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Johannes Gutenberg Universität Mainz
1.
Schuhmacher, Swenja.
Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation.
Degree: 2010, Johannes Gutenberg Universität Mainz
URL: http://ubm.opus.hbz-nrw.de/volltexte/2010/2540/ 
► Die AMPK ist ein ubiquitär exprimiertes, heterotrimeres Enzym, das bei Energiemangel das Überleben der Zelle sichert. Um diese Funktion ausüben zu können fungiert die AMPK…
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▼ Die AMPK ist ein ubiquitär exprimiertes, heterotrimeres Enzym, das bei Energiemangel das Überleben der Zelle sichert. Um diese Funktion ausüben zu können fungiert die AMPK als sogenannter „Energie-Sensor“, der durch steigende AMP Mengen aktiviert wird. In diesem Zustand werden ATP verbrauchende Reaktionen inhibiert und gleichzeitig ATP generierende Vorgänge induziert. Im vaskulären System konnte gezeigt werden, dass die endotheliale NOSynthase durch die AMPK aktiviert, die Angiogenese stimuliert, die Endothelzellapoptose und das Wachstum von Gefäßmuskelzellen inhibiert wird. All diese Prozesse sind fundamental in der Entwicklung von kardiovaskulären Krankheiten, was auf eine protektive Funktion der AMPK im vaskulären System hindeutet. In der vorliegenden Arbeit sollten die Effekte der in vivo Modulation der AMPK Aktivität auf Endothelfunktion, oxidativen Stress und Inflammation untersucht werden. Dazu wurden zwei unterschiedliche Mausmodelle genutzt: Einerseits wurde die AMPK Aktivität durch den pharmakologischen AMPK-Aktivator AICAR stimuliert und andererseits die vaskulär vorherrschende AMPK-Isoform durch knock out ausgeschaltet. Zur Induktion von oxidativem Stress wurde ein bereits charakterisiertes Angiotensin II-Modell angewandt. Zur Untersuchung gehörten neben den Superoxid-Messungen auch die Bestimmung der Stickstoffmonoxid-Mengen in Serum und Aortengewebe, die Relaxationsmessungen in isometrischen Tonusstudien sowie HPLC-basierte Assays. Es konnte gezeigt werden, dass durch die Aktivierung der AMPK mittels AICAR die Angiotensin II induzierte Endotheldysfunktion, der oxidative Stress und auch die vaskuläre Inflammation verbessert werden konnte. Weiterhin zeigte sich dass der knock out der vaskulären Isoform (α1) im Angiotensin II Modell eine signifikant verstärkte Endotheldysfunktion, oxidativen Stress und Inflammation nach sich zog. Anhand der erhobenen Daten konnte die NADPH-Oxidase als Hauptquelle des Angiotensin II induzierten oxidativen Stresses identifiziert werden, wobei sich diese Quelle als AMPK sensitiv erwies. Durch die Aktivierung konnte die Aktivität der NADPH-Oxidase verringert und durch die α1AMPK Defizienz signifikant erhöht werden. Auch die mitochondriale Superoxidproduktion konnte durch die Modulation der AMPK Aktivität beeinflusst werden. Die vaskuläre Inflammation, die anhand der Surrogaten VCAM-1, COX-2 und iNOS untersucht wurde, konnte durch Aktivierung der AMPK verringert werden, der knock out der α1AMPK führte so einer sehr starken Expressionssteigerung der induzierbaren NO-Synthase, was in einem starken Anstieg der NO-Produktion und somit der Peroxynitritbildung resultierte.Die dargestellten Daten deuten stark auf eine protektive Funktion der AMPK im vaskulären System hin und sollte als therapeutisches Ziel, nicht nur in Bezug auf diabetische Patienten, in Betracht gezogen werden.
The AMP-activated protein kinase (AMPK) is an ubiquitous expressed heterotrimeric enzyme in mammalian cells which allows cellular survival under conditions of decreased energy supply. As a cellular fuel…
Subjects/Keywords: AMPK; AMPK; Natural sciences and mathematics
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APA (6th Edition):
Schuhmacher, S. (2010). Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation. (Doctoral Dissertation). Johannes Gutenberg Universität Mainz. Retrieved from http://ubm.opus.hbz-nrw.de/volltexte/2010/2540/
Chicago Manual of Style (16th Edition):
Schuhmacher, Swenja. “Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation.” 2010. Doctoral Dissertation, Johannes Gutenberg Universität Mainz. Accessed June 24, 2019.
http://ubm.opus.hbz-nrw.de/volltexte/2010/2540/.
MLA Handbook (7th Edition):
Schuhmacher, Swenja. “Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation.” 2010. Web. 24 Jun 2019.
Vancouver:
Schuhmacher S. Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation. [Internet] [Doctoral dissertation]. Johannes Gutenberg Universität Mainz; 2010. [cited 2019 Jun 24].
Available from: http://ubm.opus.hbz-nrw.de/volltexte/2010/2540/.
Council of Science Editors:
Schuhmacher S. Einfluss der AMPK-Aktivität auf Endothelfunktion, oxidativen Stress und vaskuläre Inflammation. [Doctoral Dissertation]. Johannes Gutenberg Universität Mainz; 2010. Available from: http://ubm.opus.hbz-nrw.de/volltexte/2010/2540/
2.
정, 재원.
Roles of AMPK in Drosophila circadian clock.
Degree: 2015, Ajou University
URL: http://repository.ajou.ac.kr/handle/201003/11829
;
http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019513
► 국문요약 ⅰ 차례 ⅳ 그림 차례 ⅵ 표 차례 ⅶ Ⅰ. 서론 1 Ⅱ. 재료 및 방법 5 A. Schneider 2 (S2) 세포에서 발현시키기 위한…
(more)
▼ 국문요약 ⅰ
차례 ⅳ
그림 차례 ⅵ
표 차례 ⅶ
Ⅰ. 서론 1
Ⅱ. 재료 및 방법 5
A. Schneider 2 (S2) 세포에서 발현시키기 위한 plasmid 5
B. S2 세포의 배양과 transfection 6
C. 형질전환 초파리 6
D. Locomotor Activity Monitoring System 8
E. 초파리 entrainment와 수확 8
F. 단백질액 추출 (lysis) 9
1. S2 세포에서 단백질액 추출 9
2. 초파리 머리에서 단백질액 추출 9
G. Immunoblotting (western blotting) 10
H. 면역침강법 (ImmunoPrecipitation; IP) 12
1. AMPKγ 와 dCLK 또는 dCLKΔ657-707 간의 상호작용 확인 12
2. dCLK과 AMPK α, β, γ subuit 간의 상호작용 확인 13
I. Tandem affinity purification (TAP) 15
J. 면역조직화학 (Immunohistochemistry) 16
Ⅲ. 결과 18
A. S2 세포에서 dCLK은 AMPK와 결합한다. 18
B. tim 발현 세포에서 AMPK의 발현이 저하된 초파리의 생체리듬 분석 21
C. AMPKα와 γ KD 초파리에서 AMPKα 단백질의 양이 감소하였다. 24
D. AICAR를 처리한 S2 세포에서 western blotting으로 본 dCLK은 시간에 따라 mobility가 증가한다. 26
E. AMPK KD 초파리 머리에서 얻은 단백질액의 dCLK과 PER 양상에서는 유의미한 차이가 발견되지 않았다. 28
F. AMPKγ KD 초파리의 LNvs, LNds, DNs에서 PER의 양이 감소한다. 30
G. AMPKγ 초파리에서 s-LNvs의 neural projection이 보이지 않는다. 32
H. pdf 발현세포에서 AMPK의 발현이 저하된 초파리의 생체리듬 분석. 34
I. tim 발현 세포에서 성체에서만 AMPK의 발현을 저하시킨 초파리의 생체리듬 분석. 40
Ⅳ. 고찰 33
Ⅴ. 결론 47
참고문헌 49
ABSTRACT 54
Master
Advisors/Committee Members: 201225148, 정, 재원.
Subjects/Keywords: circadian clock; AMPK
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APA ·
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APA (6th Edition):
정, . (2015). Roles of AMPK in Drosophila circadian clock. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/11829 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019513
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
정, 재원. “Roles of AMPK in Drosophila circadian clock.” 2015. Thesis, Ajou University. Accessed June 24, 2019.
http://repository.ajou.ac.kr/handle/201003/11829 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019513.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
정, 재원. “Roles of AMPK in Drosophila circadian clock.” 2015. Web. 24 Jun 2019.
Vancouver:
정 . Roles of AMPK in Drosophila circadian clock. [Internet] [Thesis]. Ajou University; 2015. [cited 2019 Jun 24].
Available from: http://repository.ajou.ac.kr/handle/201003/11829 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019513.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
정 . Roles of AMPK in Drosophila circadian clock. [Thesis]. Ajou University; 2015. Available from: http://repository.ajou.ac.kr/handle/201003/11829 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019513
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Boston University
3.
Allen, Katherine.
The effects of troglitazone and PMA on AMPK in HepG2 cells.
Degree: MS, Medical Sciences, 2016, Boston University
URL: http://hdl.handle.net/2144/16783
► Type 2 diabetes, as well as other metabolic diseases, is an increasing global health concern and many of the mechanisms of both the disease and…
(more)
▼ Type 2 diabetes, as well as other metabolic diseases, is an increasing global health concern and many of the mechanisms of both the disease and its current drug treatments have not been fully described. It has been shown that the anti-diabetic class of drugs, the thiazolidinediones, work via both a known PPARγ-dependent, and a lesser known PPARγ-independent mechanism of action. This PPARγ-independent mechanism likely involves the metabolic regulatory molecule AMPK, which has a newly elucidated inhibitory site of phosphorylation at Ser485/Ser491. In this study we sought to determine if the thiazolidinedione troglitazone affects AMPK in HepG2 liver cells via phosphorylation at both the known Thr172 site as well as the letter understood Ser485 site. We also looked for potential upstream kinases of the Ser485 site by comparing our results to recently proposed mechanisms of phosphorylation here.
HepG2 cells were cultured in the lab and treated with troglitazone to determine time- and dose- dependent effects on AMPK. We also treated cultured HepG2 cells with PMA as well as troglitazone and PMA in order to compare mechanisms of action of troglitazone on AMPK. Results were analyzed using common western blot techniques and statistical analysis.
Our data found that troglitazone increased AMPK activity by increasing phosphorylation at Thr172 in a time- and dose- dependent manner. The inhibitory site Ser485 was also increasingly phosphorylated with troglitazone treatments, although the net result of troglitazone treatment remained AMPK activation. The recently elucidated results from our laboratory showing the mechanism of p-AMPK Ser485 phosphorylation via PKD after PMA treatment also occurred in HepG2 cells, although this did not appear to be the mechanism by which troglitazone phosphorylated AMPK at Ser485.
These data support the current research that there is an AMPK mediated PPARγ-independent mechanism of troglitazone treatment for type 2 diabetes and other metabolic diseases. The results do however bring into question the full effects of the drug on AMPK at a molecular level and leaves room for new research in this area, specifically the exact mechanism by which troglitazone phosphorylates AMPK at Ser485. Our data also brings up new questions as to the simultaneous phosphorylation of AMPK at both Thr172 and Ser485 and what this means for the activity of the molecule as a whole, a current area of critical research. Lastly our data support the newly elucidated mechanism of AMPK phosphorylation at Ser485 via PKD1, an exciting and novel discovery and potential target for therapeutic intervention.
Subjects/Keywords: Endocrinology; AMPK; Troglitazone
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APA ·
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APA (6th Edition):
Allen, K. (2016). The effects of troglitazone and PMA on AMPK in HepG2 cells. (Masters Thesis). Boston University. Retrieved from http://hdl.handle.net/2144/16783
Chicago Manual of Style (16th Edition):
Allen, Katherine. “The effects of troglitazone and PMA on AMPK in HepG2 cells.” 2016. Masters Thesis, Boston University. Accessed June 24, 2019.
http://hdl.handle.net/2144/16783.
MLA Handbook (7th Edition):
Allen, Katherine. “The effects of troglitazone and PMA on AMPK in HepG2 cells.” 2016. Web. 24 Jun 2019.
Vancouver:
Allen K. The effects of troglitazone and PMA on AMPK in HepG2 cells. [Internet] [Masters thesis]. Boston University; 2016. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/2144/16783.
Council of Science Editors:
Allen K. The effects of troglitazone and PMA on AMPK in HepG2 cells. [Masters Thesis]. Boston University; 2016. Available from: http://hdl.handle.net/2144/16783
University of North Texas
4.
LaRue, Bobby Lee, Jr.
Genetic and Environmental Factors that Mediate Survival of Prolonged Oxygen Deprivation in the Nematode Caenorhabditis Elegans.
Degree: 2010, University of North Texas
URL: https://digital.library.unt.edu/ark:/67531/metadc103350/
► Ischemic events of even a very short duration are not tolerated Ill in humans. The human cost of ischemia, when looked at as combined cardiovascular…
(more)
▼ Ischemic events of even a very short duration are not tolerated Ill in humans. The human cost of ischemia, when looked at as combined cardiovascular disease, dwarfs all other causes of death in the United States. Annually, CVD kills as many people in the US as does cancer, chronic lower respiratory disease, accidents, and diabetes mellitus combined. In 2005 (the latest year for which final statistics are available), CVD was responsible for 864,480 deaths or 35.3 percent of total deaths for the year. In my study, I have used the nematode Caenorhabditis elegans to determine genetic and environmental modulators of oxygen deprivation a key component of ischemia. I have found that animals with mutations in insulin like signaling pathways, neuronal function, electron transport chain components, germline function, and animals that are preconditioned by being raised on a diet of E. coli HT115 bacteria at 25°C have an enhanced ability to survive long-term (>72 hours) anoxia (<.005 kPa O2) at 20°C. The enhanced anoxia survival phenotype partially correlates with increased levels of carbohydrate stores in the nematodes. Suppression of this enhanced anoxia survival phenotype is possible by altering expression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, the FOXO transcription factor DAF-16, and 5’-AMP kinase.
