To see the other types of publications on this topic, follow the link: Forkhead Transcription Factors – metabolism.
Dissertations / Theses on the topic 'Forkhead Transcription Factors – metabolism'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Forkhead Transcription Factors – metabolism.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
St-Pierre, Jessica. "The role of CD4⁺ Foxp3⁺ naturally-occurring regulatory T cells in the host immune response to Plasmodium chabaudi AS /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111941.
Full textAbstract:
Naturally-occurring CD4+Foxp3+ regulatory T cells (nTreg) play a central role in maintaining immune self-tolerance as well as modulating immunity towards pathogens. Pathogens may establish chronic infections in immunocompetent hosts by engaging nT reg in order to promote immunosuppression. The goal of the research described here is to test the hypothesis that nTreg modulate protective immunity to malaria, and consequentially affect susceptibility to the parasite. To investigate this question, the functional dynamics of CD4+Foxp3 + nTreg cells were evaluated in mice infected with blood-stage Plasmodium chabaudi AS. Adoptive transfer of nTreg to infected wild-type C57BL/6 (B6) mice or infection of transgenic B6 mice over-expressing Foxp3 resulted in increased parasitemia and reduced survival compared to control mice. Moreover, while resistant B6 mice exhibited decreased splenic nT reg frequencies at day 7 post infection, susceptible A/J mice maintained high numbers of nTreg at this time. Investigation of the effects of nTreg regulation on immune cell function in P. chabaudi AS-infected mice revealed that increased nTreg frequencies led to decreased malaria-specific lymphoproliferation and increased systemic levels of IL-10. Unlike B6 mice, increased splenic nTreg frequencies in infected A/J mice correlated with decreased effector T cell proliferation and IFN-gamma secretion, decreased B cell and NK cell proliferation as well as deficient IFN-gamma secretion by NK cells. Finally, nTreg proliferated within infected sites in both B6 and A/J mice, albeit to a greater extent in susceptible A/J mice. Altogether, these results demonstrate that nTreg suppressed anti-malarial immunity, and in turn promoted parasite growth and persistence.
2
Greberg, Maria Hellqvist. "Cloning and characterization of FREACs, human forkhead transcription factors." Göteborg : Dept. of Cell and Molecular Biology, Göteborg University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39751934.html.
Full text
3
Chen, Xi. "The DNA-binding specificity of forkhead transcription factors." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/the-dnabinding-specificity-of-forkhead-transcription-factors(bc02fd29-30d0-47da-9b4f-448687504463).html.
Full textAbstract:
The healthy development of a living cell requires precise spatial-temporal gene expression. The code that dictates when and where genes are expressed is stored in a pattern of specific sequence motifs, which can be recognised by transcription factors. Understanding the interaction between these DNA sequence motifs and transcription factors will help to elucidate how genomic sequences build transcriptional control networks. However, the DNA-binding specificities of ~1400 human transcription factors are largely unknown. The in vivo DNA-binding events of transcription factors involve great subtlety, because most transcription factors recognise degenerate sequence motifs and related transcription factors often prefer similar or even identical sequences. Forkhead transcription factors exemplify these challenges. To understand how members within the Forkhead transcription factor family gain their binding and functional specificities, we used chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) to interrogate the genome-wide chromatin binding events of three Forkhead transcription factors: FOXM1, FOXO3 and FOXK2. We find that FOXM1 specifically binds to the promoters of a large array of genes whose activities peak at the G2 and M phases of the cell cycle. The canonical Forkhead consensus GTAAACA is not enriched within the FOXM1 cistrome. It gains its own specific binding events and biological functions by interacting and cooperating with the MMB complex. FOXO3 and FOXK2 are recruited to chromatin by the canonical Forkhead consensus GTAAACA, and they bind both shared and specific regions in the genome. FOXO3 mostly binds to the regions which are also bound by FOXK2, but no competitive or assisted binding between FOXO3 and FOXK2 is detected within those regions. Overall, these results help explain how individual members of the Forkhead transcription factor family gain binding specificity within the genome yet raises new questions of how functional specificity is achieved by other family members.
4
何明孝 and Ming-how Ho. "Sequence variation and covariation in forkhead domains." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970552.
Full text
5
Ho, Ming-how. "Sequence variation and covariation in forkhead domains." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25155283.
Full text
6
Karadedou, Christina Theano. "Forkhead transcription factors in the regulation of VEGF in breast cancer." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/7113.
Full textAbstract:
High levels of the major angiogenic factor VEGF, have been reported in a number of cancer cell lines and in clinical specimens derived from breast. The forkhead transcription factors important for the regulation of many different physiological processes have been implicated in VEGF regulation in breast cancer. In this study, we have shown the interplay between FOXO3a and FOXM1 in breast cancer, with FOXO3a acting as a direct transcriptional repressor of VEGF. The mode of action of FOXO3a on the promoter of VEGF is dictated by events such as the competition with the VEGF transcriptional activator FOXM1, and the subsequent recruitment of a FOXO3a/HDAC2 complex on the exact binding site. This action results in the repression of VEGF transcription and the decrease of VEGF expression and cell migration. Mutating the putative forkhead responsive element affects promoter activity, and silencing FOXO3a results in up-regulation of VEGF expression. Apart overexpression of FOXO3a also results in the repression of FOXM1 expression, by its direct binding to the FOXM1 promoter. This event is also involved, indirectly, in the regulation of VEGF repression. Apart from FOXO3a and FOXM1, two other forkhead transcription factors that are implicated in breast cancer, FOXA1 and FOXC2, are also involved in the regulation of VEGF. FOXA1, a good prognosis factor in breast cancer, seems to inhibit the expression of FOXC2, a poor prognosis factor. FOXA1 is directly recruited on its binding site of the FOXC2 promoter, affecting its transcription and conferring a significantly low expression. Silencing FOXA1 results in high FOXC2 protein levels. The mode of action of these two factors between them affects the expression of VEGF. These findings provide information on the cross-talk between different forkhead transcription factors and a crucial factor of tumour migration, invasion, angiogenesis and metastasis.
7
Lopes, Jared Emery. "Amino terminal region of FOXP3 coordinates the regulation of transcriptional targets in regulatory and effector T cell lineages /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8354.
Full text
8
Stavrou, Emmanouil. "Regulation of FOXO transcription factors by gonadotropin-releasing hormone." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5686.
Full textAbstract:
G protein-coupled receptors (GPCRs) are a large family of trans-membrane receptors that transmit signals from extracellular stimuli to target intracellular signal transduction pathways. The gonadotropin-releasing hormone receptor (GnRH-R) is a GPCR which binds the decapeptide GnRH. In the pituitary gonadotrope, GnRH stimulates gonadotropin (LH and FSH) biosynthesis and secretion to regulate reproduction. GnRH and the GnRH-Rs are also present in many extra-pituitary tissues, although their role at these sites remains largely undetermined. GnRH-Rs are known to recruit a diverse array of signalling pathway mediators in different cell-types. These include; Gq/11-PLCβ-IP3/DAG-Ca2+/PKC signalling, monomeric G-proteins and integrins to mediate cell adhesion and migration, the activation of the major members of the mitogen-activated protein kinase (MAPK) super-family (extracellular signal-regulated kinase (ERK), c-Jun N-terminal Kinase (JNK) and p38MAPK), and β-catenin and other mediators of the canonical Wnt signalling pathway. This thesis describes the regulation of Forkhead Box O (FOXO) transcription factors by GnRH. The mammalian FOXO transcription factors, FOXO1, FOXO3a and FOXO4, are emerging as an important family of proteins that modulate the expression of genes involved in cell-cycle regulation, induction of apoptosis, DNA damage repair and response to oxidative stress. In this thesis, emphasis is placed on delineating the novel role of FOXO transcription factors in mediating two important and widely-researched areas of GnRH biology. Firstly, the role of FOXO transcription factors in mediating cell-growth inhibition in response to GnRH treatment is assessed in a heterologous HEK293/GnRH-R expressing cell line. Secondly, the role of transcription factors in regulating luteinising hormone-β (LHβ)-subunit expression is investigated in the LβT2 gonadotrope cell line. Activation of the GnRH-R can inhibit cell proliferation and induce apoptosis in certain tumour-derived cell lines. Several studies have reported that these events can occur as a result of changes in the expression profiles of specific cell-cycle regulatory and apoptotic genes, many of which are FOXO-target genes, including GADD45, FasL, p21Cip1 and p27Kip1. In this thesis, a role for FOXOs in targeting the expression of several of these genes in response to GnRH is assessed, highlighting a specific role for FOXO3a in mediating GADD45 and FasL expression. The signalling mechanisms through which FOXO3a regulates GADD45 expression in response to GnRH is also described. Finally, a stable FOXO3a-knock-down cell line was generated in order to further examine FOXO3a involvement in GnRH-induced cell-growth inhibition. GnRH is an essential regulator of the reproductive process by stimulating the synthesis of LH and FSH in pituitary gonadotropes, thereby regulating gametogenesis and steroidogenesis. Diverse signalling pathways have been reported to regulate LHβ-subunit expression in response to GnRH, including the ERK/JNK/p38MAPK cascades and factors such as Egr1, SF1 and β-catenin. In the second part of this thesis, the role of FOXOs in regulating LHβ-subunit expression in response to GnRH is described. The data presented suggests that GnRH can regulate LHβ-subunit expression through both indirect and direct FOXO3a-mediated mechanisms. Firstly, FOXO3a was found to regulate Egr1 expression to indirectly target LHβ-promoter activity. Secondly, a role for β-catenin as a FOXO3a co-factor to directly regulate LHβ-subunit expression, together with Egr1 and SF1, is also proposed. FOXO3a expression and sub-cellular localisation was assessed and demonstrated in LβT2 cells and in adult human male pituitary sections. The research presented in this thesis adds to the diversity of signalling pathways and mediators that GnRH can target in different cellular backgrounds in order to mediate a variety of cellular processes. The antiproliferative and apoptotic effects of GnRH on tumour-derived cell lines are well-documented, and this research highlights a novel role for FOXO3a in mediating these events. The regulation of gonadotropin synthesis remains an important topic of research, and the novel implication of FOXO3a in mediating LHβ-subunit expression adds further complexity to gonadotrope physiology.
