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Lloyd, Kenneth P. "Understanding Human Erythrocyte Glucose Transporter (GLUT1) Mediated Glucose Transport Phenomena Through Structural Analysis". eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/962.
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GLUT1-mediated, facilitated sugar transport is proposed to be an example of transport by a carrier that alternately presents exofacial (e2) and endofacial (e1) substrate binding sites, commonly referred to as the alternating access carrier model. This hypothesis is incompatible with observations of co-existent exo- and endofacial ligand binding sites, transport allostery, and e1 ligand (e.g. cytochalasin B) induced GLUT1 sugar occlusion. The fixed-site carrier model proposes co-existent, interacting e2 and e1 ligand binding sites but involves sugar translocation by geminate exchange through internal cavities. Demonstrations of membrane-resident dimeric and tetrameric GLUT1 and of e2, e1 and occluded GLUT conformations in GLUT crystals of monodisperse, detergent-solubilized proteins suggest a third model. Here, GLUT1 is an alternating access carrier but the transporter complex is a dimer of GLUT1 dimers, in which subunit interactions produce two e2 and two e1 conformers at any instant. The crystallographic structures in different conformations can be utilized to further understand the transport cycle, ligand binding behavior and complex kinetics observed in GLUT1. Specifically, the GLUT1 crystal structure and homology models based upon related major facilitator superfamily proteins were used in this study, to understand inhibitor binding, ligand binding induced GLUT1 transport allostery and the existence of helix packing/oligomerization motifs and glycine induced flexibility. These studies suggest that GLUT1 functions as an oligomeric allosteric carrier where cis-allostery is an intramolecular behavior and trans-allostery is an intermolecular behavior. Additionally, mutations of a dynamic glycine affect the turnover of the transporter while mutations to helix packing motifs affect affinity.
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Ojelabi, Ogooluwa A. "Small Molecule Modulation of GLUT1-Mediated Glucose Transport". eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/950.
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The glucose transport protein, GLUT1, is highly expressed in rapidly proliferating cells, including cancer cells, while decreased GLUT1 levels are found in diseases such as GLUT1 deficiency syndrome and Alzheimer’s. There is increased interest in developing GLUT1 inhibitors as novel anticancer therapeutics, and the discovery of compounds that directly stimulate GLUT1 function. This work investigates how small molecules stimulate and/or inhibit GLUT1-mediated glucose transport, either directly or through the AMPK pathway.
Using sugar transport assays and docking analyses to explore Ligand–GLUT1 interactions and specificity of binding, we show that: 1) Ligands inhibit GLUT1 by competing with glucose for binding to the exofacial or endofacial sugar binding sites; 2) Subsaturating inhibitor concentrations stimulate sugar uptake; 3) Ligands inhibit GLUT1–, GLUT3– and GLUT4–mediated sugar uptake in HEK293 cells; and 4) Inclusion of a benzonitrile head group on endofacial GLUT1 inhibitors confers greater inhibitory potency.
Furthermore, we investigated AMPK-regulated GLUT1 trafficking in cultured blood-brain barrier endothelial cells, and show that inhibition of GLUT1 internalization is not responsible for increased cell surface levels of GLUT1 observed with AMPK activation in these cells.
This study provides a framework for screening candidate GLUT1 inhibitors for specificity, and for optimizing drug design and delivery. Our data on transport stimulation at low inhibitor concentrations support the idea that GLUT1 functions as a cooperative oligomer of allosteric alternating access subunits.
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Brenner, Corinne. "Immune-mediated regulation of glucose uptake in human adipocytes". Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/7126.
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I have investigated the potential role of Toll-Like Receptors (TLRs) in mediating adipose inflammation in obesity. TLRs are a family of pattern recognition receptors that play a key role in host defence and are also implicated in chronic inflammatory disorders. The finding that TLR4-deficient mice are protected against obesity-induced diabetes led me to hypothesise that TLR expression on adipocytes could play a role in obesity-induced adipose inflammation and metabolic dysfunction. The first chapter investigates the expression and function of TLRs in in vitro differentiated human subcutaneous adipocytes. I found that stimulation with ligands for TLR2, TLR3 and TLR4 but not the other TLRs, induces the expression of pro-inflammatory cytokines. I also explored the use of the TLR adapter molecules MyD88, Mal and TRIF by different TLRs. The second chapter examines whether TLR activation in adipocytes has an effect on glucose uptake. I established a 3H-2-deoxy-D-glucose (2DOG) uptake assay which led to an interesting yet unexpected observation: Stimulation with TLR3 and TLR4 ligands led to a decrease in insulin-stimulated glucose uptake but at the same time, insulin-independent glucose uptake was increased. I showed that these observations are at least partly due to altered expression of different glucose transporter (GLUT) isoforms. As the effects were seen only after prolonged TLR stimulation, I speculated that this was mediated via a secondary secreted factor. The third chapter is based on a cytokine and adipokine array, which I performed to identify cytokines that may be responsible for the effects described in Chapter 2. The secretion of several cytokines/chemokines with diverse pro-inflammatory functions was observed following stimulation with TLR3 and TLR4 ligands. The contribution of some of these factors to altered glucose handling was investigated. Whilst a contribution for ENA-78 was ruled out, I present evidence that IL-1 can contribute to this.
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Harper, Alice C. "Modified Electrodes for Amperometric Determination of Glucose and Glutamate Using Mediated Electron Transport". Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/28098.
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The main goal of this research was to develop an easy to prepare and sensitive biosensor that would be able to detect glutamate in solution using ionic self-assembly methods. This was accomplished by preparing an ionically-self-assembled monolayer that included an electron transport mediator and an enzyme that would generate a current proportional to the concentration of analytes in solution. Biosensors were produced for the detection of glucose and glutamate.
Ferrocene poly(allylamine) (FePAA) was assembled on negatively charged self-assembled monolayer and shown to be electrostatically bound by cyclic voltammetry. Model films were made of FePAA and poly(styrenesulfonate) to determine if multilayer films could be assembled using electrostatic assembly. These experiments demonstrated that 7 bilayers is the maximum number of bilayers oxidizable by the heterogeneous reaction at the electrode surface.
ISAMs were then assembled on a 2 mm gold electrode and on a gold fiber microelectrode using FePAA and glucose oxidase. Using cyclic voltammetry, these ISAMs were shown to be able to oxidize glucose in solution. The LOD was determined to be lower for the microelectrode than for the 2 mm gold electrode, which was expected, while both compared well to the literature. The Km? were found to be smaller than other glucose biosensors while the Icat increased with increasing number of bilayers. This demonstrated that the GluOx is making good electrical contact with the layer below. These glucose oxidase ISAMs, however, do not exhibit structural stability in flow-injection experiments.
As a solution to the ISAM modified electrodes degrading in the flowing system, a covalently modified surface was developed. Using cyclic voltammetry, these covalently modified surfaces were shown to be able to oxidize glucose in solution. The LOD of the covalently modified 2 mm gold electrode was calculated to be lower than the 2 mm ISAM modified gold electrode, due to the fast heterogeneous kinetics on the covalently modified electrode surface. The Km? and Icat for the covalently modified 2 mm gold electrode were found to be the similar to the 2 mm ISAM modified gold electrode indicating that the covalently modified electrodes will be a suitable replacement. The covalently modified surfaces exhibit excellent structural stability and detect much lower glucose amounts in flow-injection experiments.
ISAMs were subsequently assembled on gold fiber microelectrodes using FePAA and glutamate oxidase. Glutamate was able to be detected in solution at biologically significantly quantities using cyclic voltammetry. The Km? was shown to be comparable to literature values and Icat was shown to increase with increasing number of bilayers. These results demonstrate that an ISAM constructed using FePAA/GlutOx is a feasible way to detect glutamate in a system.Ph. D.
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Dwyer, Peter M. "Effects of daipose-specific glucose transporter type 4 expression on glucose homeostasis mediated through alterations in adipose tissue composition". Thesis, Boston University, 2012. https://hdl.handle.net/2144/12356.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Objective: Rates of obesity are rising in the U.S. and on a global scale. With this increasing incidence of obesity we are seeing an accompanying rise in the pathologies associated with type II diabetes mellitus (DMII) such as altered insulin sensitivity and glucose homeostasis. The notion of the adipocyte as a biologically dynamic cell is becoming more prevalent and recent evidence implicates the adipocyte as a key regulator in the onset of the aforementioned pathologies. The aim of this study is to further elucidate how changes in the expression of glucose transporter type 4 (GLUT4) in adipocytes may alter adipose tissue function and biology, specifically, if and how these alterations may affect downstream metabolic functions such as glucose uptake. Methods: Male and female adipose-specific GLUT4 overexpressor (AG40x) mice along with wild type (WT) littermates were monitored for changes in weight, body fat percentage, glucose tolerance and adipocyte metabolism over a period of 10-18 weeks. Additional cohorts of the transgenic and WT animals were also treated with a high energy diet to exacerbate any potential differences. Results: AG40x animals on a balanced diet showed high glucose clearance rates compared to WT animals; however, the high energy diet impaired glucose clearance for the AG40x animals. Overexpression of GLUT4 in adipose promotes increased weight gain and fat deposition but does not significantly alter adipose tissue composition compared to the WT balanced diet animals. Conclusion: Although overexpression of GLUT4 in adipose tissue appears to bring about undesired effects of weight gain, these animals were protected from adverse weight gain when challenged with a high energy diet. In both transgenic study groups, fat percentages are increased although adipose composition tissue was no significantly altered as seen in WT high-energy diet animals. This may contribute to the improved glucose clearance profiles seen in this particular model suggesting a potential therapeutic target for those who are high risk for DMII.
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Stone, Claire Gemma. "Antioxidants and trace elements : effect on mediated electron transfer in glucose biosensors". Thesis, University of Surrey, 2006. http://epubs.surrey.ac.uk/763/.
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Püschel, Franziska. "Cell death and cytokine-mediated inflammatory responses to glucose deprivation in cancer cells". Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667909.
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Metabolic alterations in cancer cells are primarily caused by oncogenic mutations and cancer cells are more dependent on glucose compared to non-transformed tissue. Targeting the cancer metabolism opens up a new strategy for anti-cancer therapy. In order to make drugs more efficient and applicable in the clinic, it is necessary to fully investigate the cancer cell metabolism, especially of how cancer cells die upon glucose deprivation and more importantly, the consequences on the surrounding tissue when modifying or interfering with the metabolism.
The unfolded protein response (UPR) is an intracellular stress response which is induced upon glucose deprivation. The activation of the three branches of the UPR facilitates pro-survival responses, however, chronic exposure to intra- or extracellular stress results in a switch towards a pro-death UPR response. The UPR is also described to be involved in pro-inflammatory responses due to the induction of cytokines and chemokines in several cell lines. Therefore, the release of cytokines upon glucose deprivation could facilitate the infiltration or exclusion of immune cells.
We hypothesized that cancer cells die in an UPR dependent manner and that cancer cells release inflammatory cytokines upon glucose deprivation, which promote the infiltration of immune cells.
We found that HeLa cells exposed to glucose deprivation, died in a TRAIL receptor 1 (DR4) and 2 (DR5) dependent manner, which was mediated by the activation transcription factor 4 (ATF4).