Advisors/Committee Members: Padilla, Pamela A., Benjamin, Robert C., Dzialowski, Edward M. (Edward Michael), Hynds, DiAnna, Harris Schwark.
Subjects/Keywords: Oxygen; ischemia; AMPK
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University of Dundee
5.
Auciello, Francesca Romana.
Canonical and non-canonical regulation of AMP-activated protein kinase.
Degree: PhD, 2015, University of Dundee
URL: http://hdl.handle.net/10588/2720a2b7-3f1e-445c-b008-c5c235f35395
► The AMP-activated protein kinase (AMPK) is a sensor of cellular energy stress that, once activated, promotes ATP-producing process while it switches off ATP-consuming pathways, in…
(more)
▼ The AMP-activated protein kinase (AMPK) is a sensor of cellular energy stress that, once activated, promotes ATP-producing process while it switches off ATP-consuming pathways, in order to restore the cellular energetic balance under conditions of stress. Activation of AMPK is dependent on the phosphorylation of the residue Thr172 in its α subunit. This phosphorylation is generally mediated by the known tumour suppressor LKB1, but also CaMKKβ has been shown to phosphorylate AMPK. As its name suggests, AMPK is also activated by the binding of AMP to its γ subunit. This binding causes a >10 fold allosteric stimulation, promotes phosphorylation of Thr172 by upstream kinases and protects AMPK from dephosphorylation of Thr172 by protein phosphatase(s). In 2010 it was reported that oxidative stress mediated by H2O2 activated AMPK by increasing the cellular AMP:ATP and ADP:ATP ratios (Hawley et al, 2010). However, the same year another work suggested that the mechanism of activation of AMPK by H2O2 was direct, independent of AMP and involved the oxidation of two cysteine residues in the α subunit of AMPK (Zmijewski et al, 2010). Given this discrepancy, here we provided evidence that H2O2, generated by addition of glucose oxidase in the cell medium, activates AMPK mostly through an increase of AMP:ATP and ADP:ATP ratios, as previously suggested in our laboratory. However, it seems that there might be a second, minor mechanism of activation that is independent of the changes in cellular nucleotides. This second mechanism was not identified in our previous work because we were not aware of how rapidly a single bolus of H2O2 can be metabolized by the antioxidant defences of the cell. We could not identify the alternative mechanism of activation by H2O2 but showed that H2O2 could protect Thr172 from dephosphorylation, which might suggest a direct effect of H2O2 on the phosphatase(s) dephosphorylating AMPK. However, since the identity of this phosphatase(s) remains unclear, we could not rule out the possibility that the protection from dephosphorylation that we observed could still be mediated by the increase in AMP:ATP and ADP:ATP ratios. Moreover, it remains still possible that a direct effect of H2O2 on AMPK might be responsible for the small but significant activation we detected in cell expressing a nucleotides-insensitive mutant of AMPK. Recently, a new crystal structure of AMPK obtained by Xiao et al (2013) provided new insights about AMPK structure and regulation. In particular, the authors identified a new binding pocket located at the interface between the N-lobe of the α-kinase domain and the β-CBM of AMPK, which appeared to be the binding site for two direct activators of AMPK: A769662 and 991. Here we confirm that this novel binding pocket is indeed the binding site for both A769662 and 991, and provide evidence that another direct activator of…
Subjects/Keywords: 616; AMPK; Oxidative stress
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APA ·
Chicago ·
MLA ·
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Export
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APA (6th Edition):
Auciello, F. R. (2015). Canonical and non-canonical regulation of AMP-activated protein kinase. (Doctoral Dissertation). University of Dundee. Retrieved from http://hdl.handle.net/10588/2720a2b7-3f1e-445c-b008-c5c235f35395
Chicago Manual of Style (16th Edition):
Auciello, Francesca Romana. “Canonical and non-canonical regulation of AMP-activated protein kinase.” 2015. Doctoral Dissertation, University of Dundee. Accessed June 24, 2019.
http://hdl.handle.net/10588/2720a2b7-3f1e-445c-b008-c5c235f35395.
MLA Handbook (7th Edition):
Auciello, Francesca Romana. “Canonical and non-canonical regulation of AMP-activated protein kinase.” 2015. Web. 24 Jun 2019.
Vancouver:
Auciello FR. Canonical and non-canonical regulation of AMP-activated protein kinase. [Internet] [Doctoral dissertation]. University of Dundee; 2015. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/10588/2720a2b7-3f1e-445c-b008-c5c235f35395.
Council of Science Editors:
Auciello FR. Canonical and non-canonical regulation of AMP-activated protein kinase. [Doctoral Dissertation]. University of Dundee; 2015. Available from: http://hdl.handle.net/10588/2720a2b7-3f1e-445c-b008-c5c235f35395
Queens University
6.
Snider, Trevor.
Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
.
Degree: Biology, 2013, Queens University
URL: http://hdl.handle.net/1974/8254
► The production of ATP is of the utmost importance to cell survival. To maintain energy homeostasis, cells regulate mitochondrial content through the control of degradative…
(more)
▼ The production of ATP is of the utmost importance to cell survival. To maintain energy homeostasis, cells regulate mitochondrial content through the control of degradative and synthetic processes. Mitochondrial biogenesis is primarily controlled through a small number of transcriptional regulators, primarily nuclear respiratory factor-1 (NRF-1), NRF-2, and peroxisome proliferator-activated receptors (PPARs). DNA-binding proteins regulate genes encoding the machinery of oxidative phosphorylation. In addition to these DNA-binding proteins, the coactivator PPAR gamma coactivator-1 alpha (PGC-1α) is central to control of mitochondrial genes, so much so that it has been dubbed a “master controller” of energy homeostasis in mammalian muscle tissues. Though well studied in mammals, previous studies suggest that this NRF-1-PGC1α axis may be disrupted in fish. The response to treatments such as temperature and diet cause reciprocal effects on NRF-1 and PGC-1α. A serine-rich insertion into the NRF-1 binding domain of PGC-1α most likely disrupts this interaction.
In this study I looked at the ability for the goldfish PGC-1α gene to interact with the PGC-1α binding domain of NRF-1. I have found that goldfish PGC-1α does not physically bind NRF-1, which would suggest that the PGC-1α-NRF-1 axis in fish is disrupted. To further explore the role of PGC-1α in fish we looked at the role of AMP-activated kinase (AMPK) to phosphorylate goldfish, zebrafish, and human PGC-1α. The results from this analysis show that AMPK in a zebrafish embryonic cell line (ZEB2J) have their AMPK activated by the AMPK activator AICAR. This response was shown to be both dose and time dependent. Transcript data was generated looking at typical AMPK responsive targets in the mammalian system. The target of ramapamycin (TOR) gene responded with a decrease as is expected in mammals. Hexokinase 2 (HK2), PGC-1α, and NRF-1 all decreased which is opposite of the typical mammalian response. COX7C a downstream target of the PGC-1α-NRF-1 axis did not respond to treatment. Indicating a disruption in the AMPK- PGC-1α-NRF-1 pathway.
Subjects/Keywords: PGC1;
AMPK;
Animal physiology
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APA ·
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APA (6th Edition):
Snider, T. (2013). Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
. (Thesis). Queens University. Retrieved from http://hdl.handle.net/1974/8254
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Snider, Trevor. “Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
.” 2013. Thesis, Queens University. Accessed June 24, 2019.
http://hdl.handle.net/1974/8254.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Snider, Trevor. “Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
.” 2013. Web. 24 Jun 2019.
Vancouver:
Snider T. Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
. [Internet] [Thesis]. Queens University; 2013. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/1974/8254.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Snider T. Evaluating the Role of Peroxisome Proliferator-Activated Receptor Gama Coactivator-1 Alpha in Mitochondrial Biogenesis in Goldfish
. [Thesis]. Queens University; 2013. Available from: http://hdl.handle.net/1974/8254
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of British Columbia
7.
Puthanveetil, Prasanth Nair.
Glucocorticoid and its effect on cardiac glucose utilization
.
Degree: 2008, University of British Columbia
URL: http://hdl.handle.net/2429/5038
► Glycogen is an immediate source of glucose for cardiac tissue to maintain its metabolic homeostasis. However, its excess brings about cardiac structural and physiological impairments.…
(more)
▼ Glycogen is an immediate source of glucose for cardiac tissue to maintain its metabolic
homeostasis. However, its excess brings about cardiac structural and physiological
impairments. Previously, we have demonstrated that in hearts from dexamethasone
(DEX) treated animals, glycogen accumulation was enhanced. We examined the
influence of DEX on glucose entry and glycogen synthase as a means of regulating the
accumulation of this stored polysaccharide. Following DEX, cardiac tissue had limited
contribution towards the development of whole body insulin resistance. Measurement of
GLUT4 at the plasma membrane revealed an excess presence of this transporter protein
at this location. Interestingly, this was accompanied by an increase in GLUT4 in the
intracellular membrane fraction, an effect that was well correlated to an increased
GLUT4 mR.NA. Both total and phosphorylated AMPK increased following DEX.
Immunoprecipitation of AS 160 followed by Western blotting demonstrated no change in
Akt phosphorylation at Ser473 and Thr308 in DEX treated hearts. However, there was a
significant increase in AMPK phosphorylation at Thr172, which correlated well with
AS 160 phosphorylation. In DEX hearts, there was a considerable reduction in the
phosphorylation of glycogen synthase, whereas GSK-3-β phosphorylation was
augmented. Our data suggest that AMPK mediated glucose entry, combined with
activation of glycogen synthase and reduction in glucose oxidation (Qi, D., et al. Diabetes
53:1790, 2004), act together to promote glycogen storage. Our data suggest that in the
presence of intact insulin signaling, AMPK mediated glucose entry, combined with
activation of glycogen synthase and the previously reported reduction in glucose
oxidation, act together to promote glycogen storage. Should these effects persist chronically, they may explain the increased morbidity and mortality observed with long
term excesses in endogenous or exogenous glucocorticoids.
Subjects/Keywords: AMPK;
Glycogen
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APA ·
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MLA ·
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CSE |
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APA (6th Edition):
Puthanveetil, P. N. (2008). Glucocorticoid and its effect on cardiac glucose utilization
. (Thesis). University of British Columbia. Retrieved from http://hdl.handle.net/2429/5038
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Puthanveetil, Prasanth Nair. “Glucocorticoid and its effect on cardiac glucose utilization
.” 2008. Thesis, University of British Columbia. Accessed June 24, 2019.
http://hdl.handle.net/2429/5038.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Puthanveetil, Prasanth Nair. “Glucocorticoid and its effect on cardiac glucose utilization
.” 2008. Web. 24 Jun 2019.
Vancouver:
Puthanveetil PN. Glucocorticoid and its effect on cardiac glucose utilization
. [Internet] [Thesis]. University of British Columbia; 2008. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/2429/5038.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Puthanveetil PN. Glucocorticoid and its effect on cardiac glucose utilization
. [Thesis]. University of British Columbia; 2008. Available from: http://hdl.handle.net/2429/5038
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Dundee
8.
Auciello, Francesca Romana.
Canonical and non-canonical regulation of AMP-activated protein kinase.
Degree: PhD, 2015, University of Dundee
URL: https://discovery.dundee.ac.uk/en/studentTheses/2720a2b7-3f1e-445c-b008-c5c235f35395
;
https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679087
► The AMP-activated protein kinase (AMPK) is a sensor of cellular energy stress that, once activated, promotes ATP-producing process while it switches off ATP-consuming pathways, in…
(more)
▼ The AMP-activated protein kinase (AMPK) is a sensor of cellular energy stress that, once activated, promotes ATP-producing process while it switches off ATP-consuming pathways, in order to restore the cellular energetic balance under conditions of stress. Activation of AMPK is dependent on the phosphorylation of the residue Thr172 in its α subunit. This phosphorylation is generally mediated by the known tumour suppressor LKB1, but also CaMKKβ has been shown to phosphorylate AMPK. As its name suggests, AMPK is also activated by the binding of AMP to its γ subunit. This binding causes a >10 fold allosteric stimulation, promotes phosphorylation of Thr172 by upstream kinases and protects AMPK from dephosphorylation of Thr172 by protein phosphatase(s). In 2010 it was reported that oxidative stress mediated by H2O2 activated AMPK by increasing the cellular AMP:ATP and ADP:ATP ratios (Hawley et al, 2010). However, the same year another work suggested that the mechanism of activation of AMPK by H2O2 was direct, independent of AMP and involved the oxidation of two cysteine residues in the α subunit of AMPK (Zmijewski et al, 2010). Given this discrepancy, here we provided evidence that H2O2, generated by addition of glucose oxidase in the cell medium, activates AMPK mostly through an increase of AMP:ATP and ADP:ATP ratios, as previously suggested in our laboratory. However, it seems that there might be a second, minor mechanism of activation that is independent of the changes in cellular nucleotides. This second mechanism was not identified in our previous work because we were not aware of how rapidly a single bolus of H2O2 can be metabolized by the antioxidant defences of the cell. We could not identify the alternative mechanism of activation by H2O2 but showed that H2O2 could protect Thr172 from dephosphorylation, which might suggest a direct effect of H2O2 on the phosphatase(s) dephosphorylating AMPK. However, since the identity of this phosphatase(s) remains unclear, we could not rule out the possibility that the protection from dephosphorylation that we observed could still be mediated by the increase in AMP:ATP and ADP:ATP ratios. Moreover, it remains still possible that a direct effect of H2O2 on AMPK might be responsible for the small but significant activation we detected in cell expressing a nucleotides-insensitive mutant of AMPK. Recently, a new crystal structure of AMPK obtained by Xiao et al (2013) provided new insights about AMPK structure and regulation. In particular, the authors identified a new binding pocket located at the interface between the N-lobe of the α-kinase domain and the β-CBM of AMPK, which appeared to be the binding site for two direct activators of AMPK: A769662 and 991. Here we confirm that this novel binding pocket is indeed the binding site for both A769662 and 991, and provide evidence that another direct activator of…
Subjects/Keywords: 616; AMPK; Oxidative stress
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MLA ·
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APA (6th Edition):
Auciello, F. R. (2015). Canonical and non-canonical regulation of AMP-activated protein kinase. (Doctoral Dissertation). University of Dundee. Retrieved from https://discovery.dundee.ac.uk/en/studentTheses/2720a2b7-3f1e-445c-b008-c5c235f35395 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679087
Chicago Manual of Style (16th Edition):
Auciello, Francesca Romana. “Canonical and non-canonical regulation of AMP-activated protein kinase.” 2015. Doctoral Dissertation, University of Dundee. Accessed June 24, 2019.
https://discovery.dundee.ac.uk/en/studentTheses/2720a2b7-3f1e-445c-b008-c5c235f35395 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679087.