9
Ching, Chi-yun Johannes, and 程子忻. "Transcriptional regulation of p16INK4a expression by the forkhead box transcription factor FOXM1." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29466192.
Full text
10
Carson, Bryan David. "Impaired T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8337.
Full text
11
Williams, Luke M. "The roles of the transcription factor Foxp3 in the development and maintenance of the regulatory T cell lineage /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8329.
Full text
12
Sivanandan, Kavitta. "Role of forkhead transcription factors in endocrine sensitive and resistant breast cancer cell lines." Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522211.
Full text
13
Rodríguez, Colman Maria José. "El factor transcripcional Hcm1 en la regulación del metabolismo oxidativo en Saccharomyces cerevisiae." Doctoral thesis, Universitat de Lleida, 2013. http://hdl.handle.net/10803/117207.
Full textAbstract:
Hcm1, es un factor transcripcional de la familia de los forkhead en Saccharomyces cerevisiae. Los factores forkhead se encuentran evolutivamente conservados, desde levaduras hasta humanos. En mamíferos estos factores regulan diversos procesos, entre ellos el ciclo celular, la supervivencia y la proliferación en respuesta a factores de crecimiento. Además, los factores FoxM, FoxO y sus ortólogos, participan en procesos como el envejecimiento y en enfermedades como el cáncer. Los estudios sobre Hcm1 en S. cerevisiae, indican que este factor es un regulador de la formación del spindle pole y de la expresión del cluster de genes necesarios en la fase S del ciclo celular. En el presente trabajo se estudió la regulación de Hcm1 sobre nuevos procesos celulares. En primer lugar, se demostró que Hcm1 regula positivamente la masa mitocondrial, el número de copias de ADN en esta organela y su actividad metabólica. Además, induce la metabolización de la glucosa favoreciendo el proceso oxidativo sobre la fermentación. Este cambio metabólico inducido por Hcm1, viene acompañado por una mayor resistencia celular al estrés. Además, se demostró que Hcm1 responde al estrés oxidativo aumentando su localización nuclear y su actividad transcripcional. Esta misma respuesta se observó cuando las células eran sometidas a restricción de glucosa o nitrógeno. En esta dirección estudiamos los mecanismos regulatorios de estas respuestas y se determinó que Sir2, una histona deacetilasa NAD+-dependiente relacionada con el envejecimiento y el silenciamiento genético, interacciona con Hcm1 y regula la respuesta a estrés de Hcm1. Paralelamente, analizamos la implicación de las vías AMPK y TOR/Sch9 en la regulación de Hcm1. De esta manera, demostramos que ambas vías son reguladoras de la respuesta de Hcm1 a restricción nutricional, ya que experimentos in vitro indicaron que Snf1 y Sch9 fosforilan Hcm1. El análisis de la expresión génica en la cepa salvaje y en el mutante hcm1, en diferentes puntos de la curva de crecimiento del cultivo, indicó que genes que se inducen durante esta cinética, y que están relacionados con el estrés y el metabolismo, son regulados por este factor. Los resultados obtenidos en este trabajo, permiten concluir que, además de su implicación en el ciclo celular, Hcm1 es un factor clave en la adaptación temprana de las células a la restricción nutricional y en la posterior entrada en fase diáuxica, a través de la inducción de metabolismo oxidativo mitocondrial y la respuesta a estrés.Hcm1 is a forkhead transcription factor in Saccharomyces cerevisae. The forkhead factors are evolutionary conserved from yeast to human. In mammals, these factors regulate different processes, among them, cell cycle, cell survival and cell proliferation in response to growth factors. Moreover, FoxO, FoxM and their orthologues have been related to the aging process and cancer. Studies on Hcm1 in S. cerevisae indicate that this factor is related to spindle pole dynamics and the regulation of the cluster of genes required during the S phase of the cell cycle. In this work we studied Hcm1 implication on novel cellular processes. First, we demonstrated that Hcm1 positively regulates mitochondrial mass, mtDNA copy and mitochondrial activity. In addition, Hcm1 favours oxidative metabolism of glucose over its fermentation. This metabolic shift, is accompanied by an increase in cellular stress resistance. In response to oxidative stress treatments, Hcm1 shifts to the nucleus and its transcriptional activity is activated. A similar Hcm1 response was observed when the cells were submitted to glucose or nitrogen restriction. Additionally, we analyzed the regulatory mechanisms behind these responses. We demonstrated that Sir2, a NAD+ dependent histone deacetylase involved in aging and genetic silencing, interacts with Hcm1 and regulates its response to oxidative stress. In parallel, we analyzed the role of AMPK and TOR/Sch9 pathways on Hcm1 regulation. In this context, we observed that both pathways regulate Hcm1 in response to nutrient restriction in vivo. Moreover, Snf1 and Sch9 phosphorylate Hcm1 in vitro. Gene expression analysis on wild type cells and in hcm1 mutant at different points along the growth curve, indicated that genes that are upregulated during this kinetic and are related to stress response and metabolism, are regulated by Hcm1. Taken together, our results indicate that Hcm1 not only regulates cell cycle dynamics, but is also a key factor in the early adaptation of the cells to nutrient deficiency and later, to the entry into the diauxic phase. This adaptation is mediated by Hcm1 induction of oxidative metabolism and stress response.
14
Soper, David Michael. "Interleukin-2 receptor and T cell receptor signaling in regulatory T cells /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8344.
Full text
15
Nissen, Jesper Klintø. "Control of regulatory T cell lineage differentiation by Foxp3." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609792.
Full text
16
林秀華 and Sau-wah Selma Lin. "Modulation of cyclin expression by over-expression of the forkhead boxtranscription factor FoxM1." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31224817.
Full text
17
Tong, Ho-kwan. "Functional regulation of the forkhead box M1 transcription factor by Raf/MEK/MAPK signaling." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37654597.
Full text
18
Tong, Ho-kwan, and 湯皓鈞. "Functional regulation of the forkhead box M1 transcription factor by Raf/MEK/MAPK signaling." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37654597.
Full text
19
Sather, Blythe Duke. "CD4+ Foxp3+ regulatory T cell homing & homeostasis /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/8343.
Full text
20
唐思慧 and See-wai Cindy Tong. "Over-expression of the forkhead box transcription factor foxM1 activates expression of the cyclin-dependent kinase inhibitorp16INK4a." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970795.
