liver microsomes from different species and NADPH for 60 min at 32°C under moderate agitation in Tris buffer. The negative control (test material alone) and the MAS control (MAS alone) were incubated in parallel. For each test group, 20 eggs were used for statistical robustness. Afterwards fish embryos were transferred individually into 24-well plates filled with fish medium for 48 hours at 26°C with a 12 hour-light cycle. Teratogenicity was scored after 24 and 48 hpf using morphological endpoints. The test was considered to be valid if a minimum of 90% of fish eggs developed normally for the two controls (test material alone and MAS alone). For each test material, the experiment was repeated three times with the controls satisfying the validation criteria (≤ 10% impaired embryos). Indeed, no significant teratogenic effects were observed compared to controls in fish embryos exposed to the proteratogens alone (i.e., without metabolic activation) or the MAS alone. In contrast, the four test materials induced significant abnormalities in fish embryos when co-incubated with animal liver microsomes. For cyclophosphamide, ethanol and thalidomide a concentration-response relationship was shown and the qualitative nature of the malformations was similar between fish embryos and humans. Benzo[a]pyrene was demonstrated to be significantly teratogenic in fish embryos in spite of no concentration-response and unspecific teratogenic fingerprints. We conclude that the application of animal liver microsomes will improve and refine the DarT as a predictive and valuable alternative method to screen teratogenic substances.
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Timmons, James A. "The role of pyruvate dehydrogenase complex activation in the regulation of the metabolic and functional responses to contraction in canine and human skeletal muscle." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309688.
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Busquet, François Dominique. "Development of a new screening assay to identify proteratogenic compounds using Zebrafish Danio rerio embryo combined with an exogenous mammalian metabolic activation system (mDarT)." [S.l. : s.n.], 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1228302283465-60848.
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Boisvert, Lorrie. "Critical Examination of Selected Aspects of the ToxTracker In Vitro Genotoxicity Assay: Evaluation of S9 Metabolic Activation Protocols and Quantitative Interpretation of Dose-response Data." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/41152.
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Genotoxic effects such as mutations and chromosome abnormalities can augment the risk of adverse health effects such as cancer and heritable genetic diseases; chemicals in commerce must be screened for genotoxic activity. To this end, Toxys B.V. developed the in vitro ToxTracker® assay, which detects (geno)toxicity by monitoring the activity of six reporter genes in cultured mES cells (murine embryonic stem cells), i.e., Rtkn, Bscl2, Btg2, Srxn1, Blvrb and Ddit3. The reporters respond to genotoxic stress, oxidative stress, and endoplasmic reticulum stress characterized by protein unfolding; reporter induction is monitored using flow cytometry. The ToxTracker® assay generates large amounts of multivariate concentration-response data; this study employed innovative quantitative methods to scrutinize ToxTracker® assay results. The work (i) defined a fold-change threshold for identification of a significant positive response, (ii) used two analytical approaches to define endpoint-specific Benchmark Response (BMR) values, (iii) used the BMD (Benchmark Dose) combined-covariate approach for potency ranking of assay validation compounds, and (iv) used PCA (Principal Component Analysis) to investigate functional and statistical relationships between the reporters. The results revealed fold-change cut-offs of 1.5 and 1.7 for identification of weak and strong positive responses, respectively. 1.5-fold is consistent with the value advocated by Toxys B.V.; 1.7-fold is more conservative than the Toxys-advocated 2-fold value. Potency ranking of the validation compounds permitted comparative identification of the most potent inducers of each reporter. The most potent compounds consistently included clastogens used for cancer chemotherapy. BMR values determined using the Zeller et al. (2017) approach ranged from 2.2% for Blvrb and Rtkn, to 7.0% for Ddit3, with an average of 3.9% across all the reporters. The Slob (2016) approach yielded values that ranged from 30% for Ddit3, to 52% for Rtkn, with an average of 43%. The PCA results indicated the Rtkn, Bscl2 and Btg2 reporters are functionally redundant; collectively indicative of genotoxic stress. The Blvrb and Ddit3 reporters are orthogonal indicators of oxidative stress and protein unfolding, respectively; they are essential for toxicological profiling using the ToxTracker® assay. PCA axis scores reflect the toxicological MOA (Mode of Action) of the tested compounds; hitherto unknown MOAs can be inferred using PCA axis-plot proximity to well-studied compounds. Like most in vitro (geno)toxicity assessment assays, ToxTracker® employs a material known as S9 to simulate mammalian hepatic metabolism. S9 is prepared from the livers of rats exposed to an inducer of microsomal CYP (Cytochrome P450) isozymes; the most common CYP inducer is the PCB (polychlorinated biphenyl) mixture known as Aroclor-1254. Due to restrictions in the availability of Aroclor-1254, this study also evaluated the utility of Phenobarbital (PB)/β-Naphthoflavone (BNF)-induced S9, a proposed substitute for Aroclor-induced S9. The results indicate that, despite differences in enzymatic profiles, a 24-hr protocol using 0.40% v/v PB/BNF-induced S9 yields results that are comparable to those obtained using 0.25% v/v Aroclor-induced S9. This study constitutes a significant step towards augmenting the utility of the ToxTracker® assay; it provides a foundation for eventual adoption of high-throughput reporter assays for routine regulatory screening of new and existing chemicals.
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Perel, Shireen J. C. "The impact of activation of the renin-angiotensin system in the development of insulin resistance in experimental models of obesity." Thesis, Stellenbosch : University of Stellenbosch, 2009. http://hdl.handle.net/10019.1/2664.