MLA Handbook (7th Edition):
Auciello, Francesca Romana. “Canonical and non-canonical regulation of AMP-activated protein kinase.” 2015. Web. 24 Jun 2019.
Vancouver:
Auciello FR. Canonical and non-canonical regulation of AMP-activated protein kinase. [Internet] [Doctoral dissertation]. University of Dundee; 2015. [cited 2019 Jun 24].
Available from: https://discovery.dundee.ac.uk/en/studentTheses/2720a2b7-3f1e-445c-b008-c5c235f35395 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679087.
Council of Science Editors:
Auciello FR. Canonical and non-canonical regulation of AMP-activated protein kinase. [Doctoral Dissertation]. University of Dundee; 2015. Available from: https://discovery.dundee.ac.uk/en/studentTheses/2720a2b7-3f1e-445c-b008-c5c235f35395 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679087
9.
Ríos García, Marcos.
Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis.
Degree: 2018, Universidad de Santiago de Compostela
URL: http://hdl.handle.net/10347/3711
Subjects/Keywords: Glioma; AMPK
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ríos García, M. (2018). Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis. (Thesis). Universidad de Santiago de Compostela. Retrieved from http://hdl.handle.net/10347/3711
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ríos García, Marcos. “Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis.” 2018. Thesis, Universidad de Santiago de Compostela. Accessed June 24, 2019.
http://hdl.handle.net/10347/3711.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ríos García, Marcos. “Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis.” 2018. Web. 24 Jun 2019.
Vancouver:
Ríos García M. Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis. [Internet] [Thesis]. Universidad de Santiago de Compostela; 2018. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/10347/3711.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ríos García M. Papel de AMPK en la regulación del metabolismo y proliferación celular durante el proceso de tumorogénesis. [Thesis]. Universidad de Santiago de Compostela; 2018. Available from: http://hdl.handle.net/10347/3711
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
IUPUI
10.
Steele, Hannah E.
Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration.
Degree: 2018, IUPUI
URL: http://hdl.handle.net/1805/15928
► Indiana University-Purdue University Indianapolis (IUPUI)
The biophysical microenvironment of the tumor site has significant impact on breast cancer progression and metastasis. The importance of altered…
(more)
▼ Indiana University-Purdue University Indianapolis (IUPUI)
The biophysical microenvironment of the tumor site has significant impact on breast cancer progression and metastasis. The importance of altered mechanotransduction in cancerous tissue through the integrin-mediated signaling axis has been documented, yet its role in the regulation of cellular metabolism and the potential link between cellular energy and cell migration remain poorly understood.
In this study, we investigated the role of mechanotransduction (via Src and FAK) in AMP-activated protein kinase (AMPK) activation in breast cancer cells in response to interstitial fluid flow. Additionally, we explored the involvement of AMPK in breast cancer cell migration. An in-vitro three-dimensional (3D) cell culture model utilizing collagen-Matrigel matrices was used. Interstitial fluid flow was applied to the 3D cell-matrix construct inside a flow chamber. The sub-cellular signaling activity of Src, FAK, and AMPK was visualized in real-time using fluorescent resonance energy transfer (FRET). We observed that breast cancer cells (MDA-MB-231) are more sensitive to interstitial fluid flow than normal epithelial cells (MCF-10A) in the regulation of FAK and Src. AMPK was activated in the mitochondria of MDA-MB-231 cells by interstitial fluid flow, but not in other subcellular domains (i.e., cytosol, plasma membrane, and nucleus). Subcellular AMPK in MCF-10A cells did not respond to interstitial fluid flow. The inhibition of FAK or Src abolished flow-induced AMPK activation in the mitochondria of MDA-MB-231 cells. We also observed that global AMPK activation reduced MDA-MB-231 cell migration. Interestingly, specific AMPK inhibition in the mitochondria reduced cell migration and blocked interstitial fluid flow-induced cell migration.
Our results suggest the linkage of FAK/Src and mitochondria-specific AMPK in mechanotransduction and the dual role of AMPK in breast cancer cell migration depending on its subcellular activation. Therefore, subcellular AMPK activation may play an important and distinct role in cancer invasion and progression.
Advisors/Committee Members: Na, Sungsoo.
Subjects/Keywords: Mechanotransduction; AMPK; Breast Cancer; Migration
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Steele, H. E. (2018). Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/15928
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Steele, Hannah E. “Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration.” 2018. Thesis, IUPUI. Accessed June 24, 2019.
http://hdl.handle.net/1805/15928.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Steele, Hannah E. “Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration.” 2018. Web. 24 Jun 2019.
Vancouver:
Steele HE. Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration. [Internet] [Thesis]. IUPUI; 2018. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/1805/15928.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Steele HE. Mechanotransduction of subcellular AMPK and its role in breast cancer cell migration. [Thesis]. IUPUI; 2018. Available from: http://hdl.handle.net/1805/15928
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
11.
Ybanez, Maria Cecilia D.
Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways.
Degree: MS, Biochemistry and Molecular Biology, 2013, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294
► Our previous studies have shown that acetaminophen (APAP)-induced hepatocyte necrosis is mediated by JNK. In the present study we show that protein kinase C (PKC)…
(more)
▼ Our previous studies have shown that acetaminophen
(APAP)-induced hepatocyte necrosis is mediated by JNK. In the
present study we show that protein kinase C (PKC) plays an
important role in APAP-induced liver injury through JNK-dependent
and independent pathways. Treatment of primary mouse hepatocytes
with two different broad-spectrum PKC inhibitors (Ro-31-8245,
Go6983), protected against APAP hepatotoxicity without inhibiting
JNK activation. Ro-31-8245 treatment to mice also resulted in
upregulation of p-
AMPK in the liver and protection against
APAP-induced liver injury in vivo, despite sustained JNK
activation. APAP treatment caused a decreased p-
AMPK, which was
prevented by broad-spectrum PKC inhibitors.
AMPK inhibition by
compound C or activation using
AMPK activator oppositely modulated
APAP hepatotoxicity. This suggests PKC-dependent downregulation of
AMPK-regulated survival pathways is an important component of APAP
hepatotoxicity. In contrast to broad-spectrum inhibitors, treatment
of hepatocytes with a more specific classical PKC inhibitor
(Go6976) that inhibits mainly PKC-α and PKC-βI protected against
APAP by inhibiting JNK activation. Knockdown of PKC-α using
antisense (ASO) in mice protected against APAP-induced liver injury
by inhibiting JNK activation. APAP treatment resulted in PKC-α
translocation to mitochondria, phosphorylation of mitochondrial
proteins, and decline in mitochondria respiration in the liver. JNK
1 and 2 silencing using ASO in mice decreased APAP-induced PKC-α
translocation to mitochondria, suggesting PKC-α and JNK act
together through a feed forward mechanism to mediate APAP-induced
liver injury. Conclusion: PKC-α and other PKC(s) regulate death
(JNK) and survival (
AMPK), to modulate APAP-induced liver
injury.
Advisors/Committee Members: Tokes, Zoltan A. (Committee Chair), Kalra, Vijay K. (Committee Member), Kaplowitz, Neil (Committee Member).
Subjects/Keywords: acetaminophen (APAP); AMPK; p70S6K; necrosis
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ybanez, M. C. D. (2013). Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways. (Masters Thesis). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294
Chicago Manual of Style (16th Edition):
Ybanez, Maria Cecilia D. “Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways.” 2013. Masters Thesis, University of Southern California. Accessed June 24, 2019.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294.
MLA Handbook (7th Edition):
Ybanez, Maria Cecilia D. “Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways.” 2013. Web. 24 Jun 2019.
Vancouver:
Ybanez MCD. Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways. [Internet] [Masters thesis]. University of Southern California; 2013. [cited 2019 Jun 24].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294.
Council of Science Editors:
Ybanez MCD. Protein kinase C (PKC) participates in acetaminophen
hepatotoxicity through JNK dependent and independent
pathways. [Masters Thesis]. University of Southern California; 2013. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/247992/rec/5294
12.
Mohsen Mroueh, Fatima.
Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies.
Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2017, Université de Strasbourg
URL: http://www.theses.fr/2017STRAJ117
► Le diabète est une dérégulation systémique chronique caractérisée par des perturbations métaboliques permanentes à l’origine de nombreuses complications, y compris le cancer. Le diabète augmente…
(more)
▼ Le diabète est une dérégulation systémique chronique caractérisée par des perturbations métaboliques permanentes à l’origine de nombreuses complications, y compris le cancer. Le diabète augmente le risque du cancer colorectal (CRC) de 1,2 à 1,5 fois. Cependant, les voies moléculaires et cellulaires en jeu ne sont pas assez élucidées. Nos résultats témoignent d’une dérégulation de la voie AMPK/mTORC1 dans le diabète et le CRC avec une surexpression de la NADPH oxydase Nox4, augmentant ainsi la production de ROS. Ceci provoque un stress oxydatif qui s’élève en cas de diabète et contribue à la progression du CRC. De plus, nos résultats montrent que ce stress induit une altération de la voie de signalisation AMPK/mTORC1, aboutissant à une agressivité accrue du comportement des cellules cancéreuses du côlon et de la formation de polypes. Notre projet permet, d’une part, d’identifier de nouveaux mécanismes moléculaires impliqués dans la progression du CRC induite par le diabète et d’autre part, de développer des stratégies thérapeutiques efficaces pour inverser la progression du CRC chez les patients diabétiques.
Diabetes is a chronic systemic malfunction characterized by persistent metabolic disturbances that culminate in a high rate of complications to which cancer was recently annexed. In fact, diabetes inflates colorectal cancer (CRC) risk by 1.2-1.5 folds. However, the cellular and molecular pathways involved are not well understood. Our results show that AMPK/mTORC1 pathway is deregulated in both diabetes and CRC. This was paralleled by an elevation in the expression of the NADPH oxidase Nox4 leading to an increase in ROS production. Furthermore, our results show that oxidative stress, secondary to alteration in the level and activity of Nox4 is augmented in diabetes and contributes to the progression of CRC. The resulting oxidative stress further led to an alteration in the signaling of the AMPK/mTORC1 pathways culminating in an exacerbated aggressiveness in cancer cell behavior and colon polyp formation. Our project allows the identification of novel molecular mechanisms involved in diabetes-induced CRC progression and development of effective therapeutic strategies to reverse the progression of CRC in diabetic patients.
Advisors/Committee Members: Sauleau, Erik-André (thesis director), Eid, Assaad (thesis director).
Subjects/Keywords: Diabète; CRC; ROS; AMPK; Diabetes; CRC; ROS; AMPK; 572.8; 616.99; 616.4
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APA ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mohsen Mroueh, F. (2017). Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies. (Doctoral Dissertation). Université de Strasbourg. Retrieved from http://www.theses.fr/2017STRAJ117
Chicago Manual of Style (16th Edition):
Mohsen Mroueh, Fatima. “Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies.” 2017. Doctoral Dissertation, Université de Strasbourg. Accessed June 24, 2019.
http://www.theses.fr/2017STRAJ117.
MLA Handbook (7th Edition):
Mohsen Mroueh, Fatima. “Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies.” 2017. Web. 24 Jun 2019.
Vancouver:
Mohsen Mroueh F. Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies. [Internet] [Doctoral dissertation]. Université de Strasbourg; 2017. [cited 2019 Jun 24].
Available from: http://www.theses.fr/2017STRAJ117.
Council of Science Editors:
Mohsen Mroueh F. Diabète et cancer colorectal : épidémiologie et physiopathologie : Diabetes and colorectal cancer : epidemiological and physiopathological studies. [Doctoral Dissertation]. Université de Strasbourg; 2017. Available from: http://www.theses.fr/2017STRAJ117
13.
Gsaier, Linda.
Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis.