Full text
21
Tong, See-wai Cindy. "Over-expression of the forkhead box transcription factor foxM1 activates expression of the cyclin-dependent kinase inhibitor p16INK4a." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B2517647x.
Full text
22
Holford, Rachel. "MYB transcription factors and the control of secondary metabolism in tomato." Thesis, University of East Anglia, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302213.
Full text
23
Moose, Holly Elizabeth. "Intrinsic Mechanisms Governing Retinal Progenitor Cell Biology: Retinal Homeobox Transcriptional Regulation and the Function of Forkhead Transcription Factors During Eye Development." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1251827616.
Full text
24
Leung, Man-hong, and 梁文康. "Investigating the role of the forkhead box transcription factor FOXM1 against oxidative stress and DNA damage in human embryonic stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/208595.
Full text
25
Oh, Seung Wook. "Regulation of Life Span by DAF-16/Forkhead Transcription Factor in Caenorhabditis elegans: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/22.
Full textAbstract:
The insulin/IGF-1 signaling pathway plays a pivotal role in life span regulation in diverse organisms. In Caenorhabditis elegans, a PI 3-kinase signaling cascade downstream of DAF-2, an ortholog of the mammalian insulin and insulin-like growth factor-1 (IGF-1) receptor, negatively regulates DAF-16/forkhead transcription factor. DAF-16 then regulates a wide variety of genes involved in longevity, stress response, metabolism and development. DAF-16 also receives signals from other pathways regulating life span and development. However, the precise mechanism by which DAF-16 directs multiple functions is poorly understood.
First, in Chapter II, we demonstrate that JNK is a novel positive regulator of DAF-16 in both life span regulation and stress resistance. Our genetic analysis suggests that the JNK pathway acts in parallel with the insulin-like signaling pathway to regulate life span and both pathways converge onto DAF-16. We also show that JNK-1 directly interacts with and phosphorylates DAF-16. Moreover, in response to heat stress, JNK-1 promotes the translocation of DAF-16 into thc nucleus. Our findings define a novel interaction between the stress response pathway (JNK) and the master regulator of life span (DAF-16), and provide a mechanism by which JNK regulates longevity and stress resistance.
Next, in Chapter III, we focus on the downstream targets of DAF-16. Here, we used a modified chromatin immunoprecipitation (ChIP) method to identify direct target promoters of DAF-16. We cloned 103 target sequences containing consensus DAF-16 binding sites and randomly selected 33 targets for further analysis. The expression of majority of these genes is regulated in a DAF-16-dependent manner. Moreover, inactivation of more than 50% of these genes significantly altered DAF-16-dependent functions such as longevity, fat storage and dauer diapause. Our results show that the ChIP-based cloning strategy leads to greater enrichment of DAF-16 target genes, compared to previous studies using DNA micro array or bioinformatics. We also demonstrate that DAF-16 is recruited to multiple promoters to coordinate regulation of its downstream target genes.
In summary, we identified the JNK signaling pathway as a novel input into DAF-16 to adapt animals to the environmental stresses. We also revealed a large number of novel outputs of DAF-16. Taken together, these studies provide insight into the complex regulation by DAF-16 to control diverse biological functions and eventually broaden our understanding of aging.
26
Casadomé, Burriel Laura. "Transcription factors under the control of the yeast Hog1 MAPK." Doctoral thesis, Universitat Pompeu Fabra, 2005. http://hdl.handle.net/10803/7086.
Full textAbstract:
Yeast cells are exposed to a wide variety of environment stresses, among them changes in the osmotic conditions. An osmolar upshift leads to fast loose of intracellular water, so living cells have developed mechanisms to counteract this lost. In Saccharomyces cerevisiae changes in the osmotic conditions are sensed by the HOG pathway. The HOG pathway is a MAPK signalling pathway and the functional homolog of the stress activated MAPK JNK MAPK and p38 present in mammals. Because there is a high degree of conservation of these cascades, the HOG pathway is a good model to study osmotic adaptation processes.Recent reports have shown that the Hog1 MAPK can regulate several processes such as cell cycle control, metabolic adaptation or regulation of gene expression.
At the beginning of this work, the mechanisms by which the Hog1 MAPK was controlling gene expression were unclear because transcription factors under the control of the MAPK were not well characterized. Our goal was the identification of new transcription factors under the control of the MAPK. Therefore, we designed a genetic screen and selected clones from a multicopy genomic library that were able to induce the expression of Hog1 dependent genes in non stress conditions. One of these clones was the SMP1 gene. Smp1 encodes for a MEF2-like transcription factor. Its overexpression induced the expression of osmoresponsive genes such as STL1, whereas smp1 cells were defective in their expression. smp1 cells showed reduced viability upon osmotic shock. Smp1-Hog1 interaction was checked by coprecipitation. Moreover, Smp1 was phosphorylated upon osmotic stress in a Hog1-dependent manner and in vitro phosphorylation experiments showed that Hog1 phosphorylated Smp1 at the C-terminal region. This phosphorylation was important for Smp1 osmoadaptation functions.
Moreover Hog1 was implicated in cell adaptability to stationary phase through Smp1.
On the other hand, microarrays studies showed that HXT1 hexose transporter was upregulated upon an osmotic shock in a Hog1 dependent manner. Expression of the HXT1 gene, which encodes a low affinity glucose transporter in Saccharomyces cerevisiae, is induced in response to glucose by the general glucose induction pathway, involving the Snf3/Rgt2 membrane glucose sensors, the SCF-Grr1 ubiquitination complex and the Rgt1 transcription factor. In addition to the glucose signalling pathway, we have found that, regulation of HXT1 expression also requires the HOG pathway. Deletion of components on both pathways results in impaired HXT1 expression. Genetic analyses identified Sko1 as the transcription factor under the control of Hog1 that was modulating HXT1 expression.
Our studies here have shown that both Smp1 and Sko1 are transcription factors under the control of the MAPK.
27
Tebay, Lauren. "Investigating the role of transcription factors Nrf2 and Pparα in hepatic lipid metabolism during fasting." Thesis, University of Dundee, 2015. https://discovery.dundee.ac.uk/en/studentTheses/1b72ca52-bb47-4732-b18e-83e80ac6d3af.
Full textAbstract:
The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) controls the basal and inducible expression of a plethora of genes, predominantly those associated with oxidative stress response through its regulation of the glutathione and thioredoxin based antioxidant systems, and the maintenance of cellular redox homeostasis. While Nrf2 has long been studied in this context, it has more recently become apparent that the role of Nrf2 goes far beyond this narrow spectrum, including a clear role in the regulation of pathways involved in NADPH generation, gluconeogenesis, and lipid metabolism, although the true extent of the contribution of Nrf2 in vivo to many of these processes has yet to be fully elucidated. When the Nrf2 gene is disrupted, many genes involved in lipogenesis, which are known to be regulated by Pparα, are upregulated, indicating a potential role for Nrf2 in the repression of Pparα, a master regulator of hepatic lipid metabolism. The primary aim of this thesis was to further define the role of Nrf2 during metabolic stress and to determine the mechanism of action of such a function. Genetically altered animals of the genotypes WT, Nrf2-/-, Pparα-/- and Nrf2-/-/::Pparα-/- double knockout were utilised during the course of this study in an effort to tease apart the interactions of transcription factors Nrf2 and Pparα under acute and extended fasting conditions, when Pparα is strongly activated, to better understand their in vivo relationship. Data presented within this thesis demonstrate that during periods of extended fasting, Nrf2 serves to diminish the magnitude of gene induction mediated by Pparα in response to fasting. In Nrf2-/- animals during 48 hr fasting, the level of Pparα target gene expression is significantly higher, with corresponding lower plasma free fatty acid concentration than their WT counterparts. Upon genetic knockout of Pparα the target genes which were upregulated in the Nrf2-/- animals were not induced in response to fasting, indicating that their increased expression in response to fasting is solely regulated by Pparα. In order to further verify that the induction of these fasting-associated genes in the absence of Nrf2 was Pparα-dependent, animals null for both transcription factors were subjected to an extended fast and were shown not to support increased expression of the Pparα target genes despite the absence of Nrf2. Together, these data substantiate our hypothesis that under prolonged fasting conditions, the Pparα response is negatively regulated by Nrf2. Examination of gene induction at the more acute 24 hr time point revealed that Nrf2-/- animals showed similar expression levels of Pparα target genes as WT animals, in addition to exhibiting similar plasma free fatty acid concentrations as their WT counterparts, suggesting that the negative regulation of Pparα by Nrf2 reflects chronic biochemical changes. Additionally, it was demonstrated for the first time that robust activation of Nrf2 occurs in response to prolonged fasting, with highly significant induction of the prototypic Nrf2 target gene Nqo1. Importantly, this activation also occurred in the absence of Pparα, indicating that it is not via direct crosstalk between the transcription factors, nor is it a consequence of the generation of reactive oxygen species by the oxidation of fatty acids. In conclusion, this thesis describes data that provide further insight into the physiological role of Nrf2 in fatty acid metabolism. Future work is required to build upon this foundation and fully elucidate the signal(s) which leads to Nrf2 activation in response to prolonged periods of fasting.