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Thesis (MScMedSc (Biomedical Sciences. Medical Physiology))--University of Stellenbosch, 2009.Insulin stimulates the production of nitric oxide (NO) in endothelial cells and cardiac myocytes by a signalling pathway that involves the insulin receptor substrate (IRS)-1, phosphatidylinositol-3-kinase and protein kinase B (PKB/Akt). Physiological concentrations of NO play an important part in maintaining normal vascular function. It has been suggested that nitric oxide synthase (NOS) activity and NO production are chronically impaired in diabetes mellitus by an unknown mechanism. The reninangiotensin system and subsequent production of angiotensin II (Ang II) are elevated in obesity and diabetes while antagonism of the AT1 receptor with Losartan has beneficial effects in patients with insulin resistance and type II diabetes. Aims: We therefore aimed to investigate (i) the effect of Ang II on myocardial insulin signalling with regards to key proteins (IRS-1, PKB/Akt, eNOS and p38 MAPK) in correlation with NO production, (ii) the effect of Losartan on these parameters. Methods: Hyperphagia-induced obese, insulin resistant rats (DIO=diet supplemented with sucrose and condensed milk) were compared to age-matched controls. Half the animals were treated with 10mg/kg Losartan per day for 1 week. Isolated hearts were perfused with or without 0.03 μIU/mL insulin for 15 min. Blood glucose, bodyweight, intraperitoneal fat and plasma insulin and Ang II were recorded. Proteins of interest and their phosphorylation were determined by Western blotting. NO production was flow cytometrically analyzed. ANOVA followed by the Bonferroni correction was used with a p< 0.05 considered significant. Results: DIO animals had significant elevated bodyweight, blood glucose, plasma insulin and Ang II levels. Our data showed that the hearts from the DIO animals are insulin resistant, ultimately reflected by the attenuated activation of the key proteins (IRS-1, PKB/Akt and eNOS) involved in insulin signalling as well as NO production. AT1 receptor antagonism improved NO production in isolated adult ventricular myocytes from DIO animals while concurrently enhancing expression of eNOS, PKB/Akt and p38 MAPK. In contrast, NO production as well as expression of eNOS and PKB/Akt was attenuated in control animals after Losartan treatment. Conclusion: These results suggested that Ang II via AT1 or AT2 receptors, modulates protein expression of both PKB/Akt and eNOS. This encouraged us to investigate the involvement of AT2 receptors in the observed changes. To investigate this we needed to establish a culture of neonatal rat cardiac myocytes treated with raised fatty acids and Ang II. If similar changes were induced as observed in the hearts of DIO animals, the involvement of the AT1 and AT2 receptors could be investigated using specific antagonists against these receptors. Primary cultured ventricular myocytes were isolated from 1-3 day old Wistar rat pups. They were cultured for 48 hours before the addition of palmitate and oleate at a concentration of 0.25 mM each and were treated with or without the fatty acids for a period of 4 days. After 18 hours of serum starvation, cells were stimulated with or without 10 nM insulin for 15 minutes. The effect of fatty acid treatment on cell viability and glucose uptake were assessed by trypan blue and propidium iodide staining and 2-deoxy-D-3[H] glucose uptake respectively. Protein levels and phosphorylation of key proteins (PKB/Akt, PTEN and p38 MAPK) in insulin signalling was determined by Western blotting. 0.25 mM Fatty acids did not result in the loss of cell viability. Contrary to expectation, fatty acid treatment led to enhanced basal glucose uptake but lower Glut 1 protein expression. Basal protein expression of PPARα was, however, upregulated as was the expression of the phosphatase, PTEN. The latter could explain the lower PKB/Akt phosphorylation also documented. From these results we conclude that neonatal cardiac myocytes, cultured in the presence of elevated fatty acids, did not respond in a similar manner as the intact hearts of our animals and further modifications of the system might be needed before it can be utilized as initially planned.
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Kleis, Kevin Michael. "Eccentric Workloads Generated by a Powered Rowing Machine and its Effects on Muscular Contraction and Metabolic Cost." Cleveland State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=csu1534697072520532.
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Stuart, Charles A., Andrew S. Layne, Mark A. South, S. Nasrallah, Mary E. A. Howell, Melanie P. McCurry, Michael W. Ramsey, and Michael H. Stone. "Lack Of Improvement In Insulin Responsiveness In The Metabolic Syndrome After Resistance Training Only May Be Due To Fewer Muscle Slow‐Twitch Fibers And Decreased Activation Of AMPK." Digital Commons @ East Tennessee State University, 2010. https://dc.etsu.edu/etsu-works/5097.
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Lack of Improvement in Insulin Responsiveness in the Metabolic Syndrome after Resistance Training Only May Be Due to Fewer Muscle Slow-Twitch Fibers and Decreased Activation of AMPK Ten non-diabetic subjects (fi Ten non-diabetic subjects (five males, five females) with the Metabolic Syndrome underwent eight weeks of supervised strength training. Training consisted of five weekly sessions. A brief orientation period was followed by two blocks of progressively increasing intensity training. Nine control subjects were trained at the same time following the same protocols. At the completion of training, strength and VO[sub]2[/sub]max increased by 10% in both groups, but body composition and body weight had not changed. Insulin responsiveness, quantified using a three hour euglycemic clamp procedure, did not improve in the insulin resistant Metabolic Syndrome subjects, but increased significantly (13%) in the control group. Control subjects had significantly more slow-twitch muscle fibers at baseline (50% vs. 36%). The fiber composition was not changed in either group by training. Expression of GLUT4, the principle insulin-responsive glucose transporter, increased significantly in both groups (39% in Metabolic Syndrome subjects, 76% in the control group). The muscle mitochondrial biogenesis pathway reflected by AMPK total expression and activation, and the muscle hypertrophy pathway as indicated by mTOR expression and activation were increased in both groups. Even though total AMPK and total mTOR increased about 40% in both groups, the change in activated phospho-AMPK was greater in the control group (38% vs. 8%), and the activated phospho-mTOR increased more in the Metabolic Syndrome group (50% vs. 25%). Since AMPK is predominantly expressed in slow-twitch muscle fibers and mTOR is expressed at higher levels in fast-twitch fibers, these data may reflect the difference in fiber composition between the two groups. Strength training resulted in qualitatively similar effects on muscle remodeling in persons at low risk or high risk for diabetes, but greater activation of AMPK was associated with increased insulin responsiveness. In Metabolic Syndrome subjects, resistance training alone activated muscle hypertrophy pathways and increased muscle GLUT4 expression, but did not improve insulin responsiveness.