Degree: Docteur es, Biologie cellulaire, 2018, Lyon
URL: http://www.theses.fr/2018LYSE1208
► Durant la régénération du muscle suite à une lésion, les cellules souches musculaires, aussi appelées les cellules satellites, quittent leur état de quiescence et s’activent.…
(more)
▼ Durant la régénération du muscle suite à une lésion, les cellules souches musculaires, aussi appelées les cellules satellites, quittent leur état de quiescence et s’activent. Elles pourront soit emprunter la voie de la myogenèse afin de former de nouvelles fibres musculaires, soit retourner à leur état de quiescence pour reformer la réserve de cellules souches mobilisable en cas de lésion ultérieure. La régulation du devenir de la cellule souche est modulée par de nombreuses voies de signalisation telles que la voie Wnt, la voie Notch ou la voie des TGFb. Cependant, rares sont les données concernant l’implication du métabolisme sur le devenir de la cellule souche. Pourtant il a été démontré que l’activation des cellules satellites est étroitement liée avec le métabolisme cellulaire, dont l’un des principaux acteurs est la protéine kinase AMPK. Ce complexe hétérotrimérique, composé de trois sous-unités a, b et g est responsable de l’équilibre entre consommation énergétique et production d’énergie au sein de la cellule. Grâce à la modulation de mTORC1, il a également été prouvé que l’AMPKa1 était responsable de la croissance cellulaire et de la prolifération des précurseurs myogéniques. A l’aide de différents modèles murins, de lignées primaires et de cellules satellites en sortie de tri, nous avons déterminé le rôle que pouvait jouer chacun des isoformes, AMPKa1 et AMPKa2 au sein de la cellule souche, sur le déroulement de la myogenèse adulte post- lésionnelle ainsi que sur l’homéostasie du muscle régénéré. Dans un premier temps nous avons démontré que la voie de signalisation AMPKa1-LDH permettait de réguler l’autorenouvellement des cellules satellites grâce au contrôle du métabolisme. En effet, au moment de l’entrée de la cellule dans la voie de la différenciation, la voie de l’AMPKa1 induit une diminution de l’activité de la LDH, permettant aux cellules d’adopter un métabolisme de phosphorylation oxydative répondant à leurs besoins énergétiques. Dans un second temps, nous avons démontré que l’isoforme AMPKa2, exprimé uniquement après l’entrée de la cellule dans la voie de la myogenèse, était responsable d’une modulation de la régénération musculaire et que son absence induisait un défaut de différenciation et un retard de maturation des fibres néoformées. Nos travaux nous ont ainsi permis de confirmer la place centrale de la protéine kinase AMPK dans la modulation via le métabolisme du devenir de la cellule souche musculaire dans un contexte de régénération du tissu musculaire squelettique dans un modèle murin
During muscle regeneration following injury, muscle stem cells, also called satellite cells,leave their quiescent state and activate. MuSCs are capable of both differentiating torepair muscle tissue after an injury and self-renewing to replenish the pool of stem cells.The regulation of their fate is modulated by several signaling pathways such as Wnt,Notch or TGFb pathway. However, there are few data concerning the involvement ofmetabolism in the fate of satellite cells. Yet it has been shown that the…
Advisors/Committee Members: Mounier, Rémi (thesis director).
Subjects/Keywords: Muscle; Régénération; Métabolisme; Myogenèse; AMPK; Muscle; Regeneration; Metabolism; Myogenesis; AMPK; 570
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Gsaier, L. (2018). Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis. (Doctoral Dissertation). Lyon. Retrieved from http://www.theses.fr/2018LYSE1208
Chicago Manual of Style (16th Edition):
Gsaier, Linda. “Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis.” 2018. Doctoral Dissertation, Lyon. Accessed June 24, 2019.
http://www.theses.fr/2018LYSE1208.
MLA Handbook (7th Edition):
Gsaier, Linda. “Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis.” 2018. Web. 24 Jun 2019.
Vancouver:
Gsaier L. Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis. [Internet] [Doctoral dissertation]. Lyon; 2018. [cited 2019 Jun 24].
Available from: http://www.theses.fr/2018LYSE1208.
Council of Science Editors:
Gsaier L. Rôle du métabolisme sur le devenir des cellules souches musculaires et l'homéostasie du muscle squelettique : Role of cell-autonomous regulation of metabolism on muscle stem cell fate and skeletal muscle homeostasis. [Doctoral Dissertation]. Lyon; 2018. Available from: http://www.theses.fr/2018LYSE1208
NSYSU
14.
Chen, Shin-yi.
The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer.
Degree: Master, Institute of Biomedical Sciences, 2011, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0809111-135626
► STK11/LKB1, a serine/threonine protein kinase, is a key upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary kinase in the control of metabolism for…
(more)
▼ STK11/LKB1, a serine/threonine protein kinase, is a key upstream kinase of adenine monophosphate-activated protein kinase (
AMPK), a necessary kinase in the control of metabolism for maintaining energy homeostasis. Although it has become clear that LKB1 is mutated in a significant number of PeutzâJeghers syndrome (PJS) and sporadic cancers, most frequently in adenocarcinoma of the lung, little is known about how the LKB1 signaling regulates the metabolic process and energy production underlying hypoxia and increased radiosensitivity of lung tumor. Here, we employed lung cancer cells as a model system to dissect the functional roles of LKB1 signaling in human lung adenocarcinoma. We found that LKB1 inhibits lung cancer cell migration, transformation and chemo-resistance in vitro after we restored LKB1 expression in LKB1 null A549 and H460 lung cancer cells. We also found that LKB1 prevents UV-induced DNA damage in human lung cancer cell lines by comet assay and activated UV-induced apopotsis by MTT assays. Furthermore, we designed a systems biology approach to provide a comprehensive protein-protein interaction analysis in order to elucidate the LKB1 tumor suppressor network in vivo. We employed Immunoprecipitation-HPLC- Mass Spectrometry (IP-LC-MS) to identify the novel proteins interacting with LKB1 under different cellular stress conditions. We have identified that LKB1 is involved in CFTR synthesis pathway underlying normoxia condition and participates in the glycolysis and gluconeogenesis pathways underlying hypoxia condition. Together, our findings indicated that LKB1 is involved in the regulation of cell migration, energy metabolism and DNA repair in lung cancer cells, and should provides insights to further exploit the concept of deranged cancer bioenergetics and aberrant growth signals to achieve more effective and selective strategies for lung cancer patients.
Advisors/Committee Members: Hong-wun Huang (chair), Kuang-Hung Cheng (committee member), Chang-Chun Hsiao (chair).
Subjects/Keywords: Wnt pathway; LKB1; AMPK; PJS; hypoxia
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APA (6th Edition):
Chen, S. (2011). The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0809111-135626
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Chen, Shin-yi. “The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer.” 2011. Thesis, NSYSU. Accessed June 24, 2019.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0809111-135626.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Chen, Shin-yi. “The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer.” 2011. Web. 24 Jun 2019.
Vancouver:
Chen S. The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer. [Internet] [Thesis]. NSYSU; 2011. [cited 2019 Jun 24].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0809111-135626.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Chen S. The role of LKB1 in the regulation of energetic checkpoints and DNA damage in the lung cancer. [Thesis]. NSYSU; 2011. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0809111-135626
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Gothenburg / Göteborgs Universitet
15.
Cansby, Emmelie.
Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25.
Degree: 2014, University of Gothenburg / Göteborgs Universitet
URL: http://hdl.handle.net/2077/35938
► Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder that has reached epidemic proportions globally, and is now considered to be one of the…
(more)
▼ Type 2 diabetes mellitus (T2DM) is a widespread metabolic disorder that has reached epidemic proportions globally, and is now considered to be one of the main threats to human health. The currently available treatment options in T2DM suffer from inadequate efficacy and durability, as well as liabilities, including hypoglycemia, weight gain, edema and gastrointestinal intolerance. Since the efficacy and patient compliance of existing treatments are in many cases unsatisfactory, there is a pronounced need for novel targets, which could complement current treatment.
Evidence accumulated during the last two decades indicates that excessive caloric intake and obesity lead to a chronic low-grade inflammation in metabolic tissues, and increased inflammation may be directly involved in the pathogenesis of T2DM. Therefore, novel pharmacological treatments targeting both the metabolic and inflammatory disruptions seen in T2DM are warranted.
AMP-activated protein kinase (AMPK) is a central master switch important for regulating energy homeostasis at cellular as well as whole body level. Recently, evidence for a role of AMPK in regulation of inflammatory balance has emerged. By using AMPK agonists AICAR and metformin in liver cell lines, primary hepatocytes and in mouse model system in vivo, we demonstrate that AMPK activation in liver leads to decreased inflammatory response to the proinflammatory cytokine IL-6. We further show that the anti-inflammatory action of AMPK was mediated via decreased phosphorylation of several downstream components of the canonical IL-6 receptor signalling pathway. Inhibition of the IL-6 signalling cascade in liver by AMPK supports a role of this kinase as a crucial point of convergence of metabolic and inflammatory pathways in hepatocytes.
Serine/threonine protein kinase 25 (STK25) is broadly expressed in mouse, rat and human tissues. When activated, this kinase is part of several cell processes, such as development, migration and apoptosis. We, for the first time, show that STK25 also has metabolic effects. By using small interfering RNA for Stk25 in rodent muscle cell line L6, we demonstrate that STK25 is involved in regulation of glucose uptake and lipid oxidation. Furthermore, mice overexpressing STK25, when challenged with a high-fat diet, develop reduced glucose tolerance and insulin sensitivity compared to wild-type siblings. Increased triglyceride deposition in liver and skeletal muscle, and adipocyte hypertrophy, as observed in Stk25 transgenic mice, suggest that the underlying cause of insulin resistance in conditions of excess dietary fuels is a shift in the metabolic balance from lipid oxidation toward lipid storage in peripheral tissues. Furthermore, Stk25 transgenic mice show increased infiltration of inflammatory cells in liver.
Taken together, both AMPK and STK25 emerge as interesting targets for future treatment of T2DM, enabling to target the dysregulation of both metabolism and inflammation seen in connection with this disease.
Subjects/Keywords: AMPK; STK25; Metabolism; Type 2 diabetes; Inflammation
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APA (6th Edition):
Cansby, E. (2014). Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25. (Thesis). University of Gothenburg / Göteborgs Universitet. Retrieved from http://hdl.handle.net/2077/35938
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Cansby, Emmelie. “Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25.” 2014. Thesis, University of Gothenburg / Göteborgs Universitet. Accessed June 24, 2019.
http://hdl.handle.net/2077/35938.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Cansby, Emmelie. “Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25.” 2014. Web. 24 Jun 2019.
Vancouver:
Cansby E. Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25. [Internet] [Thesis]. University of Gothenburg / Göteborgs Universitet; 2014. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/2077/35938.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Cansby E. Regulation of metabolism and inflammation by two protein kinases - AMPK and STK25. [Thesis]. University of Gothenburg / Göteborgs Universitet; 2014. Available from: http://hdl.handle.net/2077/35938
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Toronto
16.
Ehsan, Mehroz.
Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction.
Degree: 2015, University of Toronto
URL: http://hdl.handle.net/1807/71230
► Monocyte-derived microparticles (MPs) have been suggested to link cardiovascular risk factors to vascular injury. We hypothesized that adiponectin, an anti-inflammatory and vasculoprotective adipokine, limits the…
(more)
▼ Monocyte-derived microparticles (MPs) have been suggested to link cardiovascular risk factors to vascular injury. We hypothesized that adiponectin, an anti-inflammatory and vasculoprotective adipokine, limits the production and/or action of monocytic MPs on endothelial cells. Adiponectin attenuated MP release from untreated THP-1 monocytes and lipopolysaccharide (LPS)-treated conditions. Furthermore, peritoneal monocytes from Adipoq−/− mice generated significantly greater MPs than those from Adipoq+/+ littermates in the absence and presence of LPS. LPS-induced MP expression of NLRP3 inflammasome and its principal components, namely cleaved ASC, caspase-1, and IL-1β (pro- and cleaved), were all markedly attenuated by adiponectin treatment. HUVECs incubated with MPs from LPS-treated THP-1 cells exhibited an increase in the expression of VCAM-1; adiponectin inhibited this effect. The effects of adiponectin on MP release and molecular signaling occurred at least in part through modulation of the AMPK-Akt and NFκB pathways. The findings highlight another pleiotropic effect of adiponectin in limiting endothelial activation.
M.Sc.
2016-05-25 00:00:00
Advisors/Committee Members: Verma, Subodh, Medical Science.
Subjects/Keywords: Adiponectin; AMPK; inflammation; Microparticles; microvesicles; 0564
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APA (6th Edition):
Ehsan, M. (2015). Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction. (Masters Thesis). University of Toronto. Retrieved from http://hdl.handle.net/1807/71230
Chicago Manual of Style (16th Edition):
Ehsan, Mehroz. “Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction.” 2015. Masters Thesis, University of Toronto. Accessed June 24, 2019.
http://hdl.handle.net/1807/71230.
MLA Handbook (7th Edition):
Ehsan, Mehroz. “Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction.” 2015. Web. 24 Jun 2019.
Vancouver:
Ehsan M. Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction. [Internet] [Masters thesis]. University of Toronto; 2015. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/1807/71230.
Council of Science Editors:
Ehsan M. Role of Adiponectin in Monocytic Microparticle-Induced Endothelial Dysfunction. [Masters Thesis]. University of Toronto; 2015. Available from: http://hdl.handle.net/1807/71230
University of California – San Diego
17.
Lombardo, Portia Sachi.
Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis.