28
Skogsberg, Josefin. "PPAR delta : its role in cholesterol metabolism /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-604-9.
Full text
29
Black, Markaisa. "FOX proteins as novel negative regulators of lung fibrosis and mitochondrial respiration." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530270199796482.
Full text
30
Skirycz, Aleksandra. "Functional analysis of selected DOF transcription factors in the model plant Arabidopsis thaliana." Phd thesis, Universität Potsdam, 2007. http://opus.kobv.de/ubp/volltexte/2008/1698/.
Full textAbstract:
Transcription factors (TFs) are global regulators of gene expression playing essential roles in almost all biological processes, and are therefore of great scientific and biotechnological interest. This project focused on functional characterisation of three DNA-binding-with-one-zinc-finger (DOF) TFs from the genetic model plant Arabidopsis thaliana, namely OBP1, OBP2 and AtDOF4;2. These genes were selected due to severe growth phenotypes conferred upon their constitutive over-expression.
To identify biological processes regulated by OBP1, OBP2 and AtDOF4;2 in detail molecular and physiological characterization of transgenic plants with modified levels of OBP1, OBP2 and AtDOF4;2 expression (constitutive and inducible over-expression, RNAi) was performed using both targeted and profiling technologies. Additionally expression patterns of studied TFs and their target genes were analyzed using promoter-GUS lines and publicly available microarray data. Finally selected target genes were confirmed by chromatin immuno-precipitation and electrophoretic-mobility shift assays. This combinatorial approach revealed distinct biological functions of OBP1, OBP2 and AtDOF4;2.
Specifically OBP2 controls indole glucosinolate / auxin homeostasis by directly regulating the enzyme at the branch of these pathways; CYP83B1 (Skirycz et al., 2006). Glucosinolates are secondary compounds important for defence against herbivores and pathogens in the plants order Caparales (e.g. Arabidopsis, canola and broccoli) whilst auxin is an essential plant hormone. Hence OBP2 is important for both response to biotic stress and plant growth.
Similarly to OBP2 also AtDOF4;2 is involved in the regulation of plant secondary metabolism and affects production of various phenylpropanoid compounds in a tissue and environmental specific manner. It was found that under certain stress conditions AtDOF4;2 negatively regulates flavonoid biosynthetic genes whilst in certain tissues it activates hydroxycinnamic acid production. It was hypothesized that this dual function is most likely related to specific interactions with other proteins; perhaps other TFs (Skirycz et al., 2007).
Finally OBP1 regulates both cell proliferation and cell expansion. It was shown that OBP1 controls cell cycle activity by directly targeting the expression of core cell cycle genes (CYCD3;3 and KRP7), other TFs and components of the replication machinery. Evidence for OBP1 mediated activation of cell cycle during embryogenesis and germination will be presented. Additionally and independently on its effects on cell proliferation OBP1 negatively affects cell expansion via reduced expression of cell wall loosening enzymes.
Summing up this work provides an important input into our knowledge on DOF TFs function. Future work will concentrate on establishing exact regulatory networks of OBP1, OBP2 and AtDOF4;2 and their possible biotechnological applications.Biologische Prozesse, wie beispielsweise das Wachstum von Organen und ganzen Organismen oder die Reaktion von Lebewesen auf ungünstige Umweltbedingungen, unterliegen zahlreichen Regulationsmechanismen. Besonders wichtige Regulatoren sind die sogenannten Transkriptionsfaktoren. Dabei handelt es sich um Proteine, die die Aktivität von Erbeinheiten, den Genen, beeinflussen. In Pflanzen gibt es etwa 2000 solcher Regulatoren. Da sie wichtige Kontrollelemente darstellen, sind sie von großem wissenschaftlichen und biotechnologischen Interesse. Im Rahmen der Doktorarbeit sollte die Funktion von drei Transkriptionsfaktoren, genannt OBP1, OBP2 und AtDOF4;2, untersucht werden. Sie wurden bei der Suche nach neuen Wachstumsregulatoren identifiziert. Als Untersuchungsobjekt diente die in der Öffentlichkeit kaum bekannte Pflanze Ackerschmalwand, lateinisch als Arabidopsis thaliana bezeichnet. Um die Funktion der Regulatoren zu entschlüsseln, wurden an der Modellpflanze genetische Veränderungen durchgeführt und die Pflanzen dann mit molekularbiologischen und physiologischen Methoden analysiert. Es zeigte sich, dass OBP1 an der Regulation der Zellteilung beteiligt ist. Alle Lebewesen sind aus Zellen aufgebaut. Gelingt es, die Zellteilung gezielt zu steuern, kann damit beispielsweise die Produktion von pflanzlicher Biomasse verbessert werden. Das OBP1-Protein übt auch einen Einfluss auf die Zellstreckung aus und beeinflusst auch auf diesem Wege das pflanzliche Wachstum. Die beiden anderen Proteine steuern Prozesse, die im Zusammenhang mit der Bildung von Pflanzeninhaltsstoffen stehen. OBP2 ist Teil eines zellulären Netzwerkes, dass die Synthese von sogenannten Glucosinolaten steuert. Glucosinolate kommen unter anderem in Broccoli und Kohl vor. Sie fungieren als Abwehrstoffe gegen Fraßinsekten. Einigen Glucosinolaten wird auch gesundheitsfördernde Wirkung zugesprochen. Das Protein AtDOF4;2 ist Komponente eines anderen Netzwerkes, dass die Bildung von Phenylpropanoiden steuert. Diese Substanzen haben strukturelle Funktion und spielen darüber hinaus eine Rolle bei der pflanzlichen Toleranz gegenüber tiefen Temperaturen. Mit der Doktorarbeit konnte das Wissen über die Transkriptionsfaktoren erheblich erweitert und die Grundlage für interessante zukünftige Arbeiten gelegt werden. Von großer Bedeutung wird es dabei sein, die Netzwerke, in die die Transkriptionsfaktoren eingebunden sind, noch besser zu verstehen. Dann wird es möglich sein, auch Teilnetzwerke gezielt zu beeinflussen, was für biotechnologische Anwendungen, beispielsweise bei der Präzisionszüchtung von nachwachsenden Rohstoffen, von zentraler Bedeutung ist.
31
Fu, Wei. "Regulation of FOXO stability and activity by MDM2 E3 ligase." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002222.
Full text
32
Jasinski, Jean Marie. "Simplification of the immunogenetics of type 1A diabetes through transgenic T cell receptor mouse models /." Connect to abstract via ProQuest. Full text is not available online, 2008.
Find full text
33
Rosenquist, Sara. "Plant sugar signaling : regulation of starch and fructan metabolism /." Uppsala : Dept. of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, 2007. http://epsilon.slu.se/200779.pdf.
Full text
34
Maynard, Craig Lueland. "IL-10-competent regulatory T cells development, phenotype and function /." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/maynard.pdf.
Full text
35
Waller, J. L. "Characterisation of transcription factors with potential roles in the circadian optimisation of Crassulacean acid metabolism in Kalanchoë fedtschenkoi." Thesis, University of Liverpool, 2015. http://livrepository.liverpool.ac.uk/3000503/.