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Khan, Nazimuddin [Verfasser], Manfred [Akademischer Betreuer] Konrad, and Kai [Akademischer Betreuer] Tittmann. "Biochemical Characterization of Human Guanylate Kinase and Mitochondrial Thymidine Kinase: Essential Enzymes for the Metabolic Activation of Nucleoside Analog Prodrugs / Nazimuddin Khan. Gutachter: Manfred Konrad ; Kai Tittmann. Betreuer: Manfred Konrad." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2015. http://d-nb.info/1074758528/34.
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Asp, Vendela. "In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE." Doctoral thesis, Uppsala universitet, Ekotoxikologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-122721.
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The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO2-DDE) is bioactivated by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of mice and forms irreversibly bound protein adducts, reduces glucocorticoid secretion, and induces cell death selectively in cortisol-producing adrenocortical cells. 3-MeSO2-DDE has therefore been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) therapy. The aims of this thesis were to (1) develop in vitro test systems based on murine and human adrenocortical cell lines and to (2) investigate the mechanisms behind 3-MeSO2-DDE toxicity in adrenocortical cells. The cytotoxic and endocrine-modulating effects of 3-MeSO2-DDE were compared to those of o,p′-DDD (mitotane), the current ACC therapy, and to those of several structurally analogous compounds in both murine and human cell lines. 3-MeSO2-DDE bioactivation and cytotoxicity proceeded in a similar manner in the murine adrenocortical Y-1 cell line as in mice in vivo. The effects were highly structure-specific. Moreover, 3-MeSO2-DDE formed irreversibly bound protein adducts and caused cell death also in the human H295R cell line, and was slightly more cytotoxic than o,p′-DDD. However, 3-MeSO2-DDE toxicity in human cells was not affected by the CYP11B1 inhibitor etomidate, suggesting that bioactivation in human cells is performed by additional/other enzyme(s) than CYP11B1. 3-MeSO2-DDE generated biphasic responses in cortisol and aldosterone secretion and in expression levels of the steroidogenic genes CYP11B1, CYP11B2, and StAR. Such hormesis-like responses were not seen for o,p′-DDD or the precursor DDT metabolite p,p′-DDE. In addition, the two o,p′-DDD enantiomers (R)-(+)-o,p′-DDD and (S)-(-)-o,p′-DDD exhibited slight differences in cytotoxic and endocrine-modulating activity in H295R cells. In conclusion, this thesis provides extended knowledge on the mechanisms of action of 3-MeSO2-DDE and points out important differences in effects between murine and human cells. Lead optimisation studies of 3-MeSO2-DDE using the herein presented in vitro test systems are ongoing.
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Ali, Sakina. "Rôle des vésicules extracellulaires dans la pathogenèse de la résistance à l’insuline dans le syndrome métabolique LPS-enriched small extracellular vesicles from metabolic syndrome patients trigger endothelial dysfunction by activation of TLR4." Thesis, Angers, 2020. http://bu.univ-angers.fr/Contact.
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Le syndrome métabolique (SMet) est un ensemble de troubles métaboliques associés à une dysfonction endothéliale et à une résistance à l’insuline. Grâce à leur cargaison qu’ils peuvent transférer d’une cellule à l’autre, les vésicules extracellulaires (VEs), incluant les grandes (lEVs) et les petites (sEVs) vésicules sont impliquées dans différentes voies de communication intercellulaire. Parmi toutes les recherches menées sur les VEs, l’étude de leur implication dans la physiopathologie des maladies métaboliques a mis en évidence de nombreuses communications intercellulaires délétères pour le système vasculaire et pour la signalisation de l’insuline. Les objectifs de mon projet de thèse étaient de caractériser les sEVs circulants de patients SMet et non-SMet, d’évaluer leur effet métabolique sur la fonction endothéliale et enfin d’analyser l’effet des lEVs et des sEVs sur les cellules et tissus cibles de l’insuline. Premièrement, nous avons montré que la concentration circulante des sEVs étaient positivement corrélées avec les critères du SMet, notamment l’obésité viscérale, l’hypertension, la résistance à l’insuline et la dyslipidémie. Nous avons montré que les SMet-sEVs, enrichies en LPS, sont impliqués dans le développement d’une dysfonction endothéliale via l’activation de la voie de signalisation de TLR4. Deuxièmement, nous avons démontré que les deux sous-types de VEs peuvent induire une résistance à l’insuline dans les organes périphériques via des mécanismes moléculaires différents. Ces résultats ont permis de mettre en évidence les voies moléculaires par lesquelles les VEs participent aux altérations métaboliques associées à la dysfonction endothéliale et à la résistance à l’insuline pendant le MetSMetabolic syndrome (MetS),characterized by interconnecting metabolic disorders, is associated with endothelium dysfunction and insulin resistance. Thanks to their ability to transfer their cargo to recipient cells, extracellular vesicles (EVs), including large(lEVs) and small (sEVs) vesicles are involved indifferent intercellular communication pathways. Among the research conducted on EVs, the study of their involvement in the pathophysiology of metabolic diseases have highlighted numerous intercellular communication that are deleterious for the vascular system and for insulin pathways. My thesis project aims were to characterize circulating EVs from non-MetS and MetSpatients, to evaluate their metabolic effect on endothelial function, and to analyze lEVs andsEVs effects on insulin target cells and tissues. First, we shown that circulating concentration of sEVs were positively correlated with MetS criteriain cluding visceral obesity, hypertension, insulin resistance and dyslipidemia. We have shown that MetS sEVs, enriched with LPS, are involved in the development of endothelial dysfunction through the activation of the TLR4 signaling pathway. Second, we demonstrated that both subtype of EVs can induce insulin resistance in peripheral tissues via different molecular mechanisms.These results allow understanding the molecular pathways by which EVs participate in metabolic alterations associated with endothelial dysfunctions and insulin resistance during MetS
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Alandas, Mohammed N. "An investigation into the metabolic activation of novel chloromethylindolines by isoforms of cytochrome P450. Targeting drug metabolising enzymes in cancer: analysis of the role and function of selected cytochrome P450 oxidising novel cancer prodrugs." Thesis, University of Bradford, 2012. http://hdl.handle.net/10454/6289.