Degree: Biology, 2017, University of California – San Diego
URL: http://www.escholarship.org/uc/item/515006px
► Our laboratory recently identified the autophagy initiating kinase ULK1 as a novel AMPK substrate, which directly connects the highly conserved AMPK-mediated energy sensing pathway to…
(more)
▼ Our laboratory recently identified the autophagy initiating kinase ULK1 as a novel AMPK substrate, which directly connects the highly conserved AMPK-mediated energy sensing pathway to the regulation of autophagy. Genetic deletion of ULK1 led to an accumulation of mitochondria with abnormal morphology, supporting a role for ULK1 kinase activity in the maintenance of mitochondrial homeostasis, yet few mammalian ULK1 substrates have been identified beyond those involved in the canonical initiation of autophagy. Here we have identified and validated the E3 ligase Parkin, a known mediator of mitochondrial quality control and the most commonly mutated gene in autosomal recessive early-onset Parkinson’s disease, as a direct ULK1 substrate. ULK1-mediated phosphorylation of Parkin was required for maximal Parkin activity in multiple assays of Parkin function. These data reveal an important role for ULK1-mediated Parkin phosphorylation in the regulation of mitochondrial homeostasis, as this modification seems to prime Parkin for maximal activity following depolarization. Further studies using mouse models have indicated that Parkin is phosphorylated in vivo in mouse livers and primary hepatocytes in response to activators of the AMPK/ULK1 pathway, including Metformin, the most widely prescribed drug for the treatment of Type II diabetes. These data suggest the potential for profound in vivo relevance for the regulation of Parkin function downstream of the AMPK/ULK1 signaling cascade.
Subjects/Keywords: Molecular biology; AMPK; mitophagy; Parkin; ULK1
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lombardo, P. S. (2017). Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis. (Thesis). University of California – San Diego. Retrieved from http://www.escholarship.org/uc/item/515006px
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Lombardo, Portia Sachi. “Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis.” 2017. Thesis, University of California – San Diego. Accessed June 24, 2019.
http://www.escholarship.org/uc/item/515006px.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Lombardo, Portia Sachi. “Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis.” 2017. Web. 24 Jun 2019.
Vancouver:
Lombardo PS. Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis. [Internet] [Thesis]. University of California – San Diego; 2017. [cited 2019 Jun 24].
Available from: http://www.escholarship.org/uc/item/515006px.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Lombardo PS. Phosphorylation of Parkin by the autophagy initiating kinase ULK1 regulates mitochondrial homeostasis. [Thesis]. University of California – San Diego; 2017. Available from: http://www.escholarship.org/uc/item/515006px
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of California – Riverside
18.
Marin, Traci.
AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes.
Degree: Biochemistry and Molecular Biology, 2013, University of California – Riverside
URL: http://www.escholarship.org/uc/item/5z46r2s4
► Mitochondria serve to regulate energy and redox homeostasis, ultimately determining cell fate. While mitochondrial dysfunction is characteristic of many metabolic, cardiovascular and neurodegenerative diseases, AMP-activated…
(more)
▼ Mitochondria serve to regulate energy and redox homeostasis, ultimately determining cell fate. While mitochondrial dysfunction is characteristic of many metabolic, cardiovascular and neurodegenerative diseases, AMP-activated protein kinase (AMPK), an energy and stress sensor, is known to regulate mitochondrial biogenesis and function. This work is to study a novel mechanism by which AMPK regulates both energy and redox homeostasis through regulation of NAD+ synthetase 1 (NADSYN) and two epigenetic modulators, DNA methyltransferase 1 (DNMT1) and retinoblastoma binding protein 7 (RBBP7). This study combines bioinformatics screening and experimental validation to discover novel substrates of AMPK that are involved in energy and mitochondrial homeostasis in the cell.
Subjects/Keywords: Biochemistry; AMPK; chromatin; DNMT1; epigenetic; Mitochondria; transcription
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APA ·
Chicago ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Marin, T. (2013). AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes. (Thesis). University of California – Riverside. Retrieved from http://www.escholarship.org/uc/item/5z46r2s4
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Marin, Traci. “AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes.” 2013. Thesis, University of California – Riverside. Accessed June 24, 2019.
http://www.escholarship.org/uc/item/5z46r2s4.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Marin, Traci. “AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes.” 2013. Web. 24 Jun 2019.
Vancouver:
Marin T. AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes. [Internet] [Thesis]. University of California – Riverside; 2013. [cited 2019 Jun 24].
Available from: http://www.escholarship.org/uc/item/5z46r2s4.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Marin T. AMPK Targets Involved in Energy Homeostasis and Epigenetic Regulation of Mitochondrial Function-related Genes. [Thesis]. University of California – Riverside; 2013. Available from: http://www.escholarship.org/uc/item/5z46r2s4
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
19.
Shim, Hong Seok.
Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis.
Degree: PhD, Integrative and Evolutionary Biology, 2016, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/566322/rec/1984
► Dietary or calorie restriction has been a well‐studied strategy for increasing survival and preventing carcinogenesis in mammals. Short‐term starvation, an extreme form of dietary restriction,…
(more)
▼ Dietary or calorie restriction has been a well‐studied
strategy for increasing survival and preventing carcinogenesis in
mammals. Short‐term starvation, an extreme form of dietary
restriction, can augment cancer treatment efficacy and can be
effective in delaying cancer progression in the absence of
chemotherapy. However, the underlying molecular mechanisms of these
dietary interventions remain elusive. ❧ Here I describe REV1, a
specialized DNA polymerase involved in DNA repair, as an important
signaling node linking nutrient sensing and metabolic control to
cell fate in cancer cells. I have identified that REV1 is a novel
binding partner of the tumor suppressor p53 and regulates its
activity, and that short‐term starvation facilitates the
modifications of these proteins. Under starvation, REV1 is modified
by SUMO2/3, resulting in consequent relief of REV1’s inhibition of
p53 and enhancing p53 activation, pro‐apoptotic genes expression
and in turn p53‐mediated apoptosis in breast cancer and melanoma
cells. Thus, fasting through its effect on REV1 is a promising
non‐toxic strategy to increase p53‐dependent cell death and to
enhance the efficacy of cancer therapies. ❧ In addition, my study
reveals that
AMPK, PKA, and EGR1 are the molecular components of
functional signaling pathway that allows cardiomyocytes to sense
and react to nutrient availability.
AMPK activation and PKA
inhibition under glucose restriction and metformin treatment are
required to promote the induction of EGR1, an immediately early
response gene, and the expression of antioxidant and stress
resistance genes in cardiomyocytes. EGR1 has a consequent
cardioprotective function following doxorubicin treatment. This
study provides that short‐term starvation and metformin have a
protective role in doxorubicin‐induced cardiotoxicity through
AMPK/PKA-EGR1 pathway. ❧ In conclusion, this thesis provides
molecular evidence for short‐term starvation as the promising
intervention to exert differential effects in normal and cancer
cells, contributing to their protection and death in response to
stress, respectively. These data describe REV1 and EGR1 as the
important signaling nodes linking nutrient sensing and metabolic
control under starvation conditions.
Advisors/Committee Members: Longo, Valter D. (Committee Chair), Lee, Amy S. (Committee Member), Tower, John G. (Committee Member).
Subjects/Keywords: starvation; REV1; sumoylation; p53; EGR1; AMPK; PKA
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Shim, H. S. (2016). Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/566322/rec/1984
Chicago Manual of Style (16th Edition):
Shim, Hong Seok. “Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis.” 2016. Doctoral Dissertation, University of Southern California. Accessed June 24, 2019.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/566322/rec/1984.
MLA Handbook (7th Edition):
Shim, Hong Seok. “Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis.” 2016. Web. 24 Jun 2019.
Vancouver:
Shim HS. Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis. [Internet] [Doctoral dissertation]. University of Southern California; 2016. [cited 2019 Jun 24].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/566322/rec/1984.
Council of Science Editors:
Shim HS. Differential effects of starvation in normal and cancer
cells: from EGR1-dependent protection to p53-mediated
apoptosis. [Doctoral Dissertation]. University of Southern California; 2016. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/566322/rec/1984
20.
정, 종갑.
Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice.
Degree: 2016, Ajou University
URL: http://repository.ajou.ac.kr/handle/201003/13021
;
http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474
► PART 1. TM-25659-induced activation of FGF21 level decreases insulin resistance and inflammation in skeletal muscle via GCN2 pathways 1 Ⅰ. INTRODUCTION 2 Ⅱ. MATERIALS AND…
(more)
▼ PART 1. TM-25659-induced activation of FGF21 level decreases insulin resistance and inflammation in skeletal muscle via GCN2 pathways 1
Ⅰ. INTRODUCTION 2
Ⅱ. MATERIALS AND METHODS 8
A. MATERIALS 9
B. METHODS 10
1. Preparation of PA 10
2. Cell culture 10
3. Immunoblot analysis 11
4. RNA isolation and quantitative real-time polymerase chain reaction (PCR) 12
5. siRNAs 13
6. Uptake of 2-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino-2-deoxyglucose (2-NBDG) 14
7. Animal experiments 14
8. FGF21 secretion 15
9. IL-1β assay 15
10. Statistical analysis 15
Ⅲ. RESULTS 16
A. TM-25659 restored PA-induced insulin resistance and inflammation in skeletal muscle cells 17
B. TM-25659 increased FGF21 levels by GCN2 pathways in skeletal muscle cells 22
C. Effects of TM-25659 reduced insulin resistance and inflammation in skeletal muscle cells treated with or without FGF21 siRNA 27
D. TM-25659 prevented HF-diet induced obesity 31
E. TM-25659 restored the insulin signaling pathways in DIO mice skeletal muscle 33
F. TM-25659 lowered the muscle pro-inflammatory cytokine levels in DIO mice 35
G. TM-25659 regulates expression of both FGF21 mRNA and protein in DIO mice skeletal muscles 37
Ⅳ. DISCUSSION 38
Ⅴ. CONCLUSION 42
PART 2. Protective effects of TM-25659 on high-fat diet-induced insulin resistance in liver via AMPK pathways 44
Ⅰ. INTRODUCTION 45
Ⅱ. MATERIALS AND METHODS 52
A. MATERIALS 53
B. METHODS 54
1. Preparation of PA 54
2. Cell culture 54
3. Immunoblot analysis 54
4. RNA isolation and quantitative real-time polymerase chain reaction (PCR) 55
5. Animal experiments 56
6. Insulin tolerance tests 57
7. Glucose tolerance tests 57
8. Statistical analysis 57
Ⅲ. RESULTS 58
A. TM-25659 restored PA-induced reduction of insulin signaling pathway and induction of in flammation in HepG2 cells 59
B. TM-25659 increased AMPK and ACC phosphorylation in HepG2 cells 62
C. TM-25659 reduced PA-induced reduction of insulin signaling pathway in HepG2 cells 65
D. TM-25659 reduced PA-induced reduction of inflammation in HepG2 cells 67
E. TM-25659 improved glucose homeostasis and insulin sensitivity in DIO mice 69
F. TM-25659 restored the insulin signaling pathways in DIO mice liver 71
G. TM-25659 lowered the serum and liver pro-inflammatory cytokine levels in DIO mice 73
H. TM-25659 activated AMPK pathways in DIO mice liver 77
I. TM-25659 repressed serum lipid levels in HF-diet fed mice 79
J. TM-25659 prevented HF-diet induced hepatic steatosis 81
K. TM-25659 reduced expression of lipogenic genes but increased expression of fatty acid oxidation genes in HF diet-fed mice 83
Ⅳ. DISCUSSION 85
Ⅴ. CONCLUSION 88
REFERENCES 90
국문요약 108
Doctor
Advisors/Committee Members: 201225058, 정, 종갑.
Subjects/Keywords: TAZ; TM-25659; insulin resistance; FGF21; AMPK
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MLA ·
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Export
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APA (6th Edition):
정, . (2016). Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/13021 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
정, 종갑. “Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice.” 2016. Thesis, Ajou University. Accessed June 24, 2019.
http://repository.ajou.ac.kr/handle/201003/13021 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
정, 종갑. “Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice.” 2016. Web. 24 Jun 2019.
Vancouver:
정 . Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice. [Internet] [Thesis]. Ajou University; 2016. [cited 2019 Jun 24].
Available from: http://repository.ajou.ac.kr/handle/201003/13021 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
정 . Protective effect of TM-25659, known as TAZ activator, on high-fat diet-induced insulin resistance in C57BL/6J mice. [Thesis]. Ajou University; 2016. Available from: http://repository.ajou.ac.kr/handle/201003/13021 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000021474
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Virginia Tech
21.
Xu, Pingwen.
Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight.
Degree: PhD, Animal and Poultry Sciences, 2011, Virginia Tech
URL: http://hdl.handle.net/10919/37680
► This study was to determine (1) if genetic selection for high (HWS) or low (LWS) body weight in chickens has altered the hypothalamic AMP-activated protein…
(more)
▼ This study was to determine (1) if genetic selection for high (HWS) or low (LWS) body
weight in chickens has altered the hypothalamic AMP-activated protein kinase (
AMPK)
system and (2) if this alteration contributes to the dissimilar feeding response to various
appetite modulators between HWS and LWS lines. Compared to HWS, LWS chickens
had higher levels of
AMPK α and acetyl-CoA carboxylase (ACC) phosphorylation,
which was caused by upregulation of the upstream factor calcium/calmodulin-dependent
protein kinase kinase 2 (CAMKK β). There was greater mRNA expression of carnitine
palmitoyltransferase I (CPT1), leptin receptor (LEPR) and neuropeptide Y (NPY) and
less mRNA expression of ACC α, fatty acid synthase (FAS), fat mass and obesity
associated gene (FTO), pro-opiomelanocortin (POMC) and orexin in LWS than HWS
chickens. At 5 days of age, intracerebroventricular (ICV) injection of AICAR, 5-amino-
4-imidazolecarboxamide riboside, caused a quadratic dose-dependent decrease in food
intake in LWS but not HWS chicks. Compound C, (6-(4-(2-piperidin-1-yl-ethoxy)-
phenyl))-3-pyridin-4-yl-pyrazolo(1,5-a)-pyrimidine, caused a quadratic dose-dependent
increase in food intake in HWS but not LWS chicks. The anorexigenic effect of AICAR
in LWS chicks and orexigenic effect of Compound C in HWS chicks resulted from either
activation or inhibition of other kinase pathways separate from
AMPK. There is a lower
threshold for the anorexigenic effect of ghrelin in LWS than HWS chicks, which was
associated with differential hypothalamic
AMPK signaling. ICV injection of ghrelin
iii
inhibited corticotrophin-releasing hormone (CRH), 20-hydroxysteroid dehydrogenase
(20HSD), glucocorticoid receptor (GR), CPT1 and FTO expression in LWS but not HWS
chicks. Additionally, the hypothalamic mRNA level of ghrelin was significantly higher in
LWS than HWS chicks, which may also contribute to the differential threshold response
to ghrelin in these two lines. Obestatin caused a linear dose-dependent increase in food
intake in HWS but not LWS chicks. The orexigenic effect of obestatin in HWS chicks
was not associated with altered
AMPK. Obestatin inhibited LEPR and FTO expression in
HWS but not LWS chicks. Thus, selection for body weight may alter the hypothalamic
response to ghrelin by the
AMPK pathway, CRH pathway, CPT1 and FTO, and to
obestatin by LEPR and FTO.