Furthermore, we found the release of pro-tumorigenic cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6) and the leukemia inhibitory factor (LIF) from glucose deprived cancer cells as well as upon treatment with anti-metabolic drugs. We found that IL 6 and IL-8 but not LIF were regulated by ATF4 and p65 upon glucose deprivation. Moreover, the conditioned media of glucose deprived A549 promoted the migration of macrophage-like THP-1 cells as well as primary B cells and neutrophils isolated from human blood.
These findings are important, since interfering with the cancer metabolism by using anti metabolic drugs could suppress the anti-tumorigenic effect of these drugs by promote pro-tumorigenic responses.
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GRIMOLIZZI, FRANCO. "Neutrophils alter placental glucose metabolism in gestational diabetes mellitus via neutrophil elastase mediated IRS1 degradation". Doctoral thesis, Università Politecnica delle Marche, 2017. http://hdl.handle.net/11566/245194.
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La gravidanza è da considerarsi una condizione pro-inflammatoria dove si osserva un’attivazione dei neutrofili circolanti. Con l'avanzare della gravidanza la concentrazione nel sangue di nucleosomi e mieloperossidasi aumenta e riflette la produzione delle trappole extracellulari dei neutrofili (NETs). Abbiamo dimostrato che in corso di diabete mellito gestazionale (GDM) tale produzione è aumentata in confronto ad una gravidanza fisiologica. Elevati livelli di glucosio e TNF-a, segni tipici presenti in corso di GDM, in vitro agiscono in modo sinergico e sono in grado di pre-attivare i neutrofili ed indurre il rilascio delle NETs. Abbiamo ipotizzato che, lo stato di iperattivazione osservato a livello sistemico possa essere associato ad una aumentata attività leucocitaria a livello placentare. A sostegno della nostra ipotesi, si osserva nei villi coriali isolati da placente GDM un’aumentata infiltrazione di PMNs pro-NETotici in associazione ad un accumulo della neutrofili elastasi (NE). Per valutare un possibile effetto pro-infiammatorio del glucosio a livello placentare, abbiamo incubato cellule di trofoblasto (BeWo) in presenza di un’elevata concentrazione di glucosio e successivamente valutato la produzione di TNF-a. È stato interessante rilevare un aumento nel rilascio di TNF- a tale da indurre un effetto pro-NETotico sui PMN con consequente rilascio della NE. Da recenti ricerche è emerso come in corso di diabete e tumore la NE possa essere internalizzata dalle cellule ed alterare la trasduzione del segnale insulinico attraverso la degradazione del substrato 1 del recettore insulinico (IRS1). Esperimenti in vitro hanno dimostrato che in presenza della NE si osserva una riduzione di IRS1 nelle cellule BeWo ed una diminuzione dell’internalizzazione del glucosio. Poichè l’espressione di IRS1 risulta ridotta nelle placente GDM é verosimile ipotizzare che la massiva presenza di NE ne può essere la causa. In conclusione, i nostri dati suggeriscono che in corso di GDM si verifica un’elevata produzione di NETs ed una massiva infiltrazione di pro-NETotici PMN nella placenta. Queste scoperte dimostrano come la NETosi abbia una significativa utilità diagnostica in corso di GDM e la NE un nuovo potenziale bersaglio terapeutico.Human pregnancy is associated with a mild pro-inflammatory state characterized by activation of circulatory neutrophils (PMNs). Skewing of PMNs responses toward to neutrophil extracellular traps generation (NETs) is reflected in an increased of circulating nucleosomes and myeloperoxidase with advancing gestational age. Our data indicated that this pro-NETotic profile is enhanced in women with gestational diabetes mellitus (GDM). Maternal hyperglycemia and increased levels of TNF-a are a hallmark of GDM and we show a synergistic effect of both factors on the priming and release of NETs. Moreover, we hypothesized that systemic activation was associated with activated PMN in placenta. Indeed, we observed a massive infiltration of pro-NETotic PMNs and neutrophil elastase (NE) accumulation along chorionic villi of GDM placentas. To further explore whether hyperglycemia predisposes to exaggerated inflammatory response in placenta we incubated trophoblast BeWo cells in high glucose conditions and we next tested the TNF-a production capacity. Interestingly, TNF-a level was incresed and exert a pro-NETotic effect on PMN with consequent NE release. Recent studies in cancer tissues and diabetes models have described that released NE induce profound changes in the surrounding cells, altering the signal transducing cascade and promoting insulin resistance via degradation of insulin receptor substrate 1 (IRS1). Our in-vitro data indicate that addition of NE to trophoblast cell line BeWo causes degradation of IRS1 with consequent glucose uptake impairment. IRS1 is reduced in GDM placentas when compared to control placentas, suggesting that the presence of NE might be the causal factor. Taken together, our data showed that GDM is characterized by excessive NET formation and by a massive influx of pro-NETotic PMN into placentas. These findings underline the competence of NETs as a highly relevant diagnostic biomarker for GDM and NE as a new potential therapeutic target.
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Bahari, Meisam. "Use of Viologens in Mediated Glucose Fuel Cells and in Aqueous Redox Flow Batteries to Improve Performance". BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8681.
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This dissertation presents my efforts to use viologens to improve the performance of glucose fuel cells and aqueous redox flow batteries. These two electrochemical systems have the potential to efficiently exploit renewable sources of energy. The contributions and significance of this work are briefly described below. Glucose Fuel cells. For glucose fuel cells, viologens were adopted as an electron mediator to facilitate the transfer of electrons from glucose to electrodes for power generation. Use of a mediator circumvents the need for precious metal electrodes to catalyze glucose oxidation. Both the oxidation efficiency and rate of glucose oxidation are important to the viability of glucose fuel cells. Oxidation efficiency is defined as the extent to which the carbons of a carbohydrate (glucose for instance) are oxidized relative to full oxidation to carbon dioxide. The efficiency measured in this study depended on the initial molar ratio of viologen to glucose and also on the rate of the regeneration of the mediator. The maximum conversion efficiency observed was ~22%, which is about three times larger than the values observed for precious-metal-based fuel cells. Rate performance is another important aspect of a glucose fuel cell. Detailed simulations demonstrated that rate performance of viologen-mediated cells was limited principally by mass transfer. The maximum obtainable current density was ~200 mA/cm2, which is significantly higher than the rates available from biological fuel cells and comparable to the values observed for precious-metal-based fuel cells. Viologen-mediated fuel cells offer the potential for higher oxidation efficiency and high current densities at a significantly lower cost. This makes viologen-mediated cells an appealing option for future development of glucose fuel cells. Redox Flow Battery. An asymmetric viologen called MMV was assessed for potential use in aqueous flow batteries to improve performance. With an asymmetric structure, MMV demonstrated one of the most negative redox potentials reported to date for organic electroactive compounds. MMV also showed a relatively high solubility in neutral electrolytes. The electrochemical reaction of MMV involved a reversible single electron transfer with fast kinetics. These characteristics support MMV as a promising anolyte for flow battery applications to improve capacity, energy density, and cell potential. MMV, however, exhibited poor cycling performance at elevated concentrations since it underwent irreversible or partially reversible side reactions. Signs of dimerization and precipitation were observed during cycling. These undesired reactions can be potentially mitigated by synthesizing asymmetric MMV derivatives that possess a higher charge than that possessed by MMV (+1). This modification can reduce the extent of dimerization by increasing repulsive forces between the monomers, and it also has the potential to reduce precipitation by increasing the solubility limit of the compounds.
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Iwata, Masahiro, 全広 岩田, Kimihide Hayakawa, Taro Murakami, Keiji Naruse, Keisuke Kawakami, Masumi Inoue-Miyazu, Louis Yuge i Shigeyuki Suzuki. "Uniaxial Cyclic Stretch-Stimulated Glucose Transport Is Mediated by a Ca2+-Dependent Mechanism in Cultured Skeletal Muscle Cells". Thesis, Karger, 2007. http://hdl.handle.net/2237/11109.
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"Uniaxial Cyclic Stretch-Stimulated Glucose Transport Is Mediated by a Ca2+-Dependent Mechanism in Cultured Skeletal Muscle Cells" Pathobiology, v.74, n.3, pp.159-168を、博士論文として提出したもの。名古屋大学博士学位論文 学位の種類:博士（リハビリテーション療法学）（課程）学位授与年月日:平成19年3月23日
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Maamoun, Hatem. "Heme oxygenase (HO)-1 induction prevents endoplasmic reticulum stress-mediated endothelial cell death and impaired angiogenic capacity induced by high glucose". Thesis, University of Surrey, 2017. http://epubs.surrey.ac.uk/842136/.
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Most diabetic cardiovascular complications are mediated by endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum [ER] and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes. The cytoprotective effects of Hemeoxygenase-1 [HO-1] were extensively studied; however, its role in alleviating ER stress-induced endothelial dysfunction remains elusive. We aim here to test the role of HO-1 against high glucose-mediated ER stress response and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Primary Human Umbilical Vein Endothelial cells [HUVECs] were harbored in culture medium containing high glucose (33 mM) for 5 days with 8 hrs intermittent recovery periods to mimic the diabetic milieu. Using a wide array of molecular biology techniques, we were able to show that this chronic and intermittent exposure of HUVECs to high glucose significantly increased mRNA and protein expression of key ER stress markers namely, binding immunoglobulin protein [BiP], activation transcription factor-4 [ATF-4], CCAAT-enhancer-binding protein homologous protein [CHOP], and phosphorylated eukaryotic initiation factor2α [p-eIF-2α]. In addition, there was a significant elevation in ROS associated with significant increased phosphorylation of p47phox regulatory subunit of NADPH oxidase [NOX]. Moreover, inflammatory and apoptotic responses were also elicited, featured mainly by significant increase in phosphorylation/activation of IκB kinase [IKK] and c-Jun, and upregulation of IL-6, whereas apoptosis was featured by showing significantly increased caspase3/7 activity and cell death. Vascular endothelial growth factor-A [VEGF-A] expression, Nitric Oxide [NO] production, and tube formation capacity were also significantly inhibited by high glucose. Pre-treatment by HO-1 inducer Cobalt protoporphyrin IX [CoPP] significantly abolished all the observed effects with high glucose. Altogether, to the best of our knowledge, we present for the first time the role of HO-1 induction as a potential antagonist to ER stress response against high glucose mediated endothelial dysfunction and impaired angiogenesis.
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Hagan, G. Nana. "Adipocyte Insulin-Mediated Glucose Transport: The Role of Myosin 1c, and a Method for in vivo Investigation: A Dissertation". eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/403.
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The importance of insulin delivery and action is best characterized in Type 2 Diabetes, a disease that is becoming a pandemic both nationally and globally. Obesity is a principal risk factor for Type 2 Diabetes, and adipocyte function abnormalities due to adipose hypertrophy and hyperplasia, have been linked to obesity. Numerous reports suggest that the intracellular and systemic consequences of adipocyte function abnormalities include adipocyte insulin resistance, enhanced production of free fatty acids, and production of inflammatory mediators. A hallmark of adipocyte insulin sensitivity is the stimulation of glucose transporter isoform 4 (GLUT4) trafficking events to promote glucose uptake. In the Type 2 diabetic and insulin resistant states the mechanism behind insulin-stimulated GLUT4 trafficking is compromised. Therefore, understanding the role of factors involved in glucose-uptake in adipose tissue is of great importance.