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Introduction Cytochromes P450 (CYPs) are the major family of enzymes responsible for detoxification and metabolism of a wide range of both endogenous and xenobiotics chemicals in living organisms. The use of CYPs to activate prodrugs to cytotoxins selectively in tumours has been explored including AQ4N, Phortress and Aminoflavone. CYP1A1, CYP1B1, CYP2W1, and CYP4F11 have been identified as expressed in tumour tissue and surrounding stroma at high frequency compared to most normal tissues.
Aim is to investigate the differential metabolism of novel chloromethylindoline by high frequency expressed CYPs in tumours. This differential may be exploited to elicit a selective chemotherapeutic effect by metabolising inert small molecules to potent cytotoxins within the tumour environment.
Materials and Methods Sensitive and specific LC/MS/MS techniques have been developed to investigate the metabolism of chloromethylindolines. Recombinant enzymes and transfected cell lines were used to investigate the metabolic profiles with a focus on production of the cytotoxic derivatives of chloromethylindolines. Results Detailed metabolic studies show that (1-(Chloromethyl)-1,2-dihydropyrrolo
[3,2-e]indol-3(6H)-yl)(5-methoxy-1H-indol-2-yl) methanone (ICT2700) and other chloromethylindolines are converted by CYP1A1 mediated hydroxylation at the C-5 position leading to highly potent metabolites. In vitro cytotoxicity studies showed differentials of up to 1000-fold was achieved between CYP1A1 activated compared to the non-metabolised parent molecules. The reactivity of metabolites of ICT2700 was also explored using glutathione as a nucleophile. The metabolites were identified by a combination of LC/MS and LC MS/MS techniques. Investigations using mouse and human liver microsomes show that a large number of metabolites are created though none were shown to be associated with a potential anticancer effect. Studies focused on CYP2W1 show that this isoform metabolised ICT2706 to a cytotoxic species and a pharmacokinetic study showed a good distribution of ICT2706 into mouse tissues including tumour. However metabolism of ICT2726 by CYP2W1 resulted only in a non-toxic metabolite profile and may have potential as a biomarker for functional CYP2W1 in tissues. Preliminary studies show that palmitic acid hydroxylation is a useful marker of functional CYP4F11. Summary and conclusion The in vitro results show that the chloromethylindolines are a novel class of agent with potential as prodrugs that following specific hydroxylation by CYP1A1 and CYP2W1 are converted to ultra-potent cytotoxins. Other metabolites are also evident which are not cytotoxic. Studies in vivo show that selected chloromethylindolines possess a good pharmacokinetic profile and show potential as prodrug anticancer agents that require activation by CYP1A1 or CYP2W1. The methods, results, progress and suggestions for future work are presented in this thesis.
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Alandas, Mohammed Nasser. "An investigation into the metabolic activation of novel chloromethylindolines by isoforms of cytochrome P450 : targeting drug metabolising enzymes in cancer : analysis of the role and function of selected cytochrome P450 oxidising novel cancer prodrugs." Thesis, University of Bradford, 2012. http://hdl.handle.net/10454/6289.
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Introduction: Cytochromes P450 (CYPs) are the major family of enzymes responsible for detoxification and metabolism of a wide range of both endogenous and xenobiotics chemicals in living organisms. The use of CYPs to activate prodrugs to cytotoxins selectively in tumours has been explored including AQ4N, Phortress and Aminoflavone. CYP1A1, CYP1B1, CYP2W1, and CYP4F11 have been identified as expressed in tumour tissue and surrounding stroma at high frequency compared to most normal tissues. Aim is to investigate the differential metabolism of novel chloromethylindoline by high frequency expressed CYPs in tumours. This differential may be exploited to elicit a selective chemotherapeutic effect by metabolising inert small molecules to potent cytotoxins within the tumour environment. Materials and Methods: Sensitive and specific LC/MS/MS techniques have been developed to investigate the metabolism of chloromethylindolines. Recombinant enzymes and transfected cell lines were used to investigate the metabolic profiles with a focus on production of the cytotoxic derivatives of chloromethylindolines. Results: Detailed metabolic studies show that (1-(Chloromethyl)-1,2-dihydropyrrolo [3,2-e]indol-3(6H)-yl)(5-methoxy-1H-indol-2-yl) methanone (ICT2700) and other chloromethylindolines are converted by CYP1A1 mediated hydroxylation at the C-5 position leading to highly potent metabolites. In vitro cytotoxicity studies showed differentials of up to 1000-fold was achieved between CYP1A1 activated compared to the non-metabolised parent molecules. The reactivity of metabolites of ICT2700 was also explored using glutathione as a nucleophile. The metabolites were identified by a combination of LC/MS and LC MS/MS techniques. Investigations using mouse and human liver microsomes show that a large number of metabolites are created though none were shown to be associated with a potential anticancer effect. Studies focused on CYP2W1 show that this isoform metabolised ICT2706 to a cytotoxic species and a pharmacokinetic study showed a good distribution of ICT2706 into mouse tissues including tumour. However metabolism of ICT2726 by CYP2W1 resulted only in a non-toxic metabolite profile and may have potential as a biomarker for functional CYP2W1 in tissues. Preliminary studies show that palmitic acid hydroxylation is a useful marker of functional CYP4F11. Summary and conclusion: The in vitro results show that the chloromethylindolines are a novel class of agent with potential as prodrugs that following specific hydroxylation by CYP1A1 and CYP2W1 are converted to ultra-potent cytotoxins. Other metabolites are also evident which are not cytotoxic. Studies in vivo show that selected chloromethylindolines possess a good pharmacokinetic profile and show potential as prodrug anticancer agents that require activation by CYP1A1 or CYP2W1. The methods, results, progress and suggestions for future work are presented in this thesis.
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Lepers, Capucine. "Pollution atmosphérique de proximité et toxicité respiratoire : recherche in vitro des mécanismes d'action toxique induits par des aérosols atmosphériques particulaires (PM₂.₅) industriels, urbains et ruraux." Thesis, Littoral, 2013. http://www.theses.fr/2013DUNK0352/document.