Full textAbstract:
Crassulacean acid metabolism (CAM) is a metabolic adaptation of photosynthesis that is optimised via strict temporal regulation of its biochemistry by the circadian oscillator. CAM plants achieve high water use efficiency and thus thrive in seasonally dry regions unsuitable for C3 food crops such as rice or wheat. Climate change and the associated challenges of global food and energy security, mean that CAM research is currently of urgent and pressing need, as CAM may reveal methods for the generation of more water use efficient crops. The efficiency of CAM is optimised by the circadian clock, through the regulation of PHOSPHOENOLPYRUVATE CARBOXYLASE KINASE (PPCK) expression and nocturnal CO2 fixation, but the signalling pathway between the central clock and CAM has yet to be elucidated. Whole genome sequencing and detailed RNA-seq datasets for C3 and CAM leaves of the model CAM species Kalanchoë fedtschenkoi have enabled the discovery of novel genes that could function to link CAM to the circadian clock. Three CAM-induced and clock-controlled transcription factor (TF) genes were identified from the RNA-seq datasets: MYB-LIKE 439 (KfMYB439), CAM-INDUCED BZIP1 (KfCIB1) and CYCLING DOF FACTOR2 (KfCDF2). Both over-expressor and RNAi knockdown transgenic lines of K. fedtschenkoi were generated for each TF, facilitating the further elucidation of their biological functions. Over 200 transgenic lines were screened for altered expression levels, and changes to the dawn and dusk levels of key CAM metabolites: malate and starch. Four transgenic lines for each TF, two over-expressor and two RNAi lines, were used for detailed phenotypic analysis of CAM-associated traits. Transgenic perturbation of any one of the three TFs caused small but widespread changes to the transcript levels of core clock- and CAM-associated genes. KfMYB439 is a REVEILLE family TF related to the clock gene CIRCADIAN CLOCK ASSOCIATED1 (CCA1). Data revealed that KfMYB439 functioned close to the core circadian oscillator. Mis-regulation of KfMYB439 led to the perturbation of efficient dark CO2 fixation, reduced levels of starch and malate, and reduced productivity during drought. KfCIB1, was found to feed back to influence the core circadian clock as well as regulating CAM. In constant light conditions, KfCIB1 mis-expression led to perturbed timing of KfCCA1 and TIMING OF CAB1 (KfTOC1) . KfCIB1 mis-regulation also impacted on stomatal control. At dusk and dawn, large and rapid changes in stomatal conductance resulted in spikes of CO2. Mis-expression also resulted in small improvements in productivity in water-limited environments. KfCDF2 was found to function not only in the clock control of CAM, but also in the photoperiodic control of flowering time. In terms of CAM and the clock, KfCDF2 mis-expression caused changes to CCA1, TOC1 and PPCK expression, and arrhythmic CO2 fixation in constant conditions. It also impacted on water retention during drought, with both over-expressor and RNAi lines displaying higher succulence than the wild type lines after 90 days of drought. KfCDF2 over-expression in both K. fedtschenkoi and K. laxiflora caused constitutive flowering in long days, whereas wild type plants never flowered. Q-RT-PCR analysis of flowering pathway genes revealed that KfCDF2 over-expression impacted on transcript levels for CONSTANS (CO) and FLOWERING LOCUS T (FT); key proteins in the day-length dependent induction of flowering. Results suggested that all three TFs likely function in the circadian optimisation of CAM, although whether or not the often small effects were direct or indirect will require further work. Future Chromatin Immunoprecipitation and sequencing experiments will reveal the target genes regulated by these TFs, and the identification of other novel CAM-induced genes from the RNA-seq data, will allow the pathway between the circadian clock and CAM to be elucidated in much greater detail.
36
Meszter, Zsolt Roland. "Molecular characterisation of transcription factors with potential roles in the circadian regulation of Crassulacean acid metabolism in Kalanchoe fedtschenkoi." Thesis, University of Liverpool, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.539485.
Full text
37
Le, Thi Thu Giang [Verfasser]. "Characterization of transcription factors important for fatty acid and lipid metabolism in the phytopathogen Fusarium graminearum / Thi Thu Giang Le." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2011. http://d-nb.info/1237051223/34.
Full text
38
Lekgari, Goitsemang Lorato Portia. "Over-expressing ArabidopsisArabidopsis Myb transcription factors in Salvia stenophylla and sugarcane and development of micropropagation protocol for Salvia repens." Thesis, Stellenbosch : Stellenbosch University, 2015. http://hdl.handle.net/10019.1/98135.
Full textAbstract:
Thesis (MSc)--Stellenbosch University, 2015.ENGLISH ABSTRACT: Biotechnology is an important tool that is used to isolate and characterise genes. It is also used to produce clones that are genetically and phenotypically similar. Many Arabidopsis thaliana transcription factors have been isolated and characterised, but many have yet to be fully described. MYB proteins are members of a super-family of multifunctional transcription factors that can also interact with other transcription factors in the control of pathways. To date, more than 126 AtMYBs have been identified, but most have not been fully characterised, particularly in terms of the molecular role(s) they play in plants. Arabidopsis thaliana MYB3, MYB6, MYB7, MYB8 and MYB32 have been reported to be negative regulators of general phenylpropanoid metabolism. It has been reported that the five transcription factors mentioned above are likely to negatively regulate flavonoid biosynthesis, even though they may have different target genes. Studies on AtMYB13, AtMYB14 and AtMYB15 reported that they are likely regulators of general phenylpropanoid metabolism. The mentioned roles of the eight AtMYB transcription factors means that they can be manipulated in order to see what effect they have on primary and secondary metabolites in plants. The transcription factors ligated into the pUBI510-GRFCA vector were then used to transform sugarcane callus (Chapter 3). Sugarcane produces sucrose which makes up 70% of the sugar produced in the world, making sugarcane a commercially important and profitable plant. The sugarcane callus was transformed via particle bombardment. The transcription factors AtMYB3, AtMYB6, AtMYB7, AtMYB13 and AtMYB32 were successfully incorporated into the genomic DNA of the sugarcane callus. The data obtained for callus over-expressing AtMYB3, AtMYB13 and AtMYB32 on solid media and the callus in liquid media were contradictory (i.e callus on solid media producing more sucrose than the wildtype whereas the same transgenic line will poduce less sucrose that the wildtype in liquid media or vice versa). However, AtMYB13 transgenic lines produced more sucrose than the wildtype. Transgenic lines of AtMYB7 all produced less sucrose as compared to the wildtype both on solid and in liquid media. The transcription factors which resulted in increased production of starch when over-expressed were AtMYB7 and AtMYB13. The data obtained for AtMYB6 transgenic lines was highly inconsistent in lines grown on same media and across the two media. The effects of these transcription factors in the overall metabolism of the sugarcane callus, either on MSC3 solid or liquid media, could not be fully determined from the GC-MS analysis as there was no consistent phenotypic effect between different transgenic lines for any of the MYB transcription factors used. In Chapter 4, a micropropagation strategy was developed and phytochemicals and their biological activities were determined for the medicinal plant Salvia repens. Salvia plants have been found to be medicinally important due to the secondary metabolites, particularly the essential oils that they produce. The plant extracts have been found to have many biological activities such as antibacterial, anti-inflammatory, antioxidant and anticancer activities. Salvia repens was successfully germinated in vitro,with 60% germination being achieved in MS media containing 1x10-5 times diluted smoke water following scarification for 12 min in 75% (v/v) H2SO4. Success rates of 100% were achieved in the hardening off process when the seedlings were moved into the greenhouse. Germination of S. repens ex vitro was 100% in an autoclaved soil mixture of 1:1 (v/v) sand and vermiculite. Importantly the medicinal value of S. repens produced in vitro or ex vitro was not lost as the GC-MS metabolite analysis showed that the plants produced the chemicals that are medicinally important. Metabolite extracts of S. repens were for the first time reported to be active against fungi with MIC values lower than 1 mg/ml over 4-5 d period against four Fusarium spp. tested. Lastly (Chapter 5), transcription factors AtMYB6 and AtMYB13 were used to trasnform Salvia stenophylla via Agrobacterium-mediated transformation, in order to determine whether the over-expression of these transcription factors could up-regulate the production of medicinally and commercially important secondary metabolites in S. stenophylla. Whilst both A. tumefaciens and A. rhizogenes strains were utilised for the transformation procedure, transformation was only achieved using A. rhizogenes and no transformants could be generated from the A. tumefaciens-treated material. Transgenic hairy roots did not produce any of the medicinally important metabolites. The GC-MS analysis of the transgenic root material identified mainly sugars and other primary metabolites.