Studies from our laboratory suggest an important role for the unconventional myosin, Myo1c, in promoting insulin-mediated glucose uptake in cultured adipocytes. Our observations suggest that depletion of Myo1c in cultured adipocytes results in a significant reduction in the ability of adipocytes to take up glucose following insulin treatment, suggesting Myo1c is required for insulin-mediated glucose uptake. A plausible mechanism by which Myo1c promotes glucose uptake in adipocytes has been suggested by further work from our laboratory in which expression of fluorescently-tagged Myo1c in cultured adipocytes induces significant membrane ruffling at the cell periphery, insulin-independent GLUT4 translocation to the cell periphery, and accumulation of GLUT4 in membrane ruffling regions. Taken together Myo1c seems to facilitate glucose uptake through remodeling of cortical actin.
In the first part of this thesis I, in collaboration with others, uncovered a possible mechanism through which Myo1c regulates adipocyte membrane ruffling. Here we identified a novel protein complex in cultured adipocytes, comprising Myo1c and the mTOR binding partner, Rictor. Interestingly our studies in cultured adipocytes suggest that the Rictor-Myo1c complex is biochemically distinct from the Rictor-mTOR complex of mTORC2. Functionally, only depletion of Rictor but not Myo1c results in decreased Akt phosphorylation at serine 473, but depletion of either Rictor or Myo1c results in compromised cortical actin dynamic events. Furthermore we observed that whereas the overexpression of Myo1c in cultured adipocytes causes remarkable membrane ruffling, Rictor depletion in cells overexpressing Myo1c significantly reduces these ruffling events. Taken together our findings suggest that Myo1c, in conjunction with Rictor, modulates cortical actin remodeling events in cultured adipocytes. These findings have implications for GLUT4 trafficking as GLUT4 has been previously observed to accumulate in Myo1c-induced membrane ruffles prior to fusion with the plasma membrane.
During our studies of adipocyte function we noticed that current siRNA electroporation methods present numerous limitations. To silence genes more effectively we employed a lentivirus-mediated shRNA delivery system, and to standardize this technology in cultured adipocytes we targeted Myo1c and MAP4K4. Using this technology we were able to achieve clear advantages over siRNA oligonucleotide electroporation techniques in stability and permanence of gene silencing. Furthermore we showed that the use of lentiviral vectors in cultured adipocytes did not affect insulin signaling or insulin-mediated glucose uptake events. Despite our inability to use lentiviral vectors to achieve gene silencing in mice we were able to achieve adipose tissue-specific gene silencing effects in mice following manipulation of the lentiviral conditional silencing vector, and then crossing resulting founders with aP2-Cre mice. Interestingly however, only founders from the MAP4K4 conditional shRNA vector, but not founders from the Myo1c conditional shRNA vector, showed gene knockdown, possibly due to position-effect variegation. Taken together, findings from these studies are important because they present an alternative means of achieving gene silencing in cultured adipocytes, with numerous advantages not offered by siRNA oligonucleotide electroporation methods. Furthermore, the in vivo, adipose tissue-specific RNAi studies offer a quick, inexpensive, and less technically challenging means of achieving adipose tissue-specific gene ablations relative to traditional gene knockout approaches.
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Muschol, Waldemar, Gerhard Püschel, Martina Hülsmann i Kurt Jungermann. "Eicosanoid-mediated increase in glucose and lactate output as well as decrease and redistribution of flow by complement-activated rat serum in perfused rat liver". Universität Potsdam, 1991. http://opus.kobv.de/ubp/volltexte/2010/4589/.
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Rat serum, in which the complement sytem had been activated by incubation with zymosan, increased the glucose and lactate output, and reduced and redistributed the flow in isolated perfused rat liver clearly more than the control serum. Heat inactivation of the rat serum prior to zymosan incubation abolished this difference. Metabolic and hemodynamic alterations caused by the activated serum were dose dependent. They were almost completely inhibited by the cyclooxygenase inhibitor indomethacin and by the thromboxane antagonist 4-[2-(4-chlorobenzenesulfonamide)-ethyl]-benzene-acetica cid (BM 13505), but clearly less efficiently by the 5’-lipoxygenase inhibitor nordihydroguaiaretic acid and the leukotriene antagonist N-{3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-propoxy]-4-chlorine-6-methyl-phenyl}-1H-tetrazole-5-carboxamide sodium salt (CGP 35949 B). Control serum and to a much larger extent complement-activated serum, caused an overflow of thromboxane B₂ and prostaglandin F₂α into the hepatic vein. It is concluded that the activated complement system of rat serum can influence liver metabolism and hemodynamics via release from nonparenchymal liver cells of thromboxane and prostaglandins, the latter of which can in turn act on the parenchymal cells.
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SPINELLI, SONIA. "Role of the ABA/LANCL system in the insulin-independent stimulation of cell glucose uptake and energy metabolism in myoblasts and adipocytes through an AMPK-mediated mechanism". Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1081138.
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Abscisic acid (ABA) is a hormone with a very long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely the descendants, well before separation of the plant and animal kingdoms, with a conserved role as a signal regulating cell responses to environmental challenge. Nanomolar ABA is also present and active in mammals where it controls the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue with an insulin-independent mechanism and increasing brown adipose tissue activity and browning through its receptor LANCL2. Previous data showed that, in LANCL2-/- mice, the genetic ablation of the receptor doesn’t modify fasting glycemia values but results in the reduction of glucose tolerance compared with wild-type siblings. Animals are still responsive to exogenous ABA. The result that the effect of ABA was not completely abrogated by LANCL2 silencing, despite the very high percentage of reduction of protein and mRNA expression, suggests that other ABA receptors might be partly involved in the effect of ABA on muscle. LANCL1, a LANCL2 homolog, is indeed expressed in murine skeletal muscle at levels like those of LANCL2. Thus, I focused my attention on the metabolic function of the ABA/LANCL1 system. Recombinant human LANCL1 protein binds ABA with a Kd in a concentration range that lies between the low and high-affinity ABA binding sites of LANCL2. In rat L6 myoblasts, LANCL receptors similarly stimulate both basal and ABA-triggered fluorescently labeled deoxyglucose analog 2-NBDG uptake, activate mRNA levels and protein expression of the glucose transporters GLUT1 and GLUT4 and the signaling proteins AMPK/PGC-1α/Sirt1, stimulate mitochondrial respiration and the expression of the skeletal muscle (SM) uncoupling proteins sarcolipin and UCP3. Moreover, LANCL2-/- mice overexpress LANCL1 in the SM and respond to chronic ABA treatment (1 µg/kg body weight/day) with an improved glycemia response to glucose load and increased SM transcription of GLUTs, of the AMPK/PGC-1α/Sirt1 pathway and of sarcolipin, UCP3 and NAMPT. LANCL1 behaves as an ABA receptor with a somewhat lower affinity for ABA than LANCL2 but with overlapping effector functions: stimulating glucose uptake and the expression of muscle glucose transporters and mitochondrial uncoupling and respiration via the AMPK/PGC-1α/Sirt1 pathway. Furthermore, since adipose tissue seems to be a direct target of ABA, along with skeletal muscle, I investigated the browning effects of ABA in brown and white human adipocytes. ABA increases AMPK phosphorylation and AMPK and PGC-1α protein levels in pre-adipocytes overexpressing LANCL1 and LANCL2. The expression of genes related to browning, oxidative consumption, glucose transport, mitochondrial biogenesis, respiratory uncoupling and AMPK/PGC-1α/Sirt1 pathway is increased after adipocyte differentiation and further increases upon ABA treatment. Chronic ABA treatment stimulates mitochondrial DNA content in the brown adipose tissue of mice. These results suggest that ABA may be used as an anti-obesity molecule. Concluding, receptor redundancy may have been advantageous in animal evolution, given the role of the ABA/LANCL1-2 system in the insulin-independent stimulation of cell glucose uptake and energy metabolism.
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Zhang, Shiqing. "Novel mechanism of 2DG mediated cancer treatment /Zhang Shiqing". HKBU Institutional Repository, 2016. https://repository.hkbu.edu.hk/etd_oa/353.
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2-deoxy-D-glucose (2DG), a non-metabolizable glucose analog, is currently being used in clinical trials to determine its efficacy in augmenting radiotherapy and chemotherapy of various cancers. It is thought to kill cancer cells by inducing glucose deprivation state. However, 2DG only inhibits glycolysis by 15-40%, not sufficient to simulate glucose deprivation. Further, 2-flour-deoxy-D-glucose (2FDG), which is a more potent inhibitor of glycolysis than 2DG, is less effective than 2DG in killing cancer cells. These observations suggest that glucose deprivation is not the mechanism by which 2DG kills cancer cells. On the other hand, it has been shown that treatment of cancer cells with 2DG leads to increased reactive oxygen species (ROS) production, indicating that cytotoxic effect of 2DG is due to increase ROS. Our lab previously found that inhibition of aldose reductase (AR) activity attenuated 2DG-induced ROS in cardiomyocytes (Tang, et al., 2010). We therefore propose that 2DG-induced ROS increase in cancer cells is a consequence of the depletion of GSH in the process of reduction of 2DG by AR and/or by a related aldose reductase-like enzyme (ARL). These two enzymes are often overexpressed in cancer cells. This proposed project is to test our hypothesis that the cytotoxicity of 2DG is due to the depletion of GSH as a consequence of the reduction of 2DG by AR or ARL. We found that HepG2, SKOV3, HCT116 and CaCo2 cells were sensitive to 2DG, and these cells over-express AR and/or ARL proteins. However, HT29 cells and SW480 cells, which were not sensitive to 2DG, had low level of AR and ARL proteins, indicating that there is a close relationship between sensitivity to 2DG toxicity and the level of AR/ARL in these cells. Further, when AR/ARL activity were inhibited in HepG2, SKOV3, HCT116 and CaCo2 cells by AR/ARL inhibitors fidarestat or tolrestat, the cells were protected against 2DG cytotoxicity. Tolrestat or fidarestat significantly restored the drop of GSH levels in 2DG sensitive cancer cells induced by 2DG. On the other hand, MG-132 and bortezomib, which increased the expression of AR/ARL in HT29 and SW480 cells, made HT29 and SW480 cells more sensitive to 2DG. These experiments confirmed our hypothesis that 2DG toxicity in cancer cells was due to oxidative stress induced by AR/ARL. 2DG is not an efficient substrate for AR/ARL enzymes and it is not very efficient in killing cancer cells. Based on our hypothesis, better AR/ARL substrates should be more toxic to cancer cells that overexpress AR/ARL than 2DG. The cytotoxic effects of glyceraldehyde and diacetyl, which were better substrates for AR/ARL than 2DG, were tested. Both glyceraldehyde and diacetyl were more efficient in killing cancer cells that over-express AR and/or ARL (HepG2, SKOV3, HCT116 and CaCo2) than cancer cells with low levels of AR and ARL proteins (HT29 and SW480). Glyceraldehyde and diacetyl were more efficient in lowering the GSH level in cancer cells that over-express AR and/or ARL. In order to further develop glyceraldehyde and diacetyl as anti-cancer drugs, animal studies were carried out to determine their anti-cancer effects. Both glyceraldehyde and diacetyl significantly inhibited the tumor growth in nude mice tumor xenograft model. In conclusion, this thesis proposed and proved that 2DG kills cancer cells by lowering intracellular GSH levels as a consequence of its reduction by AR/ARL activities, rather than by inhibition of glycolysis. This novel mechanism predicts that better substrates for AR/ARL than 2DG would be more effective in killing cancer cells than 2DG. This was confirmed by using glyceraldehyde and diacetyl. We believe that this would lead to the development of more efficient anti-cancer drugs.