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Les particules fines (PM₂.₅) présentes dans l'air extérieur peuvent être inhalées puis retenues au niveau pulmonaire, conduisant à l'apparition ou à l'aggravation de différentes pathologies cardio-respiratoires. La composition complexe des PM₂.₅ rend d'autant plus difficile l'étude de leurs mécanismes d'action. Cette thèse s'inscrit donc dans une démarche d'identification des processus impliqués dans un éventuel potentiel cancérigène des PM₂.₅, en lien avec leur composition chimique. Nous avons étudié la toxicité de six échantillons de PM₂.₅, collectés sous influence industrielle, urbaine ou rurale au cours des saisons printemps-été 2008 et automne-hiver 2008-2009. L'étude de la fraction biologique a révélé la diversité et la richesse des particules en contaminants fongiques et bactériens. Le test d'Ames nous a permis de mettre en évidence une forte mutagénicité des PM₂.₅, vraisemblablement liée aux composés nitro-aromatiques. Sur la base de tests de cytotoxicité préalables, nous avons étudié l'effet de 3,75 et 15 µg/cm² de particules sur la lignée de cellules épithéliales bronchiques humaines BEAS-2B. Nous avons mis en évidence une induction génique de différents enzymes impliquées dans l'activation métabolique des hydrocarbures aromatiques polycycliques, associée à une augmentation d'activité catalytique. Cette induction semble conduire à la formation d'adduits encombrants à l'ADN. De plus, les PM₂.₅ induisent des cassures simple- et double-brin de l'ADN, la formation de micronoyaux, ainsi que des perturbations de l'activité télomérase. Ces effets génotoxiques sont associés à des altérations épigénétiques que sont une hyperméthylation du promoteur de P16ᴵᴺᴷ⁴ᴬ, des modifications post-traductionnelles de l'histone 3 et des changements dans l'expression des miRNA étudiés. Considérant l'influence de la composition des PM₂.₅, les composés organiques semblent être responsables des effets génotoxiques les plus importants, alors que les métaux paraissent avoir des effets épigénétiques supérieurs. En conclusion, il apparaît que les échantillons de PM₂.₅ étudiés, de par l'action conjointe de leurs fractions organique et inorganique, sont susceptibles d'induire in vitro de multiples lésions décrites dans les étapesd'initiation et de promotion de la cancérogénèse broncho-pulmonaireFine airborne particulate matter (PM₂.₅) can be inhaled and retained in deep lung for long periods, leading to onset or exacerbation of cardio-respiratory diseases. However, the complex composition of PM₂.₅ makes difficult the study of their mechanisms of action. This work fits into a global approach aiming to identify the toxicity mechanisms involved in a putative PM₂.₅ carcinogenicity, in association with PM composition. We study six PM samples collected either under industrial, urban or rural area, in spring-summer 2008 or autumn-winter 2008-2009 seasons. Biological fraction analysis revealed numerous and diverse bacterial and fungal components. We carried out Ames tests revealing a high mutagenic potency for PM samples, presumably linked to their nitro-aromatic content. Based on previous cytotoxicity assays, we studied PM effect on bronchial epithelial cell line BEAS-2B, at two concentrations (3.75 and 15µg/cm²). We demonstrated gene induction of several xenobiotic metabolizing enzymes involved in polycyclic aromatic hydrocarbons metabolic activation. This was associated with an increase in their catalytic activity, leading to bulky DNA-adducts formation in exposed cells. Furthermore, PM₂.₅ lead to DNA single- and double-strand breaks, micronuclei formation, and disturbed telomerase activity. In addition to these genotoxic effects, our study revealed epigenetic alterations such as P16ᴵᴺᴷ⁴ᴬ promoter hypermehylation, histone 3 post-translational modifications, and miRNAs expression changes. Considering the impact of chemical composition on PM toxicity, organic compounds lead to the highest genotoxicity, whereas metals seem to induce more pronounced epigenetic modifications. Altogether, our results indicate that the studied PM₂.₅ samples, through cooperative action of organic and inorganic fractions, may lead in vitro to multiple alterations involved in initiation and promotion steps toward pulmonary carcinogenesis
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Chahbane, Naima [Verfasser], Antonius Akademischer Betreuer] Kettrup, Karl-Werner [Akademischer Betreuer] Schramm, Harun [Akademischer Betreuer] Parlar, and Roland [Akademischer Betreuer] [Meyer-Pittroff. "Regulation of Cytochrome P450 enzymes in H4IIE : A tool for detection of dioxin-like activity and metabolic activation for screening of estrogenicity / Naima Chahbane. Gutachter: Harun Parlar ; Roland Meyer-Pittroff. Betreuer: Antonius Kettrup ; Karl-Werner Schramm." München : Universitätsbibliothek der TU München, 2005. http://d-nb.info/1058141295/34.
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Tian, Zhenjiao. "Oxidation and Reduction Process for Polycyclic Aromatic Hydrocarbons and Nitrated Polycyclic Aromatic Hydrocarbons." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1228333650.
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Ehlers, Kerstin Christina [Verfasser], Johann Josef [Akademischer Betreuer] Hauner, and Martin [Akademischer Betreuer] Klingenspor. "From GWAS to functionality: association of rs2014355 in the ACADS gene locus with acylcarnitine ratio and postprandial metabolic and inflammatory activation of human PBMC / Kerstin Christina Ehlers. Gutachter: Martin Klingenspor ; Johann Josef Hauner. Betreuer: Johann Josef Hauner." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1049281098/34.
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Al, Zallouha Margueritta. "Étude prospective pilote des effets d'une exposition ex vivo de lymphocytes T humains à la pollution atmosphérique particulaire : recherche de biomarqueurs et influence de l'âge." Thesis, Littoral, 2017. http://www.theses.fr/2017DUNK0472/document.