AFRIKAANSE OPSOMMING: Biotegnologie is 'n belangrike instrument wat gebruik kan word om gene te isoleer en te karakteriseer. Dit word ook gebruik om klone wat geneties en fenotipies identies is te produseer. Baie Arabidopsis thaliana transkripsiefaktore is al geïsoleer en gekarakteriseer, maar baie moet nog volledig beskryf word. MYB proteïene is lede van 'n super-familie van multifunksionele transkripsiefaktore wat ook interaksie het met ander transkripsiefaktore tydens die beheer van metaboliese weë. Tot op hede is meer as 126 AtMYBs geïdentifiseer, maar die meeste is nie volledig gekarakteriseer nie, veral nie ten opsigtigte van die molekulêre rol(le) wat hulle in plante speel nie. Arabidopsis thaliana MYB3, MYB6, MYB7, MYB8 en MYB32 is gevind om negatiewe reguleerders van algemene fenielpropanoied-metabolisme te wees. Daar is ook berig dat dié vyf transkripsiefaktore moontlik flavenoied-biosintese negatief kan reguleer, selfs al kan hulle verskillende teikengene hê. Studies op AtMYB13, AtMYB14 en AtMYB15 het berig dat hulle waarskynlik reguleerders van algemene fenielpropanoied-metabolisme is. Die genoemde rolle van die agt AtMYB transkripsiefaktore beteken dat hulle gemanipuleer kan word om te bepaal watter effek hulle op primêre en sekondêre metaboliete in plante het. Die transkripsiefaktore, wat in die pUBI510-GRFCA vektor geligeer was, is toe gebruik om suikerriet-kallus te transformeer (Hoofstuk 3). Suikerriet vervaardig sukrose wat tot 70% van die suiker wat in die wêreld geproduseer word opmaak. Dít maak suikerriet 'n kommersieel belangrike en winsgewende plant. Die suikerriet-kallus is getransformeer deur middel van partikel-bombardering. Die transkripsiefaktore AtMYB3, AtMYB6, AtMYB7, AtMYB13 en AtMYB32 was suksesvol in die DNA van die suikerriet-kallus opgeneem. Data wat verkry was vir kallus wat AtMYB3, AtMYB13 en AtMYB32 ooruitgedruk het op soliede media en kallus in vloeibare medium was teenstrydig (m.a.w. kallus op soilede media wat meer sukrose as die wildetipe op soliede media geproduseer het, terwyl dieselfde transgeniese lyn minder sukrose as die wildetipe geproduseer het in vloeibare medium, en anders om). Nietemin, het AtMYB13 transgeniese lyne meer sukrose geproduseer as die wildetipe. Transgeniese lyne van AtMYB7 het almal minder sukrose geproduseer as die wildetipem op beide soliede en vloiebare media. Die transkriopsiefaktore wat gelei het tot 'n styging in stysel produksie wanneer hulle ooruitgedruk was was AtMYB7 en AtMYB13. Data wat verkry is van die AtMYB6 transgeniese lyne was hoogs veranderlik in lyne wat op dieselfde medium gegroie was en oor die twee media. Die effek van hierdie transkripsiefaktore op die algehele metabolisme van die suikerriet-kallus, hetsy op MSC3 soliede of vloeibaremedia, kon egter nie van die GC-MS analise ten volle bepaal word aangesien daar geen konsekwente fenotipiese effek tussen die verskillende transgeniese lyne vir enige van die gebruikte MYB transkripsiefaktore was nie. In Hoofstuk 4 was ‘n mikropropagerings strategie ontwikkel. Fitochemikalieë en hul biologiese aktiwiteite was ook bepaal vir die medisinale plant Salvia repens. Salvia plante is gevind om medisinaal belangrik te wees as gevolg van die sekondêre metaboliete, veral die essensiële olies, wat hulle produseer. Dit is ook bevind dat die plant-ekstrakte baie biologiese aktiwiteite soos anti-bakteriese, anti-inflammatoriese, anti-oksidant en anti-kanker aktiwiteite het. Salvia repens is suksesvol ontkiem in vitro, met 60% ontkieming wat bereik is in MS media met 1x10-5 maal verdunde rook-water na insnyding vir 12 min in 75% (v/v) H2SO4. Suksessyfers van 100% was behaal in die afhardingsproses wanneer die saailinge na die glashuis verskuif was. Ontkieming van S. repens ex vitro was 100% in 'n geoutoklaveerde grondmengsel van 1:1 (v/v) sand en vermikuliet. Gewigtig het die medisinale waarde van S. repens wat in vitro of ex vitro geproduseer was nie verlore gegaan nie. Die GC-MS data metaboliete analise het aangetoon dat die plante die medisinaal belangrike chemikalieë geproduseer het. Metaboliet-ekstrakte van S. repens was vir die eerste keer na berig aktief teen swamme, met MIK waardes laer as 1mg/ml oor ‘n tydperk van 4-5 d, teen vier Fusarium spp wat getoets was. Laastens (Hoofstuk 5), transkripsiefaktore AtMYB6 en AtMYB13 was gebruik om Salvia stenophylla te transformeer deur Agrobacterium-bemiddelde transformasie, om sodoende te bepaal of die ooruitdrukking van hierdie transkripsiefaktore die produksie van medisinale en kommersieël-belangrike sekondêre metaboliete in S. stenophylla kan verhoog. Alhoewel beide A. tumefaciens en A. rhizogenes stamme gebruik was vir die transformasie proses, kon transformasie slegs deur die gebruik van A. rhizogenes bereik word. Geen transformante kon gegenereer word vanuit die A. tumefaciens behandelde materiaal nie. Transgeniese harigewortels het geen van die medisinaal belangrike metaboliete vervaardig nie. Die GC-MS analise van die transgeniese wortel materiaal het hoofsaaklik suikers en ander primêre metaboliete geïdentifiseer.
39
Park, Sungman. "AKT function and human oncogenesis." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001885.
Full text
40
Porquier, Antoine. "Etude des mécanismes de régulation du métabolisme secondaire chez Botrytis cinerea." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS480/document.