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Moreira, Guillaume. "Synthèse de copolymères greffés d'acétate de cellulose-g-PS par polymérisation radicalaire contrôlée par les nitroxydes". Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM4719.
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Face à la diminution croissante des ressources d'origine fossile, une attention particulière est portée depuis plusieurs années envers l'utilisation de ressources renouvelables. Dans ce contexte, beaucoup de recherches sont orientées vers l'utilisation de polysaccharides tels que la cellulose. L'intérêt de ces composés est qu'ils sont abondants, peu chers et biodégradables. A l'inverse, ces polymères possèdent une faible résistance mécanique limitant ainsi leurs applications. De manière à moduler les propriétés de ces polymères, une alternative consiste à les modifier chimiquement par greffage de chaînes de polymères synthétiques. Néanmoins, les stratégies de greffage décrites dans la littérature présentent certaines limitations notamment sur la facilité de mise en oeuvre, la toxicité des méthodes employées, le nombre d'étapes de synthèses ou encore le contrôle des masses molaires. Par ailleurs, la caractérisation de ces architectures complexes reste délicate notamment pour prouver le greffage covalent des chaînes de polymère sur le polysaccharide. C'est précisément dans cet axe de recherche que s'insère ce sujet de thèse. Plus particulièrement, l'objectif principal consiste à mettre au point une méthode de greffage de l'acétate de cellulose robuste et facile à mettre en oeuvre, en vue d'une utilisation potentielle en tant que compatibilisant de mélange de polystyrène et d'acétate de cellulose. Afin d'atteindre cet objectif, notre stratégie a consisté à utiliser la polymérisation radicalaire contrôlée par les nitroxydes (NMP) où une attention particulière a été portée sur la caractérisation structurale des matériaux synthétisés (RMN du solide et DOSY, RPE, CES, DLS et DSC)In order to respond to the fossil resources depletion, a particular attention was paid to the use of renewable resources since several years. In this context, many researches focus on the use of polysaccharides such as cellulose. These compounds are attractive because of their abundance, low cost and biodegradability. On the other hand, these polymers suffer from weak mechanical resistance limiting their practical applications. Grafting synthetic polymers chains on these natural polymers is an alternative to this problem. Nevertheless, grafting strategies described in the literature involve certain limitations such as the difficulty of implementation, the toxicity of the used methods, the great number of synthesis steps or the control of molar mass. Moreover, the characterization of these complex architectures remains delicate in order to prove the covalent grafting of chains on the polysaccharide. In line with this research context, the topic of this thesis concerns the development of a robust method for cellulose acetate polymer grafting. Moreover, the selected method has to be easy to implement, with a possible application as a compatibilizer for blending of polystyrene and cellulose acetate. In order to achieve this purpose, our strategy is based on the use of Nitroxide-Mediated Polymerization (NMP) where particular attention was paid to the structural characterization of synthesized materials (solid state NMR, DOSY NMR, ESR, SEC of grafts, DLS and DSC)
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Izumi, Ryouta. "CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats". Kyoto University, 2019. http://hdl.handle.net/2433/242910.
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Joseph, Danzil Eugene. "Hyperglycemia-mediated onset of myocardial insulin resistance – unraveling molecular mechanisms and identifying therapeutic targets". Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86341.
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Thesis (PhD)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Background - Although acute hyperglycemic episodes are linked to lower glucose uptake, underlying mechanisms driving this process remain unclear. We hypothesized that acute hyperglycemia triggers reactive oxygen species (ROS) production and increases non-oxidative glucose pathway (NOGP) activation, i.e. stimulation of advanced glycation end products (AGE), polyol pathway (PP), hexosamine biosynthetic pathway (HBP) and protein kinase C (PKC) activation. These mechanisms attenuate cellular function, and may indeed decrease insulin-mediated cardiac glucose uptake. The role of the pentose phosphate pathway (PPP) under high glucose/diabetic conditions is a subject of contention. Activation of the PPP enzyme transketolase (TK) (by benfotiamine/BFT or thiamine) reduces flux via the other four NOGPs, and is associated with beneficial outcomes. Our aim was therefore to evaluate the effects of acute hyperglycemia on insulin-mediated glucose uptake in a cardiac-derived cell line. Specifically, we aimed to elucidate the role of ROS and NOGP induction under these conditions. Methodology - H9c2 cardiomyoblasts were exposed to 25 mM glucose for 24 hr vs. 5.5 mM glucose controls ± modulating agents during last hour of glucose exposure: a) antioxidant #1 for mitochondrial ROS (250 μM 4-OHCA), b) antioxidant #2 for NADPH oxidase-generated ROS (100 μM DPI), c) NOGP inhibitors – 100 μM aminoguanidine (AGE), 5 μM chelerythrine (PKC); 40 μM DON (HBP); and 10 μM zopolrestat (PP). We also employed BFT (50 and 100 μM) in vitro, while the effects of in vivo thiamine administration were assessed in hearts of an obese/diabetic rat model of pre-diabetes and diabetes, the OLETF strain. We evaluated insulin sensitivity by glucose uptake assay (flow cytometry), GLUT4 translocation (transfection of HA-GLUT4-GFP construct) and protein kinase B (Akt) activity assay. ROS levels (mitochondrial, intracellular) were measured by flow cytometry analysis of specific fluorescent probes. Markers of each NOGP were also assessed. Results - Acute hyperglycemia elevated ROS, activated NOGPs and blunted glucose uptake. However, TK activity (marker of PPP) did not change. Respective 4-OHCA and DPI treatment blunted ROS production, diminished NOGP activation and normalized glucose uptake. NOGP inhibitory studies identified PKCβII as a key downstream player in lowering insulin-mediated glucose uptake. When we employed BFT (known to shunt flux away from NOGPs and into the PPP), it decreased ROS generation and NOGP activation, and restored glucose uptake under acute hyperglycemic conditions. In vivo thiamine administration reduced markers of the other NOGP, while it attenuated (mainly in the pre-diabetic phase) the metabolic dysfunction observed in the OLETF rats. Conclusions - This study demonstrates that acute hyperglycemia elicits a series of maladaptive events that function in tandem to reduce glucose uptake, and that antioxidant treatment and/or attenuation of NOGP activation (PKC, polyol pathway) may limit the onset of insulin resistance.
AFRIKAANSE OPSOMMING: Agtergrond – Alhoewel akute hiperglisemie voorvalle gekoppel is aan verlaagde glukose opname, is die onderliggende meganismes wat die proses dryf steeds onduidelik. Ons hipotetiseer dat akute hiperglisemie aanleiding gee tot die produksie van reaktiewe suurstofspesies (RSS) en toename in nie-oksidatiewe glukose weg (NOGW) aktivering, i.e. stimulering van gevorderde glukasie eindprodukte (GGE), poliolweg (PW), heksosamien biosintetiese weg (HBW) en proteïenkinase C (PKC) aktivering. Hierdie meganismes verminder sellulêre funksie, en mag inderdaad insulien-bemiddelde kardiêre glukose opname verlaag. Die rol van die pentosefosfaatweg (PFW) onder hoë glukose/diabetiese kondisies is ‘n onderwerp van stryd. Aktivering van die PFW ensiem transketolase (TK) (deur benfotiamien/BFT of tiamien) verminder fluks deur die ander vier NOGWë, en is geassosieer met voordelige uitkomste. Ons doel was dus om die effekte van akute hiperglisemie op insulien-bemiddelde glukose opname te evalueer in ‘n kardiaal-afkomstige sellyn. Meer bepaald het ons gepoog om die rol van RSS en NOGW induksie onder hierdie kondisies te verstaan. Metode – H9c2 kardiomioblaste is aan 25 mM glukose vir 24 h blootgestel vs. 5.5 mM glukose kontroles ± moduleeragente tydens die laaste uur van glukose blootstelling: a) anti-oksidant #1 vir mitochondriese RSS (250 μM 4-OHCA), b) anti-oksidant #2 vir NADPH oksidase-gegenereerde RSS (100 μM DPI), c) NOGW inhibeerders – 100 μM aminoguanidien (GGE), 5 μM cheleritrien (PKC); 40 μM DON (HBW); en 10 μM zopolrestaat (PW). Ons het ook BFT (50 en 100 μM) in vitro aangewend, terwyl die effek van in vivo tiamien aanwending geassesseer is in die harte van ‘n vetsugtige/diabetiese rotmodel van pre-diabetes en diabetes, die OLETF lyn. Ons het insuliensensitiwiteit deur ‘n glukose opname toets (vloeisitometrie), GLUT4 translokasie (transfeksie van HA-GLUT4-GFP konstruk) en proteïenkinase B (Akt) aktiwiteitstoets, geëvalueer. RSS vlakke (mitochondries, intrasellulêr) is gemeet deur vloeisitometriese analise van spesifieke fluoresserende peilers. Merkers van elke NOGW is ook geassesseer. Resultate - Akute hiperglisemie het RSS verhoog, NOGWë geaktiveer en glukose opname versag. TK aktiwiteit (merker van PFW) het egter nie verander nie. Onderskeidelike 4-OHCA en DPI behandeling het RSS produksie versag, NOGW aktivering verminder en glukose opname genormaliseer. NOGW onderdrukking studies het PKCβII geïdentifiseer as ‘n sleutel deelnemer in verlaging van insulien-bemiddelde glukose opname. Die aanwending van BFT (bekend vir die wegvoer van fluks vanaf NOGWë na die PFW), het RSS skepping en NOGW aktivering verlaag, en glukose opname herwin onder akute hiperglisemiese kondisies. In vivo tiamien toediening het merkers van die ander NOGW verlaag, terwyl dit die metaboliese disfunksie waargeneem in die OLETF rotte (hoofsaaklik in die pre-diabetiese fase) verminder het. Gevolgtrekking – Hierdie studie demonstreer dat akute hiperglisemie ‘n reeks van wanaangepaste voorvalle ontlok wat gesamentlik funksioneer om glukose opname te verlaag, en dat anti-oksidant behandeling en/of vermindering van NOGW aktivering (PKC, poliolweg), die aanvang van insulien weerstand mag beperk.
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Chavez, Talavera Oscar Manuel. "Rôle des acides biliaires dans la physiopathologie de l'obésité, la résistance à l'insuline, le diabète de type 2, la stéatose hépatique non alcoolique et dans le contexte de la chirurgie bariatrique Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease Bile Acid Alterations in Nonalcoholic Fatty Liver Disease, Obesity, Insulin Resistance and Type 2 Diabetes: What Do the Human Studies Tell?” Bile acids associate with glucose metabolism, but do not predict conversion to diabetes Bile acid alterations are associated with insulin resistance, but not with NASH in obese subjects Roux-en-Y gastric bypass increases systemic but not portal bile acid concentrations by decreasing hepatic bile acid uptake in minipigs The functional relevance of bile acids in the improvement of HDL-mediated endothelial protection after bariatric surgery Metabolic effects of bile acid sequestration: impact on cardiovascular risk factors". Thesis, Lille, 2019. http://www.theses.fr/2019LILUS057.