Advisors/Committee Members: Denbow, Donald Michael (committeechair), Siegel, Paul B. (committee member), Wong, Eric A. (committee member), Denbow, Cynthia J. (committee member), Cline, Mark A. (committee member).
Subjects/Keywords: ghrelin; food intake; chicken; AMPK; obestatin
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APA (6th Edition):
Xu, P. (2011). Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight. (Doctoral Dissertation). Virginia Tech. Retrieved from http://hdl.handle.net/10919/37680
Chicago Manual of Style (16th Edition):
Xu, Pingwen. “Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight.” 2011. Doctoral Dissertation, Virginia Tech. Accessed June 24, 2019.
http://hdl.handle.net/10919/37680.
MLA Handbook (7th Edition):
Xu, Pingwen. “Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight.” 2011. Web. 24 Jun 2019.
Vancouver:
Xu P. Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight. [Internet] [Doctoral dissertation]. Virginia Tech; 2011. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/10919/37680.
Council of Science Editors:
Xu P. Involvement of AMP-activated protein kinase in differential regulation of appetite between lines of chickens selected for low or high juvenile body weight. [Doctoral Dissertation]. Virginia Tech; 2011. Available from: http://hdl.handle.net/10919/37680
University of Ottawa
22.
Al-Rewashdy, Hasanen.
Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
.
Degree: 2014, University of Ottawa
URL: http://hdl.handle.net/10393/31470
► Duchenne Muscular Dystrophy (DMD) results from the absence of a functional dystrophin protein. Among its possible therapeutic options is the upregulation of dystrophin’s autosomal analogue,…
(more)
▼ Duchenne Muscular Dystrophy (DMD) results from the absence of a functional dystrophin protein. Among its possible therapeutic options is the upregulation of dystrophin’s autosomal analogue, utrophin A. This can be achieved by a pharmacologically induced shift towards a slower, more oxidative skeletal muscle phenotype, which has been shown to confer morphological and functional improvements on models of DMD. Whether these improvements are a result of the utrophin A upregulation or other beneficial adaptations associated with the slow, oxidative phenotype, such as improved autophagy, has not been determined. To understand the importance of utrophin A to the therapeutic value of the slow, oxidative phenotype, we used the utrophin/dystrophin double knockout (dKO) model of DMD. We found the dKO mouse to have a similar skeletal muscle signaling capacity and phenotype to mdx mice. When treated with the adenosine monophosphate activated protein kinase (AMPK) agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), both dKO and mdx mice expressed a shift towards a slower, more oxidative phenotype. In the mdx mice, this shift caused improvements in muscle fiber central nucleation, IgM penetration, damage from eccentric contractions, and forelimb grip strength. These morphological and functional benefits were not seen in the AICAR treated dKO mice. This study highlights the importance of utrophin A upregulation to the benefits of the slow, oxidative myogenic program to dystrophic mice. It confirms utrophin A as a therapeutic target in DMD and the slow, oxidative myogenic program as clinically relevant avenue towards treatment of the disease.
Subjects/Keywords: Utrophin;
Duchenne Muscular Dystrophy;
Dystrophin;
AMPK;
AICAR
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APA (6th Edition):
Al-Rewashdy, H. (2014). Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
. (Thesis). University of Ottawa. Retrieved from http://hdl.handle.net/10393/31470
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Al-Rewashdy, Hasanen. “Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
.” 2014. Thesis, University of Ottawa. Accessed June 24, 2019.
http://hdl.handle.net/10393/31470.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Al-Rewashdy, Hasanen. “Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
.” 2014. Web. 24 Jun 2019.
Vancouver:
Al-Rewashdy H. Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
. [Internet] [Thesis]. University of Ottawa; 2014. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/10393/31470.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Al-Rewashdy H. Determining the Contribution of Utrophin A Versus Other Components of the Slow, Oxidative Phenotype in the Beneficial Adaptations of Dystrophic Muscle Fibers Following AMPK Activation
. [Thesis]. University of Ottawa; 2014. Available from: http://hdl.handle.net/10393/31470
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Edinburgh
23.
Mahmoud, Amira Dia.
The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body.
Degree: PhD, 2015, University of Edinburgh
URL: http://hdl.handle.net/1842/17886
► Ventilatory drive is mediated by respiratory central pattern generators that are located in the brainstem, which are continuously modulated by specialised peripheral and central chemoreceptors…
(more)
▼ Ventilatory drive is mediated by respiratory central pattern generators that are located in the brainstem, which are continuously modulated by specialised peripheral and central chemoreceptors to adjust ventilatory patterns according to changes in arterial PO2. These specialised oxygen-sensing chemoreceptors are activated in response to acute reductions in arterial PO2 and ultimately trigger a respiratory response that acts to restore oxygen-levels. However, the molecular mechanism by which mammals are able to regulate their breathing pattern in such a manner during hypoxia remains controversial. Therefore, the studies performed in this thesis aimed to investigate the possibility that this process may be mediated by the liver kinase B 1 (LKB1)/ AMP-activated protein kinase (AMPK) signalling pathway, which is central to cellular adaptations to metabolic stress. This first involved the development of transgenic mice in which Lkb1 or AMPK were deleted. Global knockout of Lkb1 (Sakamoto, 2006) or AMPK activity (Viollet et al., 2009) are embryonic lethal. Thus, the Cre/loxP system was used to develop transgenic mice that had either Lkb1 or both isoforms of the AMPK catalytic α- subunit (α1 and α2) conditionally knocked out in catecholaminergic cells (including therein hypoxia-activated cells of the brainstem and carotid body) by driving Cre expression through a tyrosine-hydroxylase-specific promoter region. The consequent effects on the ventilatory response to hypoxia were then examined using unrestrained whole-body plethysmography. This demonstrated that, in contrast to the hyperventilation evoked in controls, increased ventilation was virtually abolished in the Lkb1 and AMPK α1 and α2 double knockouts during hypoxia. Both knockout mice also exhibited periods of hypoventilation with frequent apnoeas during hypoxia. Additionally, studies on single AMPK α1 and AMPK α2 knockouts identified that the ventilatory dysfunction in AMPK α1 and α2 double knockouts was primarily caused by AMPK α1 deletion. In contrast, the severe ventilatory abnormalities exhibited during hypoxia following the deletion of Lkb1 and AMPK in catecholaminergic cells were mostly reversed upon exposure of mice to hypoxia with hypercapnia. Also, the ventilatory response to hypercapnia alone was without any major effect as a result of Lkb1 deletion or the dual-deletion of AMPK α1 and α2 catalytic subunits in catecholaminergic cells. This thesis therefore demonstrates, for the first time, that the LKB1-AMPK signalling pathway is key to respiratory adaptations during hypoxia, by regulating catecholaminergic oxygen-sensing cells, thus protecting against hypoventilation and apnoeas. The LKB1-AMPK signaling pathway can thereby determine oxygen and energy supply at both a cellular and whole-body level.
Subjects/Keywords: 616.2; hypoxia; Lkb1; AMPK; apnoeas; ventilatory response
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APA ·
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Manager
APA (6th Edition):
Mahmoud, A. D. (2015). The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/17886
Chicago Manual of Style (16th Edition):
Mahmoud, Amira Dia. “The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body.” 2015. Doctoral Dissertation, University of Edinburgh. Accessed June 24, 2019.
http://hdl.handle.net/1842/17886.
MLA Handbook (7th Edition):
Mahmoud, Amira Dia. “The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body.” 2015. Web. 24 Jun 2019.
Vancouver:
Mahmoud AD. The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body. [Internet] [Doctoral dissertation]. University of Edinburgh; 2015. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/1842/17886.
Council of Science Editors:
Mahmoud AD. The LKB1-AMPK signalling pathway drives the hypoxic ventilatory response by regulating brainstem nuclei but not the carotid body. [Doctoral Dissertation]. University of Edinburgh; 2015. Available from: http://hdl.handle.net/1842/17886
University of Minnesota
24.
Yan, Yan.
Regulation and Function of the Phosphatase PHLPP2 in Leukemia.
Degree: PhD, Pharmacology, 2017, University of Minnesota
URL: http://hdl.handle.net/11299/191472
► PHLPP2, a member of the PHLPP phosphatase family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little was…
(more)
▼ PHLPP2, a member of the PHLPP phosphatase family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little was known, however, regarding its regulation and function in hematological malignancies. The first half of this dissertation describes a novel miR-17~92-based mechanism for repression of PHLPP2 protein expression in late differentiation stage acute myeloid leukemia (AML) subtypes. ATRA (all-trans retinoic acid), a drug used for terminally differentiating AML subtypes, was able to induce PHLPP2 protein levels and phosphatase activity significantly by suppressing miR-17-92 expression. The effect of ATRA on miR-17~92 expression was mediated through its target, transcription factor C/EBP, which interacts with the intronic promoter of the miR-17~92 gene cluster to inhibit its transactivation. The second half of this dissertation provides evidence for a novel metabolic function for PHLPP2 and describes the first identification of the energy sensing kinase, AMPK, as a unique PHLPP2 substrate. PHLPP2 could dephosphorylate phospho-AMPK (T172) both intracellularly and in vitro. PHLPP2 silencing protected Jurkat T-ALL cells from an apoptotic response to low glucose-induced metabolic stress through activation of AMPK signaling. The pro-survival effect of PHLPP2 knockdown under metabolic stress is likely mediated through AMPK-activated fatty acid oxidation. PHLPP2 regulates AMPK phosphorylation in a variety of tumor types and is the first specific AMPK phosphatase to be identified. These studies on PHLPP2 expression and function expand current knowledge and understanding of the role of PHLPP phosphatases in cancer, and particularly in leukemia. In light of the pivotal role played by AMPK in a number of metabolic diseases, the PHLPP2/AMPK axis is also expected to provide new insights into therapies targeting these diseases.
Subjects/Keywords: AMPK; ATRA; leukemia; microRNA; PHLPP2; phosphatase
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Export
to Zotero / EndNote / Reference
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APA (6th Edition):
Yan, Y. (2017). Regulation and Function of the Phosphatase PHLPP2 in Leukemia. (Doctoral Dissertation). University of Minnesota. Retrieved from http://hdl.handle.net/11299/191472
Chicago Manual of Style (16th Edition):
Yan, Yan. “Regulation and Function of the Phosphatase PHLPP2 in Leukemia.” 2017. Doctoral Dissertation, University of Minnesota. Accessed June 24, 2019.
http://hdl.handle.net/11299/191472.
MLA Handbook (7th Edition):
Yan, Yan. “Regulation and Function of the Phosphatase PHLPP2 in Leukemia.” 2017. Web. 24 Jun 2019.
Vancouver:
Yan Y. Regulation and Function of the Phosphatase PHLPP2 in Leukemia. [Internet] [Doctoral dissertation]. University of Minnesota; 2017. [cited 2019 Jun 24].
Available from: http://hdl.handle.net/11299/191472.
Council of Science Editors:
Yan Y. Regulation and Function of the Phosphatase PHLPP2 in Leukemia. [Doctoral Dissertation]. University of Minnesota; 2017. Available from: http://hdl.handle.net/11299/191472
25.
Obba, Sandrine.
Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia.
Degree: Docteur es, Interactions moléculaires et cellulaires, 2015, Nice
URL: http://www.theses.fr/2015NICE4035
► La LMMC est une hémopathie est caractérisée par une monocytose persistante (>1.109/L) ainsi que par la présence anormale de granulocytes immatures dans le sang des…
(more)
▼ La LMMC est une hémopathie est caractérisée par une monocytose persistante (>1.109/L) ainsi que par la présence anormale de granulocytes immatures dans le sang des patients. Actuellement, il n’existe aucun traitement ciblé, il est donc essentiel de mieux caractériser et de comprendre les mécanismes qui causent cette monocytose afin d’établir de nouvelles stratégies thérapeutiques et de proposer des traitements ciblés. A partir de monocytes primaires humain stimulés par du CSF-1, nous avons observé que l’autophagie, est induite et qu’elle est dépendante des protéines Beclin1, ATG5, ATG7 et ULK1. Cette autophagie est également nécessaire à la différenciation macrophagique. Nous avons déterminé que l’AMP kinase (AMPK), est nécessaire à l’induction de l’autophagie et par conséquent à la différenciation macrophagique. Nous avons également découvert que le récepteur purinergique P2RY6 via la stimulation du CSF-1R active l’axe PLCβ3-CaMKKβ-AMPK-ULK1 conduisant à l’induction de l’autophagie nécessaire à la différenciation macrophagique. Enfin, dans le cadre de la LMMC, où la différenciation macrophagique est altérée, nous avons confirmé que la présence de granulocytes immatures est responsable de l’inhibition de l’axe P2RY6-AMPK. Dans ce contexte, nous avons observé que l’ajout d’agonistes du P2RY6 est capable d’une part de réinduire l’expression de l’AMPK et d’autre part de restaurer la différenciation macrophagique. L’ensemble de ces résultats souligne l’importance de l’induction du processus autophagique au cours de la différenciation macrophagique des monocytes mais également désigne l’axe P2RY6-AMPK comme cible thérapeutique potentielle dans le traitement de la LMMC.