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Les particules fines atmosphériques (PF) sont capables de pénétrer dans les poumons où certains composés transportés peuvent interagir avec les cellules pulmonaires et atteindre la circulation sanguine. L'exposition aux PF affecte particulièrement les populations sensibles telles que les personnes agées. Cette thèse s'inscrit dans une démarche d'identification des effets des PF sur les lymphocytes T humains (LT) tout en visant à déterminer des biomarqueurs liés à l'exposition et à évaluer la variation de la réponse cellulaire en fonction de l'âge. Des LT ont été isolés de prélèvements sanguins de 91 volontaires appartenant à trois classes d'age (20-30, 45-55, 70-85 ans) puis exposés ex vivo pendant 72h à 45 µg/µl de PF collectées à Dunkerque. Les étapes d'isolement, purification et activation des LT ont d'abord été optimisées. Suite à la caractérisation de la population échantillonnée, une population d'étude homogène a été sélectionnée ( 10 sujets / classe d'âge). Nous avons mis en évidence une induction génique d'enzymes impliquées dans l'activation métabolique des HAP identifiés dans l'échantillon de PF. La caractérisation du profil des Lt a permis de proposer un profil mixte Th1/Th2 causé par l'exposition. L'étude transcriptomique des miARN a mis en évidence une surexpression de miR-124-3p impliqué dans la régulation de plusieurs fonctions au niveau du système immunitaire et de miR-1290 impliqué dans plusieurs types de cancer. Quant à l'influence de l'âge, une surexpression des gènes codant pour les enzymes antioxydantes (NQO1 et HMOX1), une augmentation de la concentration des cytokines (IL-4 et IL-13) ainsi qu'une modification du profil d'expression de certains miARN ont été notées chez les sujets les plus âgésAtmospheric fine particulate matter (FP) are able to enter the lungs where some compounds can interact with lung cells and reach the bloodstream . Exposure to FP affects in particular susceptible populations such as the elderly. This thesis is part of a project aiming to identify the effects of FP on human T lymphocytes (LT) while attempting to determine biomarkers related to exposure and to evaluate the variation of the cellular response as a function of age. LT were isolated from blood samples of 91 volunteers belonging to three age groups (20-30, 45-55, 70-85 years) then exposed ex vivo for 72h to 45 µg/µl of FP collected in Dunkirk. The steps of isolation, purification and activation of LT were first optimized. Following the characterization of the sampled population, a homogeneous study population was selected (10 subjects/age class). We have demonstrated an induction of the genes coding for the enzymes involved in the metabolic activation of PAH identified in the PF sample. Characterization of the LT profile made it possible to propose a mixed th1/th2 profile cause by the exposure. Teh transcriptomic study of miRNAs revealed an overexpression of miR-124-3p involved in the regulation of several functions in the immune system and miR-1290 involved in several types of cancer. As for the influence of age, overexpression of the genes coding for the antioxidant enzymes (NQO1 and HMOX1), an increase in the concentration of cytokines (IL-4 and IL-13) as well as a modification of the expression profile of some miRNAs were noted on the elderly
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Tilney-Bassett, Amanda L. "Phospholipid metabolism in T-cell activation." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239331.
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Cernkovich, Erin Rice Harp Joyce B. "Function and activation of signal transducer and activator of transcription 3 (STAT3) in adipose tissue formation and metabolism." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1210.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition, School of Public Health." Discipline: Nutrition; Department/School: Public Health.
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Borgie, Mireille. "Étude des particules fines et ultrafines en suspension dans l'air au Liban : caractérisation physicochimique et évaluation des effets toxicologiques sur des cellules pulmonaires humaines BEAS-2B." Thesis, Littoral, 2014. http://www.theses.fr/2014DUNK0366/document.
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Les principaux objectifs de cette étude, une des premières menée au Liban, étaient d’acquérir une meilleure connaissance des caractéristiques physico-chimiques des particules atmosphériques fines (PF ou PM₂.₅₋₀.₃) et ultrafines (PUF ou PM₀.₃), et d’évaluer in vitro, leur potentiel toxique sur des cellules épithéliales bronchiques humaines (BEAS-2B). L’échantillonnage de PF et de PUF a été mené au Liban à la fois sur un site urbain (Sin El-Fil, du 18 mai au 2 sept. 2011) et un site rural (Beije, du 5 sept. au 28 oct. 2011). Les PF et les PUF ont fait l’objet d’une caractérisation physico-chimique par la détermination de leur composition en éléments et ions inorganiques, carbone total et composés organiques. Ensuite, des échantillons composites de PF et de PUF ont été préparés afin d’exposer les cellules BEAS-2B et évaluer les mécanismes toxiques sous-jacents. Nos résultats ont montré une influence des sources de combustion plus notable pour les particules collectées sur le site urbain, et cela par la présence de carbone total, de composés organiques, de métaux et d’ions inorganiques secondaires à des niveaux de concentration supérieurs à ceux rencontrés sur le site rural. D’autre part, une cytotoxicité plus prononcée a été provoquée par les PUF par comparaison aux PF. Les mécanismes de génotoxicité et de modifications épigénétiques que nous avons étudiés, à savoir l’activation métabolique des composés organiques, la modification de l’expression de trois microARNs, l’activation de la télomérase et l’induction de cassures au niveau de l’ADN, ont été induits par les deux échantillons de PF, avec un effet plus prononcé pour les particules d’origine urbaine. L’exposition des cellules BEAS-2B aux PF collectées, notamment celles d’origine urbaine, pourraient donc favoriser la transformation des cellules pulmonaires en cellules immortelles, et par conséquent, l’initiation ou la promotion de la cancérogenèse broncho-pulmonaireThe objectives of this study, one of the first conducted in Lebanon, were to acquire a better knowledge on the physico-chemical characteristics of atmospheric fine particles (FP or PM₂.₅₋₀.₃) and ultrafine ones (UFP or PM₀.₃), and to assess their potential toxicity. Particles were collected at two coastal sites between may and sept. 2011 at Sin El-Fil (urban site in Greater Beirut), and between sept. and oct. 2011 at Bejje (rural site). After sampling, FP and UFP were subjected to a physico-chemical characterization by quantifying their inorganic ions and elements, total carbon and organic compounds contents. Then, composite samples of FP and UFP were prepared in order to expose bronchial epithelial cells (BEAS-2B) in culture, and therefore to assess the underlying toxic mechanisms. Our results showed an influence of combustion sources especially for urban particles that are richer in total carbon, organic compounds, metals and secondary inorganic ions than rural ones. On the other hand, a more pronounced cytotoxicity was caused by UFP when compared to FP. In addition, epigenetic modifications and genotoxicity mechanisms, such as metabolic activation of organic compounds, changes in three microRNAs expression, telomerase activation and DNA breaks induction, which are potentially involved in the initiation and promotion of carcinogenesis, were induced by the two samples of FP, with a more pronounced effect of urban particles. Exposure of BEAS-2B cells to collected FP, especially urban ones, may therefore induce the transformation of lung cells to immortal cells, and consequently the initiation or the promotion of broncho-pulmonary carcinogenesis
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Dieme, Denis. "Caractérisation physicochimique et étude des effets toxiques sur des cellules pulmonaires BEAS-2B des polluants particulaires de la ville de Dakar (Sénégal)." Phd thesis, Université du Littoral Côte d'Opale, 2011. http://tel.archives-ouvertes.fr/tel-00818732.