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En plus de leur rôle dans la solubilisation des lipides alimentaires, les acides biliaires sont des molécules de signalisation régulant leur propre métabolisme, l'homéostasie du glucose et des lipides, la dépense énergétique, la fonction cardiovasculaire et l’inflammation, en modulant le Farnesoid X Receptor (FXR) et le Takeda G protein coupled Receptor 5 (TGR5). En effet, des modifications dans les concentrations des acides biliaires sont associées aux maladies métaboliques et ce sont des candidats pour participer à la pathophysiologie de ces maladies ou prédire leur progression.Dans la première partie de cette thèse nous avons étudié les modifications des acides biliaires dans le contexte de l'obésité, l'insulinorésistance, le diabète de type 2 et la stéatohépatite non alcoolique. Nous avons montré que les acides biliaires sont corrélés avec l’homéostasie du glucose chez l’Homme, mais qu’ils ne sont pas des prédicteurs de la bascule du prédiabète en diabète de type 2 dans un étude de cohorte.La deuxième partie de cette thèse est dédiée à l’étude des acides biliaires dans la chirurgie bariatrique. Nos résultats ont montré que la chirurgie bariatrique réduit la recapture hépatique des acides biliaires, provoquant leur augmentation dans la circulation systémique, et que ce n’est pas l’anse biliaire mais l’anse commune qui est responsable des modifications métaboliques après la chirurgie bariatrique chez le minipig. Ensuite, nous avons montré chez l’Homme que les acides biliaires liés aux lipoprotéines de haute densité (HDL) augmentent après la chirurgie bariatrique, et que cette augmentation est corrélée avec la restauration de leurs fonctions vaso-protectricesIn addition to their role in the solubilization of dietary lipids, bile acids are signaling molecules regulating their own metabolism, glucose and lipid homeostasis, energy expenditure, cardiovascular function and inflammation via the activation of the Farnesoid X Receptor (FXR) and the Takeda G protein coupled Receptor 5 (TGR5). Indeed, changes in bile acid concentrations are associated with metabolic diseases and therefore they are candidates to participate in the pathophysiology of these diseases or predict their progression.In the first part of this thesis, we studied bile acid changes in the context of obesity, insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis. We demonstrated that bile acids are correlated with glucose homeostasis in humans, but that they are not predictors for the progression from prediabetes to type 2 diabetes in a longitudinal cohort study.In the second part of this thesis, we studied the bile acids in the context of bariatric surgery. Our results showed that bariatric surgery reduces the hepatic recapture of certain bile acids, causing them to increase in the systemic circulation. Additionally, we showed that it is not the bile limb but the common limb the one responsible for metabolic changes after bariatric surgery in the minipig. Finally, we showed in humans that bile acids linked to high-density lipoproteins (HDL) increase after bariatric surgery, and that this increase is correlated with the restoration of their vasoprotective functions
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Fernandez, Arthur. "Mediated and direct electrochemical studies on glucose oxidase". Thesis, 1994. http://spectrum.library.concordia.ca/3662/1/MM97617.pdf.
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Chien, Chun-Tzu, i 簡君慈. "Investigation of glucose-6-phosphate dehydrogenase inhibitor mediated anti-cancer effects". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/3b3cf5.
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Tsai, Shu-Huai, i 蔡書槐. "High Glucose Impairs Endothelium-Derived Hyperpolarizing Factor-Mediated Dilation Of Coronary Arterioles". Thesis, 2011. http://ndltd.ncl.edu.tw/handle/55137644748924724626.
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博士東海大學
生命科學系
100
In diabetic population, more than 65% of death is related to cardiovascular diseases. Reduced myocardial blood flow is commonly observed in diabetic patients without obstructive atherosclerosis. This indicates that microvascular complications, especially the impairment of arteriolar dilation in resistant vessels, are involved in the diabetic vascular dysfunction. Endothelium-derived hyperpolarizing factor (EDHF) is an important substance released from the endothelium that regulates vasomotor function, but its role in diabetes/hyperglycemia-induced vascular impairment remains unclear. In the coronary circulation, the EDHF pathway is mediated by the cytochrome P450 epoxygenase (CYP) and its derivative epoxyeicosatrienoic acids (EETs). The present study aimed at determining the mechanistic effect of high glucose (HG) on EDHF/EET-mediated arteriolar dilation. Porcine coronary arterioles were isolated and pressurized for vasomotor study. Cultured porcine coronary artery endothelial cells (ECs) were used for molecular and biochemical analysis. Bradykinin (BK), a potent vasodilator, was used to generate endothelium-dependent vasodilation before and after high glucose (HG, 25 mM vs. 5 mM in control) treatment. We found that incubation of coronary arterioles with HG impaired vasodilation to BK but not to sodium nitroprusside (endothelium-independent vasodilator). In the presence of potassium channel inhibitor targeting EDHF-mediated vasodilation, the NO component of arteriolar dilation in response to BK was reduced by HG incubation. In the presence of inhibitors of NO synthase and cyclooxygenase, the EDHF-mediated arteriolar dilation was reduced by HG incubation. The inhibitory effect of HG was prevented by treating the vessels with superoxide scavenger Tempol. In cultured coronary artery endothelial cells (ECs), the NO production in response to BK stimulation was reduced by HG. HG also reduced endothelial EET production as well as CYP activity. The superoxide production was elevated in ECs after HG incubation. Pretreatment with superoxide scavenger Tempol before HG incubation abolished the increase of cellular superoxide and prevented the decrease of CYP activity. Collectively, our results suggest that, in addition to the NO-mediated pathway, HG impairs the EET/EDHF-mediated vasodilation in coronary arterioles by inhibiting CYP activity in coronary ECs via elevated level of superoxide. The present study provides further information on the mechanisms of hyperglycemia-induced vascular dysfunction.
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Lee, Ken Wing Kin. "High Glucose-induced ROS Production is Mediated by c-Src in Mesangial Cells". Thesis, 2012. http://hdl.handle.net/1807/33753.
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The pathogenesis of diabetic nephropathy (DN) remains incompletely understood. In previous studies, we observed the activation of Tyr kinase Src by high glucose (HG) and showed that Src is required for MAPK activation and synthesis of collagen IV in cultured rat mesangial cells (MCs). Reactive oxygen species (ROS) are also important mediators of DN, and our present study aimed to investigate the role of Src in HG-induced ROS generation. In MCs, we found that HG led to ROS accumulation that was blocked by Src inhibitors or Src-specific siRNA. Downstream of Src, Vav2 was phosphorylated/activated leading to Rac1-dependent NADPH oxidase activation. Long-term HG exposure resulted in Src-dependent Nox4 protein induction. Nox2-specific siRNA abrogated ROS production only in short-term HG, while Nox4-specific siRNA blocked ROS production only in long-term HG. Taken together, our data indicate Src to be important in mediating ROS generation from both Nox2- and Nox4-containing NADPH oxidases.
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Kuo, Jing-Ru, i 郭靜如. "The mechanism study underlying glucose uptake mediated by Canarium album in 3T3-L1 Adipocytes". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/02526765602696049578.
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碩士國立臺灣大學
食品科技研究所
103
Diabetes ranks the fourth leading cause of death in Taiwan, according to the latest report by Ministry of Health and Welfare, and the prevalence is going up. The major cause of diabetes is obesity-induced insulin resistance, which is reduced glucose uptake by peripheral tissues due to compromised sensitivity to insulin as a result of excess lipid accumulation in adipose tissues. Chinese olive is rich in bioactive compounds such as phenolics and flavonoids, and shows anti-inflammatory, antibacterial, anti-oxidative, and anti-proliferative effects. Previous in vivo studies indicate that the ethyl acetate fraction of methanol extract of Chinese olive (COE) ameliorates diabetes. The present study then aims to investigate the underlying mechanism for COE’s anti-diabetic effects using 3T3-L1 mouse adipocytes. Results of glucose uptake test show COE stimulates the uptake of 2-NBDG by mature adipocytes, and such effect is not ablated in the presence of insulin resistance, nor completely abolished by the use of inhibitors for PI3K, GLUT, or AMPK. In addition, treatment of COE can dose-dependently increase transcription of the glucose transporter 1 gene in 3T3-L1. Its regulatory role in AMPK activity in 3T3-L1 is not certain, but it is clear that COE can stimulate the expression of AKT and increase GLUT4 translocation to plasma membrane. Therefore it is postulated that the mechanism behind COE’s stimulatory effect on glucose uptake of adipocytes is different from PI3K and AMPK signaling pathways. Further study is needed to understand the underlying mechanism of how COE increases GLUT1 gene expression and glucose uptake.
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Lin, Meng-Ju, i 林孟儒. "The study of Chinese olive (Canarium album) extract mediated glucose uptake in L6 myotube". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/qw5rnn.
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碩士國立臺灣大學
食品科技研究所
101
Diabetes is the fifth leading cause of death of 2012 in Taiwan. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, however, the pathological mechanism remains unclear. Insulin resistance, a key etiology of T2DM, has been reported to associate with chronic inflammation and dysregulation of lipid metabolism. In addition to Metformin and Thiazolidinediones, the common interventions for lowering blood glucose in T2DM patients, several phytochemicals have been demonstrated to have function in lowing blood glucose and sensitizing insulin. The mechanisms of known phytochemical mediated insulin sensitizing are largely through the activation of AMPK pathway. In this study, we employed Chinese olive, which is rich in polyphenolic compounds, has been used as medicine in traditional Chinese medical science and shows anti-inflammation, anti-oxidation and anti-proliferation effects. Although Chinese olive is considered as a potential supplementary food for preventing diabetes, however, its molecular mechanism is largely unknown. Here we used L6 myotube as a cell model for measuring glucose uptake, and demonstrated that Chinese olive methanol extract – ethyl acetate partition layer (OE-MeOH-Ea) enhanced 2-NBDG uptake and sensitized the function of insulin. Additionally, OE-MeOH-Ea increases the phosphorylation of AMPK at Thr-172 in L6 myotube. We further investigated the mechanism of AMPK activation upon OE-MeOH-Ea, and found that OE-MeOH-Ea could potentiate mitochondria function, such as increased ATP production, higher mitochondrial membrane potential along with lower NADH amount. We also conclude that the OE-MeOH-Ea mediated glucose uptake is not through GLUT4, the major glucose transporter regulated by insulin in muscle, because the membrane translocation, mRNA expression and protein expression of GLUT4 are not affected after OE-MeOH-Ea treatment. Furthermore LY294002, wortmannin (PI3K inhibitors), cytochalasin B (Class I GLUT inhibitor) failed to suppress OE-MeOH-Ea-enhansed 2-NBDG uptake, indicating other glucose transporter might be involved in regulating glucose uptake. To answer this, we used proteomic analysis to analyze the differential protein expression in plasma membrane among control, OE-MeOH-Ea treated L6 myotube. The results showed that Ca2+ regulation proteins and proteins for adaptation of metabolic stress are increased after OE-MeOH-Ea treatment. In summary, OE-MeOH-Ea promotes mitochondrial function and activates AMPK to enhance glucose uptake through regulating Ca2+ signaling pathway.