Full textAbstract:
Botrytis cinerea est un champignon nécrotrophe et polyphage capable de provoquer la pourriture grise sur plusieurs centaines d’espèces végétales. Les pertes engendrées par cette maladie sont importantes à travers le monde notamment sur des espèces économiquement importantes comme la tomate, la fraise ou encore la vigne. Parmi les facteurs de virulence identifiés chez B. cinerea se trouvent deux toxines non-hôte spécifiques. Il s'agit du sesquiterpène botrydial et du polycétide acide botcinique. Même si leur rôle redondant dans la nécrotrophie a été démontré, les mécanismes qui gouvernent l’expression des clusters responsables de leur synthèse (respectivement BOT et BOA) restent inconnus. Dans ce contexte, l’objectif de mon projet de thèse était de caractériser les différents mécanismes qui régulent le métabolisme secondaire chez B. cinerea. Je me suis particulièrement intéressé aux clusters BOT et BOA ainsi qu’à un troisième cluster (PKS7) qui, d’après le phénotype d’un mutant d’insertion (ADN-T), pourrait être impliqué dans la nécrotrophie. Grâce à la disponibilité du nouvel assemblage du génome de la souche modèle B05.10, un gène candidat codant un facteur de transcription (FT) putatif a pu être identifié à proximité du cluster BOT. La caractérisation de ce gène a permis de démontrer le rôle majeur de la protéine (BcBot6) dans l’activation des gènes Bcbot et la production subséquente de botrydial. De même, la caractérisation de Bcboa13, un gène codant un FT putatif présent au sein du cluster BOA, a permis de démontrer le rôle de régulateur positif de BcBoa13 envers les gènes Bcboa. A la différence des clusters BOT et BOA, le cluster PKS7 ne contient pas de gène codant pour un potentiel FT spécifique. Afin de confirmer le rôle du métabolite putatif produit par ce cluster et d’identifier sa structure chimique, l’inactivation du gène clé codant une PKS-NRPS (Bcpks7) a été réalisée et des analyses métaboliques ont été initiées. Finalement, la présence au sein des clusters BOT et BOA de nombreux transposons ayant subi des mutations de type RIP (Repeat-Induced Point mutations) ainsi que la position sub-télomérique des clusters BOA et PKS7 nous a amené à nous intéresser au rôle de la structure chromatinienne dans la régulation de ces clusters. Dans ce cadre, trois mutants délétés dans des gènes codant des modificateurs chromatiniens putatifs (les histones méthyltransférases BcDim-5 et BcKmt6 et la protéine hétérochromatinienne BcHp1) ont été générés. L’expression des gènes clés des clusters BOT, BOA et PKS7 chez les mutants Bcdim-5, Bchp1 et Bckmt6 suggère que différents mécanismes chromatiniens interviennent pour le contrôle des clusters BOT et BOA d’une part et du cluster PKS7 d’autre part. L’ensemble des résultats obtenus pendant cette thèse apporte une contribution majeure à la compréhension des mécanismes de régulation spécifiques mais aussi de ceux en lien avec la structure chromatinienne de la production de métabolites phytotoxiques impliqués dans la nécrotrophie chez B. cinereaBotrytis cinerea is a necrotrophic polyphagous fungus able to induce the gray mold disease on hundreds of plant species. The resulting losses are important worldwide notably on economically important crops such as tomato, strawberry or grapevine. Among the virulence factors identified in B. cinerea stand two non-host specific toxins: the sesquiterpene botrydial and the polyketide botcinic acid. Although their redundant role in necrotrophy has been shown, the mechanisms governing the clusters responsible for their synthesis (respectively BOT and BOA) remain unknown. In this context, the aim of my PhD project was to characterize the different mechanisms that regulate secondary metabolism in B. cinerea. I particularly focused on BOT and BOA clusters as well as on a third one (PKS7) which, according to the phenotype of an insertion-based mutant (T-DNA), could be involved in necrotrophy. Thanks to the newly assembled genome of the B05.10 wild type strain, a candidate gene encoding a putative transcription factor (TF) could be identified near the BOT cluster. The characterization of this gene allowed pointing out the major role of the protein (BcBot6) in the activation of Bcbot genes and in the subsequent botrydial production. Similarly, the characterization of Bcboa13, a putative TF-encoding gene present into the BOA cluster, allowed demonstrating the positive regulatory role of BcBoa13 on Bcboa genes. Unlike the BOT and BOA clusters, the PKS7 one does not contain any putative TF-encoding gene. In order to confirm the role of the putative metabolite produced by this cluster and to identify its chemical structure, the inactivation of the PKS-NRPS key enzyme-encoding gene (Bcpks7) was conducted and metabolic analyses were initiated. Finally, the presence of many RIP(Repeat-Induced Point mutations)-inactivated transposons within BOT and BOA clusters as well as the subtelomeric location of BOA and PKS7 clusters raised our interest about the role of chromatin structure on those clusters regulation. In this context, three mutants inactivated into putative chromatin modifiers encoding-genes (the histone methyltransferases BcDim-5 and BcKmt6 and the heterochromatin protein BcHp1) were generated. The expression analysis of the key genes of the BOT, BOA and PKS clusters suggests different chromatin-based mechanisms that intervene for the BOT and BOA cluster on one side and on the PKS7 cluster on another. Altogether, the results generated during this PhD project are a major contribution to the comprehension of pathway-specific as well as chromatin-based mechanisms that regulate the production of necrotrophy-involved phytotoxins by B. cinerea
41
區和盛 and Wo-shing Au. "Regulation of microsomal triglyceride transfer protein gene byinsulin: the involvement of MAPKerk cascadeand HNF-1." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31225615.
Full text
42
Slebe, Concha Juan Felipe 1981. "The FoxA1/FoxA2-LIPG axis regulates beast cancer growth through changes in lipid metabolism." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/299798.
Full textAbstract:
The Fox transcription factor family comprises FoxA1, FoxA2 and FoxA3, which regulate tissue development and metabolism. In breast cancer, FoxA1 together with estrogen receptor regulates tumor growth and luminal specification. However, it is still unclear whether other members of the FoxA family participate in breast cancer pathogenesis and whether they contribute to tumor metabolic dependence. Here we show that FoxA1 and FoxA2 expression is mutually exclusive across different human breast cancer cell lines. Although both transcription factors regulate different set of genes and biological responses, they promote in vitro and in vivo tumor growth through the expression of endothelial lipase (LIPG). LIPG is ubiquitously expressed across various breast cancer subtypes, as seen in human cell lines and primary tumors. Furthermore, it has the capacity to rescue the loss of FoxA factors regulating a network enriched in oncogenic and structural lipids known to mediate proliferation. These findings collectively reveal how the FoxA1/FoxA2-LIPG axis regulates a central hub of lipids required for the growth of breast cancer.La familia de factores de transcripción FoxA está compuesta por FoxA1, FoxA2 y FoxA3. Estos factores regulan el desarrollo y el metabolismo de diversos tejidos. En cáncer de mama, FoxA1 media la acción de estrógenos y andrógenos regulando la especificación y el crecimiento del subgrupo luminal. No obstante, aún es desconocida la participación de los otros miembros de la familia en el desarrollo tumoral o su posible función en la dependencia metabólica de éstos. En esta tesis se describió que la expresión de los factores de transcripción FoxA1 y FoxA2 es mutualmente exclusiva en diferentes líneas celulares de cáncer de mama humanas. A pesar de que FoxA1 y FoxA2 controlan diferentes programas génicos y diferentes respuestas biológicas, ambos promueven el crecimiento tumoral in vitro e in vivo regulando la expresión de la enzima lipasa endotelial (LIPG). LIPG se expresa ubícuamente en líneas celulares humanas y tumores primarios de diferentes subgrupos de cáncer de mama. Además, LIPG es capaz de rescatar la pérdida de los factores FoxA regulando una red de lípidos oncogénicos y estructurales que median proliferación. Estos hallazgos revelan colectivamente que el eje FoxA1/FoxA2-LIPG regula un nicho central de lípidos que son necesarios para el crecimiento de cáncer de mama.
43
Castillo, Andreo Esther. "Regulación por estrés oxidativo de la actividad del factor de transcripción Pap1 de Schizosaccharomyces pombe." Doctoral thesis, Universitat Pompeu Fabra, 2005. http://hdl.handle.net/10803/7089.
Full textAbstract:
Las especies reactivas del oxígeno (ROS), superóxido (O2o-), peróxido de hidrógeno (H2O2), y radical hidroxilo (OHo), se generan a partir de la reducción parcial del oxígeno molecular durante procesos metabólicos como la respiración o tras la exposición a ciertos agentes ambientales como las radiaciones UV. Estas ROS pueden reaccionar con biomoléculas como lípidos, proteínas y DNA e inactivar su función, por lo que las células han desarrollado actividades enzimáticas que se encargan de mantener niveles no-tóxicos de estos oxidantes. Se llama estrés oxidativo a la situación en la cual se produce un incremento en la concentración intracelular de ROS como consecuencia de un aumento en la generación o una disminución en la degradación de las mismas. En respuesta a estrés oxidativo, la célula activa rutas de señalización y factores de transcripción específicos que activan la expresión de proteínas antioxidantes encargadas de reestablecer los niveles redox intracelulares y de reparar los desperfectos causados por estos oxidantes. La levadura Schizosaccharomyces pombe es un organismo modelo ideal para el estudio de las respuestas a estrés oxidativo en las células eucariotas ya que posee sensores específicos a estrés oxidativo como el factor de transcripción Pap1 (pombe AP-1-like) y rutas de respuesta global a estrés, como las descritas en las células de mamífero, que son activadas por diferentes tipos de estrés. En el centro de esta ruta de respuesta global a estrés se encuentra la MAPK (Mitogen-activated protein kinase) Sty1.
El factor de transcripción Pap1, de localización citoplasmática basal, se acumula en el núcleo en respuesta a estrés oxidativo. Este cambio de localización subcelular es debido a la inhibición del exporte nuclear dependiente de Crm1, aunque se desconocía el mecanismo molecular utilizado por este factor de transcripción para sensar y responder a oxidantes como H2O2 y dietilmaleto (DEM). Los resultados obtenidos indican que H2O2 oxida de forma reversible dos residuos de cisteína de Pap1 induciendo, seguramente, la formación de un puente disulfuro intramolecular, mientras que, DEM actúa como un agente alquilante que modifica de forma irreversible los residuos de cisteína del dominio C-terminal de Pap1.