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La pollution atmosphérique particulaire constitue un facteur de risque majeur pour la santé humaine. En dépit des nombreuses études réalisées, les mécanismes d'action sous-jacents à l'exposition aux particules et responsables des effets physiopathologiques observés restent encore mal connus. Notre travail a consisté en la collecte d'aérosols particulaires sur 2 sites urbains (Fann et Faidherbe) dans la ville de Dakar (Sénégal) et un site rural (Ngaparou). Les sites urbains sont caractérisés par un trafic automobile dense avec le site de Fann présentant une circulation majoritaire de véhicules de transport en commun alors qu'à Faidherbe le trafic est constitué en majorité de véhicules particuliers. la caractérisation physico-chimique des trois échantillons particulaires a montré une granulométrie fine (96% < 2,5 μm), donc capables de pénétrer profondément dans les poumons, des surfaces spécifiques comprises entre 8 et 13m²/g pouvant adsorber à leur surfaces des substances potentiellement toxiques. Leur composition chimique, riche en éléments inorganiques et organiques, démontre la diversité de leur sources (naturelle et anthropique). Après évaluation de leur cytotoxicité dans les cellules épithéliales bronchiques humaines (BEAS-2B), nous avons montré la capacité de ces aérosols particulaires à induire l'activation métabolique de leur fraction organique par l'induction de l'expression génique des enzymes de métabolisation CYP1A1, 1B1 et NQO1. Nous n'avons pas observé de réponse significative dans le processus d'altération oxydative via la péroxydation lipidique (MDA) et le statut du glutathion (GSSG/GSH). En revanche nous avons montré l'implication de ces aérosols particulaires dans le développement de la réponse inflammatoire par l'expression et la sécrétion significative de cytokines TNF-α, IL-1β, IL-6 et IL-8.
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Urquiza, Alexander Mata de. "Finding the ligand : retinoid receptor activation in the CNS /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-7349-010-5/.
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Furness, Sebastian George Barton. "Novel mechanisms for activation of the dioxin (Aryl-hydrocarbon) receptor /." Title page, table of contents and summary only, 2003. http://web4.library.adelaide.edu.au/theses/09PH/09phf988.pdf.
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Melki, Pamela. "Health impact of airborne particulate matter in Northern Lebanon : from a pilot epidemiological study to physico-chemical characterization and toxicological effects assessment." Thesis, Littoral, 2017. http://www.theses.fr/2017DUNK0444/document.
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L'exposition à la pollution atmosphérique, notamment aux particules fines (PM₂.₅), représente un risque majeur pour la santé dans le monde entier, et d'autant plus dans les pays en développement.Le Nord du Liban est ainsi affecté par plusieurs sources de pollution d'origine anthropique, urbaine et industrielle. Pourtant, dans cette région, aucune étude ne s'est intéressée à l'impact des PM₂.₅ sur la santé publique. Il faut également souligner que les mécanismes de toxicité des PM₂.₅ ne sont pas totalement identifiés. Le but de ce travail est d'étudier la nature et l'impact sanitaire de la pollution atmosphérique particulaire dans le Nord du Liban. Nous avons procédé à une enquête épidémiologique, et prélevé des particules fines que nous avons caractérisées sur les plans physico-chimiques et toxicologiques. Deux régions ont été considérées dont une est située à proximité d'activités industrielles. L'étude épidémiologique et de perception menée dans les deux zones du Nord du Liban (310 questionnaires/zone traitée), a montré une relation entre gêne, maladies respiratoires et proximité des industries. Cette enquête a ainsi confirmé l'intérêt de mener une étude toxicologique dans cette région. Afin de renforcer les connaissances sur la toxicité pulmonaire des aérosols atmosphériques particulaires avec une attention toute particulière portée à l'étude de certains des mécanismes d'action suspectés d'être impliqués dans la cancérogénécité, les caractéristiques physico-chimiques et toxicologiques des particules fines (PM₂.₅₋₀.₃) prélevées sur les deux sites ont été étudiées. Les particules collectées ont montré une composition similaire sur les deux sites concernant les espèces majeures. La contribution des activités industrielles a été mise en évidence par des teneurs légèrement plus élevées de certains éléments traces, d'HAP et surtout par une teneur jusqu'à 100 fois plus élevée en dioxines. Nos résultats ont mis en évidence l'influence de nombreuses sources de combustion (diesel, essence, charbon et biomasse) ; la combustion de déchets et d'autres procédés industriels sont également suspectées. Un potentiel génotoxique et mutagène plus prononcé a été mis en évidence pour les particules collectées sur le site sous influence industrielle par rapport aux particules provenant du site sous influence rurale, à l'aide du test d'Ames en milieur liquide et le SOS chromotest. Les effets observés sont très probablement influencés par la fraction organique des particules. Afin d'approfondir la recherche des mécanismes génotoxiques des PM, des cellules bronchiques humaines (BEAS-2B) ont été exposées à différentes concentrations de particules. Les mécanismes de toxicité, tels que l'activation métabolique des HAP(CYP1A1) et les cassures double-brins (quantification de yH2AX par cytométrie de flux et in-cell western), ont été induits par les deux échantillons de PM₂.₅₋₀.₃ avec un effet plus prononcé pour les particules industrielles. Par ailleurs, les PM ont montré une tendance à perturber le fonctionnement du système de réparation de l'ADN (par l'expression des gènes OGG1, NTH1, APE1, NUDT1, DNMT1, MGMT, XPA et XRRC1, et l'expression des protéines PARP1, DNMT1 et OGG1). Les mécanismes de réparation des dommages de l'ADN ont ainsi été réprimés jusqu'à 48h d'exposition aux PM, notamment aux PM₂.