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Tsai, Wei-Kai, i 蔡威凱. "Dual colormetric and fluorescent sensor for detection of glucose via Fe3O4-mediated catalytic reaction". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/6hs4r9.
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碩士國立中山大學
化學系研究所
107
Iron nanoparticles are usually used as peroxidase-mimic materials and combined with Glucose oxidase to measure glucose. Glucose oxidase catalyzes glucose to generate H2O2, which in turn is catalyzed by Fe3O4 nanoparticles to produce hydroxyl free radicals as an intermediate. Then, the·OH captures a H+ from the hydrogen donor to catalyze colorimetric reaction and to determine the concentration of glucose. For example, o-Phenylenediamine (OPD) can be oxidized to 2,3-Diaminophenazine by H2O2. In this study, we found that the ferrous ion chelated by Horseradish Peroxidase can catalyze the synthesis of benzimidazole derivates from OPD in the presence of O2 and glucose, which gives strong absorption and fluorescence intensity, as the dual colorimetric and fluorescent sensor of glucose. In order to enhance the stability of catalyst, we prepared the porous Fe3O4 nanospheres composed of small iron nanocrystals and carbon dots via one-pot solvothermal method. Fe3O4 nanoparticles can catalyze OPD and glucose to replace the native HRP enzyme. Organic molecules would form the carbon quantum dots, which capping on the iron nanocrystals, under the high temperature. The interaction between the carbon dots induce self-assembly of the primary iron crystals to form larger and porous nanospheres, followed with the enhancement of catalytic ability. Histidine carbon dots - modified Fe3O4 nanoparticles mimic the heme structure and show comparable activity to naked one. We use ESI to prove the formation of benzimidazole derivative in the presence of glucose and Fe3O4 nanoparticles. Therefore, we can catalyze OPD to accelerate the glucose-derivatization by Fe3O4 nanozyme and apply it to the measurement of glucose concentration in human serum.
27
Hung-Che, Chien, i 簡宏哲. "The Role of RANTES Signaling on Macrophage Migration and Activation through RANTES-Mediated Glucose Uptake". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/87237961639595267306.
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碩士國防醫學院
生理學研究所
102
Macrophage infiltration and activation plays a critical role in the development of tissue inflammation, especially in obesity-associated adipose tissue inflammation. Chemokine RANTES (also known as CCL5) has been reported to promote macrophage infiltration and its receptor CCR5 is associated with macrophage activation, but the detailed mechanism is unclear. The aim of current study is to investigate the role of RANTES signaling in the regulation of macrophage migration and activation through RANTES-mediated glucose uptake. The present result showed that RANTES increased macrophage migration and glucose uptake in a time and dose dependent manner in RAW cell model. Blockade of glucose uptake by 2-DG significantly inhibited RANTES -induced macrophage migration. RANTES could induce membrane GLUT1 expression as well as phosphorylation of AKT on Thr308、Ser473 and AMPK on Thr172 in RAW cells, but the phosphorylation of p65-NF-κB and ERK was unchanged during the observed period. In addition, inhibition of PI3K、 AMPK and PLC could significantly suppress RANTES-induced macrophage migration and glucose uptake. We also demonstrated that blockade of CCR1 and CCR5 but not CCR3 could inhibit RANTES -induced macrophage glucose uptake and also suppress RANTES -induced macrophage migration. Moreover, Inhibition of PLC and CCR5 could decrease the ability of macrophage migration and glucose uptake in a dose-dependent manner and decrease the phosphorylation of AKT on Thr308、Ser473 and AMPK on Thr172. In THP-1 macrophage cell line, RANTES could increase glucose uptake in M0、M1 and M2 type macrophage. Inhibition of PI3K、AMPK and CCR5 could suppress RANTES-induced macrophage glucose uptake. In respect of macrophage activation, there was not changed in the gene expression of TNF-α、IL-6 and CD206, but IL-10 gene expression was significantly increased after adding RANTES. Besides, the secretion of IL-6 which is M1 type marker was unchanged in treated RANTES group compared to untreated RANTES control. Taken together, the present findings indicate that RANTES could be via CCR5 receptor to activate PLC signaling to increase phosphorylation of PI3K and AMPK thus increase GLUT1 membrane expression. As a result, macrophage glucose uptake was increased and then regulated macrophage migration. However, RANTES didn’t affect the process of macrophage activation.
28
"The effect of actin reorganization in insulin mediated glucose transport on L6 rat skeletal muscle cells". 2002. http://library.cuhk.edu.hk/record=b5891370.
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Chan Chung Sing.Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.
Includes bibliographical references (leaves 93-101).
Abstracts in English and Chinese.
Acknowledgement --- p.i
Abstract --- p.ix
List of Abbreviations --- p.xvii
Chapter CHATPER ONE --- INTRODUCTION
Chapter 1.1 --- Glucose Homeostasis --- p.1
Chapter 1.1.1 --- Function --- p.1
Chapter 1.1.2 --- Origins and regulation of glucose --- p.2
Chapter 1.1.3 --- Glucoregulatory factors --- p.4
Chapter 1.1.4 --- Insulin --- p.6
Chapter 1.1.4.1 --- Function of Insulin --- p.7
Chapter 1.1.4.2 --- Discovery and Production of Insulin --- p.7
Chapter 1.1.4.3 --- Insulin Signaling Pathway --- p.8
Chapter 1.1.4.3.1 --- Insulin Receptor --- p.8
Chapter 1.1.4.3.2 --- MAPK Pathway --- p.9
Chapter 1.1.4.3.3 --- Phosphatidylinositol 3-kinase (PI3-K) Pathway --- p.10
Chapter 1.1.5 --- Glucose Transporters --- p.11
Chapter 1.1.6 --- Role of skeletal muscle in glucose homeostasis --- p.13
Chapter 1.1.7 --- Insulin Resistance --- p.14
Chapter 1.1.8 --- Glucose abnormality and its complications --- p.16
Chapter 1.2 --- Actin --- p.19
Chapter 1.2.1 --- Function of Actin --- p.20
Chapter 1.2.2 --- Actin Accessory Protein --- p.22
Chapter 1.2.3 --- Actin Polymerization --- p.23
Chapter 1.3 --- "Interaction between Insulin, GLUT4 and Actin in Glucose Homeostasis" --- p.24
Chapter 1.3.1 --- Insulin-Induced Actin Remodeling --- p.25
Chapter 1.3.2 --- Actin Remodeling and Insulin-Induced GLUT4 Translocation --- p.26
Chapter 1.3.3 --- Involvement of Insulin Signaling Molecules in Actin Remodeling --- p.27
Chapter 1.3.4 --- Actin Remodeling and Insulin Resistance --- p.30
Chapter 1.4 --- Hypothesis and Objective --- p.30
Chapter 1.4.1 --- Rationale --- p.30
Chapter 1.4.2 --- Hypothesis --- p.31
Chapter 1.4.3 --- Objective --- p.31
Chapter CHAPTER TWO --- MATERIALS AND METHODS
Chapter 2.1 --- Materials --- p.33
Chapter 2.2 --- Cell Culture --- p.36
Chapter 2.2.1 --- Cell Culture --- p.36
Chapter 2.2.2 --- Reagents Preparation and Incubation --- p.39
Chapter 2.3 --- 2-Deoxyglucose Uptake --- p.39
Chapter 2.4 --- Immunofluorescence Microscopy --- p.41
Chapter 2.4.1 --- Permeabilized cell staining --- p.41
Chapter 2.4.2 --- Membrane-intact cell staining --- p.43
Chapter 2.4.3 --- The analysis of actin remodeling reduction --- p.44
Chapter 2.5 --- Live Image Microscopy --- p.44
Chapter 2.6 --- Transmission Electron Microscope Study --- p.44
Chapter 2.7 --- Statistical Analysis --- p.46
Chapter CHAPTER THREE --- RESULTS
Chapter 3.1 --- Cell Growth --- p.48
Chapter 3.2 --- Acute Effect of Insulin on L6 myotubes --- p.48
Chapter 3.2.1 --- Immunofluorescence Microscopy --- p.49
Chapter 3.2.1.1 --- The time profile of insulin on actin cytoskeletonin permeabilized L6 myotubes --- p.49
Chapter 3.2.1.2 --- The concentration effect of insulin on actin cytoskeletonin permeabilized L6 myotubes --- p.50
Chapter 3.2.1.3 --- Relationship between actin cytoskeleton and GLUT4mycin permeabilized L6 myotubes --- p.51
Chapter 3.2.1.4 --- Translocation of GLUT4myc in membrane-intact L6 myotubes --- p.51
Chapter 3.2.1.5 --- "Effect of methyl-β-cyclodextrins, MeOH or EtOHin permeabilized and membrane-intact L6 myotubes" --- p.52
Chapter 3.2.2 --- 2-Deoxyglucose Uptake --- p.52
Chapter 3.2.2.1 --- "Effects of insulin, methyl-β-cyclodextrins, MeOH and EtOH in L6 myotubes" --- p.52
Chapter 3.2.3 --- TEM Study --- p.53
Chapter 3.2.3.1 --- Effects of insulin on actin cytoskeleton and GLUT4myc in L6 myotubes --- p.53
Chapter 3.3 --- Effect of high glucose and high insulin incubation in L6 myotubes --- p.54
Chapter 3.3.1 --- Immunofluorescence Microscopy --- p.54
Chapter 3.3.1.1 --- High insulin and high glucose preincubation in permeabilized L6 myotubes --- p.55
Chapter 3.3.1.2 --- Effect of high insulin and high glucose incubationin membrane-intact L6 myotubes --- p.55
Chapter 3.3.2 --- 2-Deoxyglucose Uptake --- p.56
Chapter 3.3.2.1 --- Effect of high insulin and high glucose incubation in L6 myotubes --- p.56
Chapter 3.3.3 --- TEM Study --- p.57
Chapter 3.3.3.1 --- Effect of high insulin and high glucose incubation in L6 myotubes --- p.57
Chapter 3.4 --- Effect of FFA incubation in L6 myotubes --- p.58
Chapter 3.4.1 --- Immunofluorescence Microscopy --- p.58
Chapter 3.4.1.1 --- FFA preincubation in permeabilized L6 myotubes --- p.58
Chapter 3.4.1.2 --- FFA incubation in membrane-intact L6 myotubes --- p.59
Chapter 3.4.2 --- 2-Deoxyglucose Uptake --- p.59
Chapter 3.4.2.1 --- FFA incubation in L6 myotubes (24 hours) --- p.60
Chapter 3.4.3 --- TEM Study --- p.62
Chapter 3.4.3.1 --- FFA incubation in L6 myotubes --- p.62
Chapter 3.5 --- Effect of CHO incubation in L6 myotubes --- p.62
Chapter 3.5.1 --- Immunofluorescence Microscopy --- p.62
Chapter 3.5.1.1 --- CHO preincubation in permeabilized L6 myotubes --- p.63
Chapter 3.5.1.2 --- CHO incubation in membrane-intact L6 myotubes --- p.63
Chapter 3.5.2 --- 2-Deoxyglucose Uptake --- p.64
Chapter 3.5.2.1 --- CHO incubation in L6 myotubes (24 hours) --- p.64
Chapter 3.5.3 --- TEM Study --- p.65
Chapter 3.5.3.1 --- CHO incubation in L6 myotubes --- p.65
Chapter 3.6 --- Overall changes in glucose uptake after preincubation experiment --- p.65
Chapter CHAPTER FOUR --- DISCUSSION
Chapter 4.1 --- Effect of insulin on L6 myotubes --- p.69
Chapter 4.2 --- "Effect of methyl-β-cyclodextrins, MeOH and EtOH on L6 myotube" --- p.75
Chapter 4.3 --- Effect of pretreatment of cells in conditions of insulin resistance --- p.76
Chapter 4.3.1 --- Effect of high glucose and high insulin preincubation on L6 myotubes --- p.76
Chapter 4.3.2 --- Effect of FFA preincubation on L6 myotubes --- p.78
Chapter 4.3.3 --- Effect of CHO preincubation on L6 myotubes --- p.82
Chapter 4.3.4 --- Effect of cell preincubation in conditions of insulin resistance on L6 myotubes (TEM) --- p.83
Chapter 4.4 --- Summary of the effects of cell preincubation in conditions of insulin resistance --- p.84
Chapter 4.5 --- Possible mechanisms involved in insulin resistance induction --- p.86
Chapter 4.5.1 --- Possible changes in GLUT expression and activities --- p.87
Chapter 4.5.2 --- Possible changes in insulin signaling propagation --- p.88
Chapter 4.5.3 --- Altered functioning of various actin accessory proteins --- p.89
Chapter 4.6 --- Limitation of the study --- p.90
Chapter 4.7 --- Conclusion --- p.90
Chapter 4.8 --- Future study --- p.91
REFERENCES --- p.93
TABLES
29
Chiang, Tai-Hsuan, i 江泰萱. "Elucidation of the Neuronal Protective Mechanisms of YII by Inducing Oxygen Glucose Deprivation-Mediated Cell Death". Thesis, 2017. http://ndltd.ncl.edu.tw/handle/25z73d.