CMML is a hematologic malignancy characterized by a persistent monocytosis (> 1.109/ L) and an abnormal presence of immature granulocytes in the blood of patients. Currently, there is no targeted therapy for this disease, so there is a real need to better understand the mechanisms leading to monocytosis in order to establish new therapeutic strategies and propose targeted treatments for CMML patients. From primary human monocytes, stimulated by CSF-1 to induce their differentiation into macrophages, we found that autophagy is induced during this process and is required for proper macrophagic differentiation. Then we were able to show that AMPK kinase (AMPK) is required for the induction of autophagy and therefore macrophage differentiation. We also found that the P2RY6 purinergic receptor via the CSF-1R stimulation, activate the PLCβ3-CaMKKβ-AMPK-ULK1 axis leading to the induction of autophagy, which is necessary for the macrophagic differentiation. Finally, in CMML context, where the macrophagic differentiation is impaired, we confirmed that the presence of immature granulocytes is responsible for the inhibition of AMPK P2RY6-axis. In this context, we observed that the addition of agonists P2RY6 is first capable of re-inducing the expression of AMPK and then restoring the macrophagic differentiation. All of these results emphasize the importance of…
Advisors/Committee Members: Auberger, Patrick (thesis director), Jacquel, Arnaud (thesis director).
Subjects/Keywords: Autophagie; Monocytes; Macrophages; AMPK; Différenciation cellulaire; Autophagy; Monocytes; Macrophages; AMPK; Cell differentiation
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APA (6th Edition):
Obba, S. (2015). Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia. (Doctoral Dissertation). Nice. Retrieved from http://www.theses.fr/2015NICE4035
Chicago Manual of Style (16th Edition):
Obba, Sandrine. “Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia.” 2015. Doctoral Dissertation, Nice. Accessed June 24, 2019.
http://www.theses.fr/2015NICE4035.
MLA Handbook (7th Edition):
Obba, Sandrine. “Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia.” 2015. Web. 24 Jun 2019.
Vancouver:
Obba S. Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia. [Internet] [Doctoral dissertation]. Nice; 2015. [cited 2019 Jun 24].
Available from: http://www.theses.fr/2015NICE4035.
Council of Science Editors:
Obba S. Caractérisation et implication de l'autophagie au cours de la différenciation macrophagique des monocytes. Application à la Leucémie Myélomonocytaire Chronique : Characterization and implication of autophagy during the macrophagic differentiation. Application to Chronic MyeloMonocytic Leukemia. [Doctoral Dissertation]. Nice; 2015. Available from: http://www.theses.fr/2015NICE4035
26.
Philippe, Chloe.
Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR.
Degree: Docteur es, Biologie cellulaire et physiopathologie, 2016, Bordeaux
URL: http://www.theses.fr/2016BORD0454
► L’AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) est un intermédiaire de la voie de biosynthèse des purines. A des concentrations importantes, ce métabolite a un effet cytotoxique sur les…
(more)
▼ L’AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) est un intermédiaire de la voie de biosynthèse des purines. A des concentrations importantes, ce métabolite a un effet cytotoxique sur les cellules cancéreuses aneuploïdes, c’est-à-dire contenant un nombre anormal de chromosome. Or,90% des tumeurs solides sont aneuploïdes. Les mécanismes responsables de cette cytotoxicité doivent donc être mieux étudiés pour une utilisation éventuelle en thérapie anti-cancéreuse.Dans la littérature, l’effet de l’AICAR est expliqué par son rôle mimétique de l’AMP sur l’AMPK.Cependant, certaines données de la littérature et du laboratoire laissent penser que l’inhibition de la croissance par l’AICAR peut impliquer plusieurs types de mécanismes dont certains sont dépendantsde l’AMPK et d’autres indépendants. L’identification des cibles de l’AICAR alternatives à l’AMPK estdonc nécessaire pour une meilleure compréhension de ses effets.Dans ce projet, j’ai pu confirmer la présence d’autres cibles de l’AICAR indépendantes de l’AMPKet responsables de son effet cytotoxique. Grâce à une approche transcriptomique, j’ai montré un effetde l’AICAR sur l’expression et l’activation de LATS1 et LATS2 (large tumor suppressor 1 and 2). Ces protéines kinases fond partie du core enzymatique de la voie HIPPO, dont le rôle en cancérologie est fondamental. Les effecteurs finaux de cette voie sont YAP et TAZ, deux cofacteurs de transcription,aussi régulés par l’AICAR. J’ai pu montrer que la cytotoxicité de l’AICAR est due en partie à l’activation de cette voie. Depuis la découverte récente de la voie HIPPO, de nombreuses études visent à identifier des molécules permettant l’inhibition directe de cette voie. L’AICAR s’avère être une molécule puissante dans le cadre d’une thérapie anticancéreuse ciblant la voie HIPPO.
AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide) is an intermediate of the purine biosynthesis pathway. At high concentrations, this metabolite has a cytotoxic effect on aneuploid cancer cells that is cells containing an abnormal chromosome number. However, 90% of solid tumorsare aneuploid. The mechanisms responsible for this cytotoxicity should be better studied for possible use in anti-cancer therapy.In the literature, the effect of AICAR is explained by its AMP mimetic role on the AMPK. However,some literature and laboratory data suggest that AICAR growth inhibition may involve several types of mechanisms, some of which are dependent and other independent of AMPK. Therefore, the identification of AMPK alternative targets is necessary for a better understanding the AICAR effects. In this project, I was able to confirm the presence of other AICAR targets independent of AMPK and responsible for its cytotoxic effect. Using a transcriptomic approach, I showed an effect of AICAR on the expression and activation of LATS1 and LATS2 (large tumor suppressor 1 and 2). These proteinkinases form part of the enzymatic nucleus of the HIPPO pathway, whose role in oncology is fundamental. The effectors of this pathway are YAP and TAZ, two…
Advisors/Committee Members: Moenner, Michel (thesis director).
Subjects/Keywords: AICAR; Voie HIPPO; Effets cytotoxiques; AMPK; AICAR; HIPPO pathway; Cytotoxic effect; AMPK
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APA ·
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Export
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APA (6th Edition):
Philippe, C. (2016). Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR. (Doctoral Dissertation). Bordeaux. Retrieved from http://www.theses.fr/2016BORD0454
Chicago Manual of Style (16th Edition):
Philippe, Chloe. “Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR.” 2016. Doctoral Dissertation, Bordeaux. Accessed June 24, 2019.
http://www.theses.fr/2016BORD0454.
MLA Handbook (7th Edition):
Philippe, Chloe. “Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR.” 2016. Web. 24 Jun 2019.
Vancouver:
Philippe C. Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR. [Internet] [Doctoral dissertation]. Bordeaux; 2016. [cited 2019 Jun 24].
Available from: http://www.theses.fr/2016BORD0454.
Council of Science Editors:
Philippe C. Modulation de la voie HIPPO par un métabolite aux propriétés anti-tumorales : l'AICAR : Modulation of the HIPPO pathway by a metabolite with anti-tumor properties : AICAR. [Doctoral Dissertation]. Bordeaux; 2016. Available from: http://www.theses.fr/2016BORD0454
Brigham Young University
27.
Merrill, John.
Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle.
Degree: MS, 2012, Brigham Young University
URL: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4482&context=etd
► To determine effects of iron deficiency on AMPK activation and signaling, as well as the AMPKα subunit composition in skeletal muscle, rats were fed a…
(more)
▼ To determine effects of iron deficiency on AMPK activation and signaling, as well as the AMPKα subunit composition in skeletal muscle, rats were fed a control (C=50-58 mg/kg Fe) or iron deficient (ID=2-6 mg/kg Fe) diet for 6-8 wks. Their respective hematocrits were 47.5% ± 1.0 and 16.5% ± 0.6. Iron deficiency resulted in 28.3% greater muscle fatigue (p<0.01) in response to 10 min of stimulation (1 twitch/sec) and was associated with a greater reduction in phosphocreatine (C: Resting 24.1 ± 0.9 micromol/g, Stim 13.1 ± 1.5 micromol/g; ID: Resting 22.7 ± 1.0 micromol/g, Stim 3.2 ± 0.7 micromol/g; p<0.01) and ATP levels (C: Resting 5.89 ± 0.48 micromol/g, Stim 6.03 ± 0.35 micromol/g; ID: Resting 5.51 ± 0.20 micromol/g, Stim 4.19 ± 0.47 micromol/g; p<0.05). AMPK activation increased with stimulation in muscles of C and ID animals. A reduction in Cytochrome c and other iron-dependent mitochondrial proteins was observed in ID animals (p<0.01). The AMPK catalytic subunit (alpha) was also examined because both isoforms are known to play different roles in responding to energy challenges. In ID animals, AMPK alpha2 subunit protein content was reduced to 71.6% of C (p<0.05), however this did not result in a significant difference in resting AMPK alpha2 activity. AMPK alpha1 protein was unchanged, however an overall increase in AMPK alpha1 activity was observed (C: 0.91 pmol/mg/min; ID: 1.63 pmol/mg/min; p<0.05). Resting phospho Acetyl CoA Carboxylase (pACC) was unchanged. This study indicates that chronic iron deficiency causes a shift in the expression of AMPK alpha subunit composition and potentially altered sensitivity to cellular energy challenges.
Subjects/Keywords: AMPK; AMPK alpha; iron deficiency; anemia; energy metabolism; skeletal muscle; Cell and Developmental Biology; Physiology
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APA (6th Edition):
Merrill, J. (2012). Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle. (Masters Thesis). Brigham Young University. Retrieved from https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4482&context=etd
Chicago Manual of Style (16th Edition):
Merrill, John. “Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle.” 2012. Masters Thesis, Brigham Young University. Accessed June 24, 2019.
https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4482&context=etd.
MLA Handbook (7th Edition):
Merrill, John. “Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle.” 2012. Web. 24 Jun 2019.
Vancouver:
Merrill J. Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle. [Internet] [Masters thesis]. Brigham Young University; 2012. [cited 2019 Jun 24].
Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4482&context=etd.
Council of Science Editors:
Merrill J. Iron Deficiency Causes a Shift in AMP-Activated Protein Kinase (AMPK) Catalytic Subunit Composition in Rat Skeletal Muscle. [Masters Thesis]. Brigham Young University; 2012. Available from: https://scholarsarchive.byu.edu/cgi/viewcontent.cgi?article=4482&context=etd
Université Paris-Sud – Paris XI
28.
Lissa, Delphine.
Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.
Degree: Docteur es, Oncologie, 2014, Université Paris-Sud – Paris XI
URL: http://www.theses.fr/2014PA11T019
► La tétraploïdie – cellule contenant le double du génome d’une cellule diploïde – est considérée comme un état métastable, à l’origine de l’aneuploïdie des cancers.…
(more)
▼ La tétraploïdie – cellule contenant le double du génome d’une cellule diploïde – est considérée comme un état métastable, à l’origine de l’aneuploïdie des cancers. Présentes dans les lésions précancéreuses, les cellules tétraploïdes sont associées à la progression tumorale. Etant donné le rôle clé de la tétraploïdie au cours de l’oncogenèse, le développement d’agents pharmacologiques éliminant spécifiquement les cellules tétraploïdes pourrait permettre de prévenir et limiter l’évolution vers un état cancéreux. Afin d'identifier des composés délétères pour les cellules tétraploïdes, nous avons développé une méthode de criblage basée sur la vidéomicroscopie à fluorescence automatisée. La chimiothèque de l'Institute of Chemistry and Cell Biology (ICCB) a été criblée, et nous avons mis en évidence plusieurs hits aux effets cytostatiques et/ou cytotoxiques préférentiels pour les cellules tétraploïdes. En raison de ses propriétés chimiopréventives, le resvératrol est le premier composé dont nous avons choisi de poursuivre la caractérisation. Sa sélectivité pour les cellules tétraploïdes a été confirmée sur différents types cellulaires, stables ou en cours de polyploïdisation. L’étude du mécanisme d’action anti-tétraploïde du resvératrol a permis d’identifier le senseur de la charge énergétique 5’-adenosine monophosphate-activated kinase (AMPK), comme une cible moléculaire responsable de la mort sélective des cellules tétraploïdes. Une série d’agents pharmacologiques activant directement ou indirectement AMPK – parmi lesquels l’aspirine et son métabolite le salicylate, dont l’action chimiopréventive a été établie par plusieurs études épidémiologiques et essais cliniques – a montré une toxicité préférentielle pour les cellules tétraploïdes. De la même manière que le resvératrol, ces agents éliminent les cellules tétraploïdes stables et limitent la polyploïdisation. Finalement, l’effet anti-tétraploïde du resvératrol et de l’aspirine a été évalué in vivo. L’administration orale de ces deux composés aux doses décrites comme chimiopréventives, réduit le développement des cellules épithéliales tétraploïdes et aneuploïdes des cryptes intestinales des souris ApcMin/+, le modèle murin de la polypose adénomateuse familiale. Collectivement les résultats de cette étude suggèrent que l’action chimiopréventive du resvératrol et de l’aspirine est associée à l’élimination des cellules tétraploïdes précurseur de tumeurs.