₅₋₀.₃ collectées sous influence industrielle, et réactivés après 72h d'exposition. Ces dommages concernent les adduits encombrants à l'ADN, et ceux causés par le stress oxydant, des cassures des brins d'ADN et la méthylation. Nos résultats suggèrent des mécanismes d'action mutagènes, génotoxiques et épigénétiques impliqués dans la cancérogénécité des particules fines, en partie liés à la composition de la fraction organiqueExposure to air pollution, especially fine particulate matter (PM₂.₅), remains a major health risk, mainly in the developing countries. Northern Lebanon is affected by several sources of anthropogenic, urban and industrial pollution. However, no studies have examined the impact of PM₂.₅ on public health in this region. In addition, it should be noted that the toxicity mechanisms of PM₂.₅ are not fully identified. The aim of this work is to study the composition and the health impact of the atmospheric particulates in Northern Lebanon. An epidemiological survey was performed and fine particles were extracted and characterized physico-chemically and toxicologically. This study was conducted in two sites, one of which is influenced by industrial activities. Perception and epidemiological survet, conducted in two areas in Northern Lebanon, rural and industrial (310 treatable questionnaires/area), showed a relationship between annoyance, respiratory diseases and living in proximity to industrial activities. Moreover, results confirmed the interest in conducting a toxicological study in this region. Hence, to contribute to fulfill the gap of knowledge about the pulmonary toxicity of particulate matter and the mechanisms of action involved in the carcinogenicity, the study of physicochemical characteristics and toxicological endpoints of PM₂.₅₋₀.₃ from both sites were performed. Physicochemical analyses of the collected particles evidenced similar characteristics in major species. In particular, we have shown slightly higher levels of PAHs and trace metals and up to 100 times higher dioxins concentrations at the vicinity of industries. Our results evidenced the influence of numerous combustion sources (diesel, gasoline, coal and biomass burning) ; waste combustion and other industrial processes are also suspected. A more pronounced genotoxic and mutagenic potential was evidenced after exposure to particles collected at the vicinity of industries when compared to the rural ones, using the Ames fluctuation test and SOS chromotest. The effects of the collected particles are probably related to their organic composition. In order to assess the underlying toxic mechanisms, human bronchial epithelial cells (BEAS-2B) were then exposed to different concentrations of the sampled PM₂.₅₋₀.₃. Genotoxicity mechanisms such as metabolic activation of organic compounds (CYP1A1) and consecutive DNA damages such as DNA strands breaks (yH2AX quantification by flow cytometry analysis and in-cell western assay) were induced by the two samples of PM₂.₅₋₀.₃ , with a more pronounced effect of industrial particles. Moreover, PM showed tendency to alter the DNA repair process (OGGI, NTH1, APE1, NUDT1, DNMT1, MGMT, XPA, XRRC1 gene expression and PARP1, DNMT1, OGG1 proteins expression). DNA repair mechanisms were repressed up to 48h of exposure to PM especially to the industrial influenced PM₂.₅₋₀.₃ and reactivated after 72h of exposure. The DNA damages involve bulky DNA adducts, oxidative stress damages, DNA strand breaks and methylation. These results suggest mutagenic, genotoxic and epigenetic mechanisms of action involved in the carcinogenicity of fine particles, partly related to their organic composition
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Houri, Nadia. "Study of ERK12 MAP kinases activation by the bradykinin type 2 receptor : characterization of beta-arrestin scaffolding function in the temporal regulation of ERK12 activation induced by the B2R." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112637.
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G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors. The beta-arrestins, adaptor proteins involved in GPCR desensitization, may also act as scaffolds for signaling pathways such as the mitogen-activated protein kinase (MAPK) cascade. The MAPK family, which includes the extracellular-signal regulated kinases (ERK) 1 and 2, promotes cellular differentiation and proliferation. Herein, the activation of ERK1/2 upon stimulation of the GPCR bradykinin type 2 receptor (B2R) with bradykinin was examined. Various B2R mutants with modified C-termini were employed to examine the temporal kinetics of ERK1/2. One of these receptor mutants displayed a loss of beta-arrestin binding as well as greatly enhanced ERK1/2 activation, compared to the wild-type receptor, when a cluster of serine/threonine residues important for B2R internalization was mutated. The other receptor mutants exhibited a correlation between their affinity for beta-arrestin and the intensity of ERK1/2 activation. Data from a mouse embryonic fibroblast cell line null for beta-arrestin suggested that beta-arrestin is involved in late-phase ERK1/2 activation by the B2R. These data point to the involvement of beta-arrestin in the activation of the ERK1/2 MAPKs through the B2R.
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Kohyama, Naoki. "Synthesis of nucleoside derivatives directed toward clarification of glucose metabolism activation." Kyoto University, 2005. http://hdl.handle.net/2433/144981.
Full textAbstract:
Kyoto University (京都大学)0048
新制・課程博士
博士(人間・環境学)
甲第11682号
人博第288号
新制||人||72(附属図書館)
16||179(吉田南総合図書館)
23325
UT51-2005-D431
京都大学大学院人間･環境学研究科文化･地域環境学専攻
(主査)教授 山本 行男, 教授 山口 良平, 教授 田村 類, 助教授 林 達也
学位規則第4条第1項該当