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碩士國立陽明大學
藥理學研究所
105
According to the Ministry of Health and Welfare, stroke is the third leading causes of death in Taiwan in 2015. Stroke is also one of the most common cardiovascular disease worldwide. More than 80% of stroke patients belong to the ischemic stroke type. It’s defined as the disturbance in the blood supply to the brain, and it causes the neuron damage and brain dysfunction quickly. Recombinant tissue-type plasminogen activator (rt-PA) is the only approved therapy for acute ischemic stroke. However, due to the short effective time window and hemorrhage side effect, the treatment for ischemic stroke needs further developments. YII is one of the key active components isolated from the protective herbal medicine based on our previous study. YII showed good neuroprotective effect in middle cerebral artery occlusion model (MCAO), but the neuroprotective mechanism of YII is still unknown. The aim of this study was to investigate the neuroprotective effect of YII and its underlying mechanisms of action by using an in vitro ischemic stroke model by inducing oxygen glucose deprivation (OGD) in Neuro-2a cells. The result showed that YII (20 μM) inhibited OGD-caused neural apoptosis by flow cytometry. The mechanisms of action in mediating YII’s neuroprotective effect was also elucidated by Western blotting. The protein expression levels of pS473Akt, pS9GSK3 and cleaved caspase 3 were significant decreased at 15 min, 60 min and 45-60 min after OGD, respectively. Bcl-2 was significant increased at 45 min after OGD. YII promoted the protein expression levels of pAkt, pSGSK3 and p35/Cdk5, which in turn may upregulate Bcl-2 and downregulate p25/Cdk5. Besides, YII might activate glucagon-like peptide 1 receptor (GLP-1R) and regulated downstream signaling pathway cAMP/PKA/CREB, which could be shown by cotreatment of YII with GLP-1R activator exendin-4 or GLP-1R inhibitor exendin-9. Finally, YII decreased the expression levels of caspase 3 in OGD model by immunofluorescence, but there was no difference in the change of an autophage marker LC3B. In conclusion, we propose that the neuroprotective effect of YII is most possibly involved GLP-1R signaling via modulation of PI3K/Akt/GSK3/p35Cdk5 and cAMP/PKA/CREB/Bcl-2 signaling pathways to protect neuronal cells against OGD-mediate cell injury.
30
Chan, Fang-Na, i 詹芳娜. "The Effect of Ginsenosides on Glucose Uptake in Human Caco-2Cells Is Mediated through SGLT-1 Expression". Thesis, 2007. http://ndltd.ncl.edu.tw/handle/25777688674570631948.
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碩士國防醫學院
生物化學研究所
95
Ginseng, an important traditional Chinese herb medicine, is widely used for a variety of distresses with no apparent adverse effects for long term usage. Despite a highly valued traditional medicine, its mechanism of action remains to be elucidated. One prominent physiological property of ginseng is its hypoglycemic activity. In our previous studies, we found that the purified ginsenoside Compound K (a main intestinal metabolite of the protopanaxadiol gisenoside Rb1) and protopanaxatriol ginsenoside Rg1 enhanced and inhibited the steady- state glucose uptake, respectively, in the differentiated human intestinal Caco-2 cells. Because the main apical transporter for active glucose uptake in small intestinal epithelial cells is the sodium-dependent glucose cotransporter (SGLT) -1, we investigated the effect of Compound K and Rg1 on the expression of SGLT-1 gene. Using western blot analysis and semi-quantitative RT-PCR, we demonstrated that the observed effects of Compound K and Rg1 on the rate glucose transport were mainly due to increased or decreased SGLT-1 protein and mRNA expression levels. In order to understand the molecular mechanism underlying the Compound K- and Rg1- mediated induction and inhibition of SGLT-1 gene expression, a series SGLT-1 promoter fragments were inserted into luciferase reporter. Transient transfection analysis demonstrated that Compound K and Rg1 conferred a specific induction and inhibition, respectively, of the SGLT-1 promoter activity through the region -169/-83. Chromation immunoprecipitation (ChIP) assay was used to evaluate the association of transcription factors bind to specific DNA motifs within this region. Our results suggest that the CREB binding protion (CBP) is responsible for the differential effects of ginsenosides Compound K and Rg1 on SGLT-1 gene expression.
31
"Uniaxial Cyclic Stretch-Stimulated Glucose Transport Is Mediated by a Ca2+-Dependent Mechanism in Cultured Skeletal Muscle Cells". Thesis, 2007. http://hdl.handle.net/2237/11109.
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32
Monaco, Sara. "CaMKII regulates insulin-mediated cell proliferation and glucose uptake in skeletal muscle cells through Erk 1/2 activation". Tesi di dottorato, 2008. http://www.fedoa.unina.it/1866/1/Monaco_Oncologia.pdf.
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Tsai, Cheng-Yen, i 蔡承諺. "Antioxidant effects of diallyl trisulfide on high glucose-induced apoptosis are mediated by the PI3K/Akt-dependent activation of Nrf2 in cardiomyocytes". Thesis, 2014. http://ndltd.ncl.edu.tw/handle/9b9w9g.
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博士中國醫藥大學
生物科技學系博士班
102
Background: Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG). Methods and results: Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucoseexposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW. Conclusions: Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2- regulated antioxidant enzymes in cardiomyocytes exposed to HG
34
Peng, Chih-Hao, i 彭芝皜. "Study on Chinese olive (Canarium album L.) mediated differential growth properties in human colon cancer cells upon different glucose concentration and the underlying molecular mechanism". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/ppymxa.
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碩士國立臺灣大學
食品科技研究所
107
The pure compounds isolated from the fruit or other parts of Chinese olive (Canarium album L.) have been proven to have many physiological functions such as liver protection, and anti-oxidation. However, little is known about the effects of Chinese olive extracts on cancer cells. Previous research in our lab indicates that the ethyl acetate fraction of ethanol extract of Chinese olive water extract residue (COE) exhibits anti-tumor effect in both cell and animal models. In the early stage of tumor formation, cancer cells rapidly proliferate, thus makes the inner cancer cells lack the supply of oxygen and glucose. Therefore, this study intends to investigate the anti-tumor effect of COE in either high or low glucose. We have treated HCT116 cells with different concentration of COE at different glucose concentrations, and examined the efficacy of COE on cell viability, colony formation, and migration. We found that COE at effectively inhibit HCT116 cell growth in high glucose. However, in low glucose, the inhibitory effect is rather poor. Also, in clonogenic assay, less inhibitory effect of COE in low glucose was observed. Furthermore, in low glucose, COE could further activate AMPK and the consequent inactivation of ACC as well as the enhancement of fatty acid oxidation (FAO) related genes. This phenomenon was less significant in high glucose, which caused opposite growth effects in different glucose levels upon COE treatment. COE dose exceeds 400 μg/ml would damage mitochondrial and leads to apoptosis, which can no longer rescue cells by the additional function of COE on increasing FAO mediated energy production. Although more and more studies point out that phytochemicals have the potential to inhibit cancer cells, here the results suggested that the opposite effects upon different concentration of glucose should be considered before using phytochemicals for cancer therapy.
35
Sęk, Jakub. "Elektrochemiczna detekcja wybranych białek i cukrów z wykorzystaniem układów mediowanych". Doctoral thesis, 2020. https://depotuw.ceon.pl/handle/item/3730.
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Niniejsza rozprawa doktorska dotyczy zagadnienia konstrukcji czujników elektrochemicznych do mediowanej detekcji istotnych z medycznego punktu widzenia biomolekuł. Praca ma klasyczny układ, jest podzielona na dwie części: teoretyczną i eksperymentalną. Część teoretyczna składa się z siedmiu rozdziałów i rozpoczyna się uzasadnieniem podjęcia tematyki dysertacji oraz sprecyzowaniem celów badawczych. W kolejnych rozdziałach zostały opisane wybrane biocząsteczki ze szczególnym uwzględnieniem białek: ceruloplazminy i białka C-reaktywnego oraz cukrów: glukozy. Z uwagi na fakt, że niniejsza rozprawa dotyczy mediowanej detekcji wybranych białek i cukrów w części literaturowej przedstawiono również zagadnienia związane z elektroaktywnością biocząsteczek oraz sposobami transportu elektronów pomiędzy biocząsteczką a powierzchnią elektrody.
W niniejszej rozprawie opisano czujniki bazujące na mediowanym transporcie elektronów do detekcji ceruloplazminy, białka C-reaktywnego oraz glukozy z wykorzystaniem nowo zsyntezowanych koniugatów ferrocenu. Funkcjonalność zaproponowanych narzędzi diagnostycznych sprawdzono na próbkach rzeczywistych jak osocze krwi, czy też napoje typu „soft drink”.