Tetraploidy – cells that contain twice the normal amount of chromosomes – is a metastable state leading to aneuploidy in cancer. Tetraploid cells have been observed in precancerous lesions and constitute a step toward tumor progression. Given the importance of tetraploidization for oncogenesis, developing drugs that selectively target tetraploid cells should prevent cancer.To discover compounds toxic to tetraploid cells, we developed an assay-system based on automatic fluorescence videomicroscopy. We screened the Institute of Chemistry and Cell Biology (ICCB) chemical library and identified several hits exerting a…
Advisors/Committee Members: Kroemer, Guido (thesis director).
Subjects/Keywords: Resveratrol; Aspirine; Tétraploïdie; AMPK; ApcMin/+; Chimioprévention; Cancer; Resveratrol; Aspirin; Tetraploidy; AMPK; ApcMin/+; Chemoprevention; Cancer
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Lissa, D. (2014). Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention. (Doctoral Dissertation). Université Paris-Sud – Paris XI. Retrieved from http://www.theses.fr/2014PA11T019
Chicago Manual of Style (16th Edition):
Lissa, Delphine. “Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.” 2014. Doctoral Dissertation, Université Paris-Sud – Paris XI. Accessed June 24, 2019.
http://www.theses.fr/2014PA11T019.
MLA Handbook (7th Edition):
Lissa, Delphine. “Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.” 2014. Web. 24 Jun 2019.
Vancouver:
Lissa D. Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention. [Internet] [Doctoral dissertation]. Université Paris-Sud – Paris XI; 2014. [cited 2019 Jun 24].
Available from: http://www.theses.fr/2014PA11T019.
Council of Science Editors:
Lissa D. Le resvératrol et l’aspirine éliminent les cellules tétraploïdes pour la chimioprévention du cancer : Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention. [Doctoral Dissertation]. Université Paris-Sud – Paris XI; 2014. Available from: http://www.theses.fr/2014PA11T019
Universidade Federal de Santa Maria
29.
Juliana Trevisan da Rocha.
EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES.
Degree: 2012, Universidade Federal de Santa Maria
URL: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=4965
► A menopausa caracteriza-se pela suspensão irreversível da função ovariana, com declínio da produção de hormônios estrogênicos. A falta desses hormônios culmina no aparecimento de alterações…
(more)
▼ A menopausa caracteriza-se pela suspensão irreversível da função ovariana, com declínio da produção de hormônios estrogênicos. A falta desses hormônios culmina no aparecimento de alterações metabólicas, cognitivas e comportamentais. Por essa razão, entender de que maneira a depleção de hormônios ovarianos contribui para o surgimento dos sintomas característicos da menopausa pode ser extremamente útil para o desenvolvimento de tratamentos alternativos à terapia de reposição hormonal. Nesse contexto, os dados aqui apresentados demonstram que ratas Wistar ovariectomizadas que foram tratadas com disseleneto de difenila [(PhSe)2] na dose de 5 mg/kg uma vez ao dia durante um período de 30 dias possuíam reduzidos níveis plasmáticos de triglicerídeos e aumentados níveis de HDL quando comparadas as ratas controle não ovariectomizadas. Além disso, a administração de (PhSe)2 foi capaz de reduzir o ganho de peso e o acúmulo de gordura abdominal nas ratas ovariectomizadas. Também foi observado que o tratamento com (PhSe)2 melhorou parâmetros hepáticos relacionados a estresse oxidativo nas ratas ovariectomizadas (níveis de ácido ascórbico e glutationa reduzida (GSH) e atividade das enzimas glutationa S-transferase e catalase). O tratamento com (PhSe)2 na dose de 5 mg/kg uma vez ao dia durante um período de 30 dias também melhorou o desempenho das ratas Wistar ovariectomizadas no teste do Labirinto Aquático de Morris, possivelmente por impedir o aumento da atividade da enzima acetilcolinesterase cerebral observado nas ratas ovariectomizadas. Dessa forma, os resultados sugerem um possível efeito benéfico do (PhSe)2 para o tratamento do declínio cognitivo associado a menopausa. Ainda com relação aos sintomas apresentados pelas mulheres durante a menopausa, dados da literatura mostram que a transição para a menopausa associa-se a um risco aumentado para o aparecimento de sintomas do tipo depressivos. Com base nisso, foi evidenciado que fêmeas ovariectomizadas de camundongos Swiss submetidas a um protocolo de estresse sub-crônico apresentavam aumento no tempo de imobilidade nos testes de Suspensão da Cauda e do Nado Forçado, ambos preditivos de comportamento do tipo depressivo.Também foi observado que esse prolongamento no tempo de imobilidade apresentado pelas fêmeas ovariectomizadas foi prevenido pelo tratamento com (PhSe)2 na dose de 10 mg/kg administrado 30 minutos antes de cada exposição ao protocolo de estresse. Além disso, evidenciou-se o envolvimento dos receptores de serotonina do tipo 5-HT2A/2C e 5-HT3 no efeito do tipo antidepressivo apresentado pelo (PhSe)2. Embora o (PhSe)2 tenha inibido a atividade de ambas isoformas da enzima monoamino oxidase (MAO-A e MAO-B) in vitro, não foi observada inibição da atividade de tais enzimas quando sua atividade foi determinada ex vivo. Com base nesses resultados sugere-se que o tratamento com (PhSe)2 pode influenciar aspectos relacionados ao humor e ao comportamento em mulheres no período pós-menopausa. No intuito de elucidar os mecanismos envolvidos no efeito hipocolesterolêmico do…
Advisors/Committee Members: Gilson Rogério Zeni, Vera Maria Morsch, Daniela Bitencourt Rosa Leal, Mauro Schneider Oliveira, Janine Inez Rossato.
Subjects/Keywords: disseleneto de difenila; episódios depressivos; prejuízo cognitivo; AMPK; dislipidemia; ovariectomia; CIENCIAS BIOLOGICAS; dyslipidemia; ovariectomy; AMPK; cognitive impairment; depressive state; diphenyl diselenide
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APA ·
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Export
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APA (6th Edition):
Rocha, J. T. d. (2012). EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES. (Thesis). Universidade Federal de Santa Maria. Retrieved from http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=4965
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Rocha, Juliana Trevisan da. “EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES.” 2012. Thesis, Universidade Federal de Santa Maria. Accessed June 24, 2019.
http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=4965.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Rocha, Juliana Trevisan da. “EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES.” 2012. Web. 24 Jun 2019.
Vancouver:
Rocha JTd. EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES. [Internet] [Thesis]. Universidade Federal de Santa Maria; 2012. [cited 2019 Jun 24].
Available from: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=4965.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Rocha JTd. EFEITOS FARMACOLÓGICOS DO DISSELENETO DE DIFENILA EM UM MODELO DE MENOPAUSA INDUZIDA POR OVARIECTOMIA EM ROEDORES. [Thesis]. Universidade Federal de Santa Maria; 2012. Available from: http://coralx.ufsm.br/tede/tde_busca/arquivo.php?codArquivo=4965
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
30.
김, 주미.
AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication.
Degree: 2015, Ajou University
URL: http://repository.ajou.ac.kr/handle/201003/11795
;
http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019519
► B형간염 바이러스(hepatitis B virus, HBV)는 Hepadnaviridae family에 속하며, genome 크기가 약 3.2kb의 작은 DNA 바이러스이다. 전 세계적으로 약 3억 5천만 명 이상이 만성으로 HBV에 감염되어…
(more)
▼ B형간염 바이러스(hepatitis B virus, HBV)는 Hepadnaviridae family에 속하며, genome 크기가 약 3.2kb의 작은 DNA 바이러스이다. 전 세계적으로 약 3억 5천만 명 이상이 만성으로 HBV에 감염되어 있다. HBV는 급성과 만성 B형 간염을 일으키며 만성 B형 간염 환자는 간경변이나 간암으로 발전할 가능성이 높다. AMP-activated protein kinase(AMPK)는 ATP 소비와 생성의 균형을 위해서 필요한 에너지 센서 단백질이다. Hepatitis C virus(HCV)의 증식을 위해서는 AMPK의 억제와mammalian target of rapamycin(mTOR)의 활성이 필요하며 이를 통해 바이러스 복제에 필요한 지질을 합성한다. HBV X 단백질(HBx)은 mTOR의 활성을 증가시켜 hepatocellular carcinoma(HCC) 세포의 증식을 유도한다. 본 연구에서는 HBV가 증식할 때 AMPK와 mTOR의 활성에 변화가 있는지 알아보았고, AMPK-mTOR 신호전달 과정의 변화가 HBV 증식에 영향을 미치는지 알아보고자 하였다. HCC 세포인 HepG2세포에서 유래한 HBV 가 증식하는 HepG2.2.15세포, PEB 세포와 Huh7세포에서 유래한 HBV 가 증식하는 Huh7 HBV WT stable 세포에서 AMPK의 발현과 인산화를 조사한 결과 세 가지 세포에서 AMPK의 인산화가 감소한 것을 밝혀냈다. HepG2.2.15세포, PEB세포와 Huh7 HBV WT stable 세포에서 mTOR 발현과 인산화가 증가하였다. HepG2.2.15 세포에서 AMPK의 인산화가 감소하였음에도 불구하고 regulatory-associated protein of mTOR(Raptor)와 tuberous sclerosis 2(TSC2)의 인산화는 증가하였다. HepG2.2.15세포에서 Akt 발현과 인산화가 증가하였다. Protein phosphatase 2A(PP2A), S6 kinase 1(S6K1)와 eukaryotic translation initiation factor 4E-binding protein 1(4E-BP1)의 발현과 인산화는 HepG2.2.15세포에서 증가하였다. Huh7 HBV WT stable 세포에서는 S6K1의 인산화, PP2A의 발현과 인산화가 증가하였다. AMPK alpha 2가 과발현 될 때 HBV의 core particle과 그 속의 핵산, HBV의 DNA가 감소하였다. HepG2.2.15 세포에 metformin을 처리하였을 때 AMPK의 인산화는 증가하였고 이에 따라Akt, mTOR, PP2A, S6K1 와 4E-BP1의 인산화도 줄어들었다. 그렇기 때문에 mTOR, Akt, PP2A, S6K1과 4E-BP1는 AMPK의 downstream으로 추정되었다. Rapamycin에 의해 HepG2.2.15 세포에서 mTOR의 인산화가 억제되었고 S6K1의 인산화 또한 감소되었다. 그리고 Akt의 인산화는 감소하였고 AMPK의 인산화는 증가하였다. 앞으로 Akt, mTOR, S6K1과 PP2A의 억제제를 처리함으로써 AMPK의 upstream과 mTOR의 downstream을 밝혀낼 것이다.
국문요약 ⅰ
차례 ⅲ
그림차례 ⅴ
Ⅰ. 서론 1
A. B형간염 바이러스 1
B. B형간염 바이러스 증식 2
C. AMPK 신호전달 과정 3
D. 연구목적 5
Ⅱ. 재료 및 방법 7
A. 세포 배양 7
B. HBV가 증식하는 stable 세포 구축 7
C. Sodium dodecyl sulfate-polyacrylamide gel(SDS-PAGE) electrophoresis 8
D. Western blotting 9
E. Reverse transcription polymerase chain reaction(RT-PCR) 10
F. HBV core particle 분석 12
G. HBV DNA 확인을 위한 Southern blotting 13
H. 억제제 혹은 활성제 처리에 의한 HBV 증식 변화 14
I. AMPK 과발현 벡터 제작 14
Ⅲ. 결과 16
A. HBV 증식 세포에서의 AMPK와 mTOR 발현 및 인산화 변화 16
B. HBV 증식 세포에서의 Raptor와 TSC2 발현 및 인산화 변화 18
C. HBV 증식 세포에서 Akt의 발현 및 인산화 변화 20
D. HBV 증식 세포에서 PP2A, S6K1과 4E-BP1 발현 및 인산화 변화 22
E. AMPK 과발현에 의한 AMPK 의 변화가 HBV증식에 미치는 영향 24
F. Metformin에 의한 AMPK-mTOR 신호전달 과정의 변화 26
G. Rapamycin에 의한 AMPK-mTOR 신호전달 과정의 변화 28
Ⅳ. 고찰 30
Ⅴ. 결론 32
참고문헌 34
ABSTRACT 44
Master
Advisors/Committee Members: 201324117, 김, 주미.
Subjects/Keywords: B형간염 바이러스; AMPK-mTOR 신호 전달과정; Akt PP2A; S6K1; 4E-BP1; HBV; AMPK-mTOR signal; Akt
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
김, . (2015). AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication. (Thesis). Ajou University. Retrieved from http://repository.ajou.ac.kr/handle/201003/11795 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019519
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
김, 주미. “AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication.” 2015. Thesis, Ajou University. Accessed June 24, 2019.
http://repository.ajou.ac.kr/handle/201003/11795 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019519.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
김, 주미. “AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication.” 2015. Web. 24 Jun 2019.
Vancouver:
김 . AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication. [Internet] [Thesis]. Ajou University; 2015. [cited 2019 Jun 24].
Available from: http://repository.ajou.ac.kr/handle/201003/11795 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019519.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
김 . AMP-activated protein kinase-mTOR signaling pathway and hepatitis B virus replication. [Thesis]. Ajou University; 2015. Available from: http://repository.ajou.ac.kr/handle/201003/11795 ; http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000019519
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
◁ [1] [2] [3] [4] [5] [6] [7] [8] ▶
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Open Access Theses and Dissertations