W przygotowaniu warstwy analitycznie aktywnej do mediowanej detekcji ceruloplazminy wykorzystano koniugat (nanocząstka magnetyczna z żelaznym rdzeniem)-ferrocen. Paramagnetyczne właściwości samej ceruloplazminy, jak i stosowanego układu receptorowego pozwoliły na prowadzenie pomiarów w obecności zewnętrznego źródła pola magnetycznego, co w konsekwencji znacznie poprawiło parametry analityczne czujnika takie jak: selektywność, czas życia czujnika oraz umożliwiło prowadzenie oznaczeń na ultra-niskim poziomie w próbkach rzeczywistych. Z kolei wykorzystanie zjawiska okluzji próbnika redoks pomiędzy cząsteczkami białka unieruchomionego na powierzchni elektrody na skutek specyficznego oddziaływania antygen – przeciwciało umożliwiło woltamperometryczną detekcję nieelektroaktywnego białka CRP, biomarkera stanów zapalnych.
Kolejnym czujnikiem przedstawionym w dysertacji był czujnik do monitorowania dyskretnych zmian stężenia glukozy, umożliwiający wczesną diagnostykę wielu chorób, jak również kontrolę poziomu cukrów w procesach technologicznych, np.: fermentacja. W tym przypadku zastosowano dwa różne podejścia, wykorzystując w roli receptora zredukowany tlenek grafenu domieszkowany różnymi pochodnymi ferrocenu oraz polimerowe pochodne kwasu fenyloboronowego. Wykorzystując nowo zsyntezowane receptory rGO-Fc oraz oksydazę glukozową skonstruowano bioczujniki II generacji. Na podstawie przeprowadzonych badań udowodniono, że sposób wprowadzenia ferrocenu na powierzchnię rGO, jak również funkcjonalizacja próbnika redoks grupami karboksylowymi pozwoliła na zminimalizowanie ilości enzymu w warstwie receptorowej z zachowaniem jego maksymalnej aktywności. Zaproponowane czujniki do amperometrycznej detekcji glukozy umożliwiają oznaczanie tego cukru na bardzo niskim poziomie. Badania z wykorzystaniem koniugatu rGO-ferrocen dotyczyły nie tylko aspektów analitycznych, ale również określenia wpływu obecności ferrocenu na strukturę rGO oraz orientacji cząsteczek ferrocenu względem grafenu. Te elementy są ważnym wkładem w zrozumienie działania czujnika.
Podejście z wykorzystaniem polimerowych pochodnych kwasu fenyloboronowego umożliwiło detekcję glukozy w obecności fruktozy. Proces rozpoznania glukozy opierał się na różnicy w powinowactwie zastosowanych pochodnych kwasu fenyloboronowego względem glukozy i próbnika redoks. Zgodnie z najnowszą wiedzą, taki sposób oznaczania glukozy został zademonstrowany po raz pierwszy. Dodatkowo, czujnik charakteryzował się dużą czułością, selektywnością, niską granicą wykrywalności i łatwością konstrukcji.
Przedstawione w niniejszej rozprawie doktorskiej wyniki stały się podstawą publikacji naukowych w międzynarodowych czasopismach o bardzo wysokim współczynniku oddziaływania (IF), tj. Biosensors & BioelectronicsThis PhD thesis relates to the construction issue of electrochemical sensors for mediated detection of medically important biomolecules. This thesis has a classic layout, and it is divided into two main parts: theoretical and experimental. The theoretical part consists of seven chapters and begins with a justification of the subject of the dissertation and specification of research objectives. The following chapters describe selected biomolecules with emphasis on proteins: ceruloplasmin, C-reactive protein, and sugars: glucose. Due to the fact that this dissertation concerns the mediated detection of selected proteins and sugars, the literature also presents important issues related to the electroactivity of biomolecules and types of electron transport between the biomolecule and the electrode surface. Much attention was also paid to the commercial methods of selected proteins and sugars analysis, emphasizing the role of nanomaterials in the construction of bioplatforms for sensors. This PhD thesis describes mediated electron transport sensors for the detection of ceruloplasmin, C-reactive protein, and glucose using newly synthesized ferrocene conjugates. The functionality of the proposed diagnostic devices was checked on real samples such as blood plasma or soft drinks. In the preparation of the analytically active layer for mediated detection of ceruloplasmin, a conjugate (magnetic nanoparticle with an iron core)-ferrocene was used. The paramagnetic properties of ceruloplasmin and the applied receptor system allowed of measurements in the presence of an external magnetic field source, which significantly improved the sensor's analytical parameters such as selectivity, sensor lifetime, and enabled an exceptionally low level of detection in real samples. The usage of redox probe occlusion phenomenon between protein molecules immobilized on the electrode surface due to the specific interaction of antigen-antibody enabled a voltammetric detection of non-electroactive CRP protein, a biomarker of inflammation. Another device presented in the dissertation was a sensor monitoring discrete changes of glucose concentration, which enables the early diagnostics of many diseases, as well as control of sugar levels in technological processes, e.g. fermentation. In this case, two different approaches were chosen, using reduced graphene oxide doped with various ferrocene derivatives and polymer derivatives of phenylboronic acid as receptors. Second generation biosensors were constructed using newly synthesized rGO-Fc receptors and glucose oxidase. Based on the conducted research, it was proved that the method of ferrocene introducing to the surface of rGO, as well as the functionalization of the redox probe with carboxyl groups allowed to minimize the amount of enzyme in the receptor layer while maintaining its maximum activity. The proposed sensors for amperometric determination of glucose enable the detection of this sugar at a very low level. Research on the rGO-ferrocene conjugate concerned not only the analytical aspects but also defining the effect of ferrocene presence on the structure of rGO and the orientation of ferrocene molecules relative to graphene. These elements are an important contribution to understanding the operation of the sensor. The approach using polymeric phenylboronic acid derivatives enabled the detection of glucose in the presence of fructose. The glucose recognition process was based on the difference between the affinity of the phenylboronic acid derivatives for glucose and the redox probe. According to recent knowledge, this method of glucose determination has been demonstrated for the first time. In addition, the sensor is characterized by high sensitivity, selectivity, low detection limit, and ease of its construction. The results presented in this dissertation have become the basis for scientific publications in international journals with a very high impact factor (IF), Biosensors & Bioelectronics.
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Jeng, Winnie. "Free radical determinants of endogenous and amphetamine-enhanced neurodegenerative disease : prostaglandin H synthase-catalyzed free radical formation, reactive oxygen species-mediated oxidative DNA damage and glucose-6-phosphate dehydrogenase-catalyzed neuroprotection". 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=94788&T=F.
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37
Kalwat, Michael Andrew. "F-Actin regulation of SNARE-mediated insulin secretion". Thesis, 2013. http://hdl.handle.net/1805/3624.
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Indiana University-Purdue University Indianapolis (IUPUI)In response to glucose, pancreatic islet beta cells secrete insulin in a biphasic manner, and both phases are diminished in type 2 diabetes. In beta cells, cortical F-actin beneath the plasma membrane (PM) prevents insulin granule access to the PM and glucose stimulates remodeling of this cortical F-actin to allow trafficking of insulin granules to the PM. Glucose stimulation activates the small GTPase Cdc42, which then activates p21-activated kinase 1 (PAK1); both Cdc42 and PAK1 are required for insulin secretion. In conjunction with Cdc42-PAK1 signaling, the SNARE protein Syntaxin 4 dissociates from F-actin to allow SNARE complex formation and insulin exocytosis. My central hypothesis is that, in the pancreatic beta cell, glucose signals through a Cdc42-PAK1-mediated pathway to remodel the F-actin cytoskeleton to mobilize insulin granules to SNARE docking sites at the PM to evoke glucose stimulated second phase insulin secretion. To investigate this, PAK1 was inhibited in MIN6 beta cells with IPA3 followed by live-cell imaging of F-actin remodeling using the F-actin probe, Lifeact-GFP. PAK1 inhibition prevented normal glucose-induced F-actin remodeling. PAK1 inhibition also prevented insulin granule accumulation at the PM in response to glucose. The ERK pathway was implicated, as glucose-stimulated ERK activation was decreased under PAK1-depleted conditions. Further study showed that inhibition of ERK impaired insulin secretion and cortical F-actin remodeling. One of the final steps of insulin secretion is the fusion of insulin granules with the PM which is facilitated by the SNARE proteins Syntaxin 4 on the PM and VAMP2 on the insulin granule. PAK1 activation was also found to be critical for Syntaxin 4-F-actin complex dynamics in beta cells, linking the Cdc42-PAK1 signaling pathway to SNARE-mediated exocytosis. Syntaxin 4 interacts with the F-actin severing protein Gelsolin, and in response to glucose Gelsolin dissociates from Syntaxin 4 in a calcium-dependent manner to allow Syntaxin 4 activation. Disrupting the interaction between Syntaxin 4 and Gelsolin aberrantly activates endogenous Syntaxin 4, elevating basal insulin secretion. Taken together, these results illustrate that signaling to F-actin remodeling is important for insulin secretion and that F-actin and its binding proteins can impact the final steps of insulin secretion.
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"Effects of Eight Weeks of High-intensity Interval Training on Blood Glucose Control, Endothelial Function, and Visceral Fat in Obese Adults". Doctoral diss., 2013. http://hdl.handle.net/2286/R.I.17773.
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abstract: Cardiovascular disease (CVD) is the number one cause of death in the United States and type 2 diabetes (T2D) and obesity lead to cardiovascular disease. Obese adults are more susceptible to CVD compared to their non-obese counterparts. Exercise training leads to large reductions in the risk of CVD and T2D. Recent evidence suggests high-intensity interval training (HIT) may yield similar or superior benefits in a shorter amount of time compared to traditional continuous exercise training. The purpose of this study was to compare the effects of HIT to continuous (CONT) exercise training for the improvement of endothelial function, glucose control, and visceral adipose tissue. Seventeen obese men (N=9) and women (N=8) were randomized to eight weeks of either HIT (N=9, age=34 years, BMI=37.6 kg/m2) or CONT (N=8, age=34 years, BMI=34.6 kg/m2) exercise 3 days/week for 8 weeks. Endothelial function was assessed via flow-mediated dilation (FMD), glucose control was assessed via continuous glucose monitoring (CGM), and visceral adipose tissue and body composition was measured with an iDXA. Incremental exercise testing was performed at baseline, 4 weeks, and 8 weeks. There were no changes in weight, fat mass, or visceral adipose tissue measured by the iDXA, but there was a significant reduction in body fat that did not differ by group (46±6.3 to 45.4±6.6%, P=0.025). HIT led to a significantly greater improvement in FMD compared to CONT exercise (HIT: 5.1 to 9.0%; CONT: 5.0 to 2.6%, P=0.006). Average 24-hour glucose was not improved over the whole group and there were no group x time interactions for CGM data (HIT: 103.9 to 98.2 mg/dl; CONT: 99.9 to 100.2 mg/dl, P>0.05). When statistical analysis included only the subjects who started with an average glucose at baseline > 100 mg/dl, there was a significant improvement in glucose control overall, but no group x time interaction (107.8 to 94.2 mg/dl, P=0.027). Eight weeks of HIT led to superior improvements in endothelial function and similar improvements in glucose control in obese subjects at risk for T2D and CVD. HIT was shown to have comparable or superior health benefits in this obese sample with a 36% lower total exercise time commitment.Dissertation/Thesis
Ph.D. Exercise and Wellness 2013