El gen que codifica para el factor de transcripción Pap1 fue aislado inicialmente como un gen que, en elevado número de copias, confería a las células un fenotipo de resistencia a ciertas drogas como estaurosporina. Esto es debido a que, tras acumularse en el núcleo en respuesta a estrés oxidativo, Pap1 activa la transcripción de genes implicados tanto en la respuesta antioxidante como en la resistencia a multidrogas. Todos aquellos genes que, al igual que pap1 fueron identificados por su implicación en la resistencia a multidrogas, codifican para proteínas que regulan la actividad del factor de transcripción Pap1. hba1 fue el único gen relacionado con resistencia a multidrogas, cuyo producto génico, una proteína con un dominio de unión a Ran (Ran-binding domain), Hba1, no había sido relacionado con la actividad de Pap1. Uno de los objetivos de mi trabajo experimental era el de determinar si Hba1 tenía un papel en la regulación de la actividad de Pap1.
Nuestros resultados indican que la proteína Hba1, localizada en el nucleoplasma de la célula, participa en el exporte nuclear mediado por Crm1 de ciertas proteínas como el factor de transcripción Pap1 y la MAPK Sty1, aunque no de otras como la proteína PKI. Por ello, la pérdida de función de Hba1, por sobreexpresión o deleción del gen hba1, induce la localización nuclear constitutiva de Pap1 y Sty1 en ausencia de estrés. Esta localización nuclear de Pap1 es suficiente para la activación transcripcional de sus genes diana. Por lo tanto, el fenotipo de resistencia aumentada a multidrogas de las cepas en las que se ha perdido la actividad de la proteína Hba1, es debido a la acumulación de Pap1 en el núcleo en condiciones de no-estrés.
44
Jain, Nitya. "Multifaceted Regulation of Peripheral T Cell Tolerance and Autoimmunity by FOXP3+ T Regulatory Cells: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/416.
Full textAbstract:
Adaptive immunity requires T cell responses to foreign pathogens to be counterbalanced with the need to limit collateral destruction of the host’s own tissues. Further, the presence of a substantial pool of lymphocytes capable of recognizing selfantigen in the periphery poses a threat to the maintenance of peripheral tolerance and prevention of autoimmunity. Regulatory T cells (Treg) that can suppress potentially self-reactive T cells are critical regulators of peripheral tolerance as well as initiation of immune responses. Treg cells employ several context-dependent mechanisms to establish regulation. In this thesis, we describe two distinct pathways of regulation used by Treg cells involving negative costimulation by CTLA-4 and immunomodulation by the morphogen, TGFβ.
CTLA-4 is a co-inhibitory receptor on T cells essential for maintaining T cell homeostasis and tolerance to self. CTLA-4 expression is induced in conventional T cells following activation, whereas it is constitutively expressed in regulatory FOXP3+CD4+ regulatory T cells. Mice lacking CTLA-4 develop an early onset, fatal breakdown in T cell tolerance. Whether this autoimmune disease occurs because of the loss of CTLA-4 function in regulatory T cells, conventional T cells, or both, is not known. We present evidence here that in addition to a critical CTLA-4 function in regulatory T cells, CTLA-4 in conventional T cells is also necessary for controlling the consequences of abnormal T cell activation. CTLA-4 expression in activated conventional T cells only in vivois unable to compensate for the impaired function of CTLA-4-less regulatory T cells that results in systemic lymphoproliferation, but it can prevent the aberrantly activated T cells from infiltrating and fatally damaging non-lymphoid tissues. These results demonstrate that CTLA-4 has a dual function in maintaining T cell homeostasis: CTLA-4 in regulatory T cells inhibits inappropriate naïve T cell activation and CTLA-4 in conventional T cells can prevent the harmful accumulation of inappropriately activated pathogenic T cells in vital organs.
In addition, we have identified Disabled-2 (Dab2), a TGFβ signaling intermediate, as a FOXP3 target gene that is expressed exclusively in Treg cells and is critical for in vitro and in vivo regulation by Treg cells. During T cell development, DAB2 is also expressed in a Foxp3-independent manner in thymic precursor cells, and acts as a sensor of TGFβ signals that is required for programming normal TGFβ responsiveness in T cell progenies. Naïve CD4+ T cells that differentiate from Dab2-deficient precursors favor Th17 cell generation at the expense of FOXP3+ Treg cells as a result of altered sensitivity to TGFβ. Importantly, retinoic acid can restore TGFβ signaling capacity of naïve CD4+ T cells generated from Dab2-deficient precursors, emphasizing the cooperative nature of retinoic acid and TGFβ signaling pathways in promoting Treg cell development and maintenance.
45
Ma, Qiuping. "Role of FoxO Factors as the Nuclear Mediator for PTEN-AR Antagonism in Prostate Cancer Cells." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002559.
Full text
46
Rafei, Moutih. "Fusokine design as novel therapeutic strategy for immunosuppression." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115882.
Full textAbstract:
The societal burden of autoimmune diseases and donor organ transplant rejection in developed countries reflects the lack of effective immune suppressive drugs. The main objective of my thesis was to develop novel fusion proteins targeting receptors linked to autoimmunity; strategies that will allow the suppression of autoreactive cells while sparing resting lymphocytes. Interleukin (IL) 15 has been demonstrated to exert its effects mainly on activated T-cells triggered via their T-cell receptor (TCR). Since we found that the fusion of granulocyte-macrophage colony stimulating factor (GMCSF) to IL15 - aka GIFT15 - paradoxically leads to aberrant signalling downstream of the IL15R and blocks interferon (IFN)-gamma secretion in a mixed lymphocyte reaction (MLR), we hypothesized to use this fusokine in proof-of-principle cell transplantation models and shown that GIFT15 can indeed block the rejection of allogeneic and xenogeneic cells in immunocompetent mice. Additionally, we found that ex vivo GIFT15 treatment of mouse splenocytes lead to the generation of regulatory B-cells (Bregs). These Bregs express high levels of MHCII, IL10 and are capable to block antigen (Ag)-presentation in vitro as third party bystander cells. Moreover, a single injection of these GIFT15-generated Bregs in mice with pre-developed experimental autoimmune encephalomyelitis (EAE) leads to long lasting remission of disease.Along those lines, we also found that mesenchymal stromal cells (MSCs) lead to the paracrine conversion of CCL2 to an antagonist form capable of specifically inhibiting plasma cells and activated Th17 cells. This mechanistic insight informed the design of a second class of suppression fusokine. Namely, the fusing of antagonist CCL2 to GMCSF - aka GMME1. We tested its potential use in autoimmune diseases such as EAE and rheumatoid arthritis (RA). We demonstrated that GMME1 leads to asymmetrical signalling and inhibition of plasma cells as well as Th17 EAE/RA-reactive CD4 T-cells. The net outcome of these pharmacological effects is the selective depletion of CCR2-reactive T-cells as demonstrated both in vitro and in vivo.
Overall, our data support the use of our fusion proteins as part of a powerful and specific immunosuppressive strategy either as directly injectable protein biopharmaceuticals or through the ex vivo generation of autologous Bregs in the case of GIFT15.
47
Rajareddy, Singareddy. "Studies of phosphatidylinositol 3 kinase (PI3K) signaling pathway in mammalian ovarian follicle activation and development." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1378.
Full text
48
Antunes, Barbara de Moura Mello [UNESP]. "Envolvimento do NF-kB e PPAR-gama na resposta inflamatória e metabólica em monócitos de pessoas com diferentes níveis de condicionamento físico na resposta ao exercício agudo de diferentes intensidades." Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/180349.
Full textAbstract:
Submitted by Barbara de Moura Mello Antunes (bah_tunes@hotmail.com) on 2019-01-04T18:20:43Z
No. of bitstreams: 1
TESE FINAL BARBARA ANTUNES_04.01.2019.pdf: 4372364 bytes, checksum: c7b051b59637595632437c162e348471 (MD5)Approved for entry into archive by ALESSANDRA KUBA OSHIRO ASSUNÇÃO (alessandra@fct.unesp.br) on 2019-01-04T18:55:48Z (GMT) No. of bitstreams: 1 antunes_bmm_dr_prud.pdf: 4372364 bytes, checksum: c7b051b59637595632437c162e348471 (MD5)
Made available in DSpace on 2019-01-04T18:55:48Z (GMT). No. of bitstreams: 1 antunes_bmm_dr_prud.pdf: 4372364 bytes, checksum: c7b051b59637595632437c162e348471 (MD5) Previous issue date: 2018-12-12
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
O estilo de vida sedentário associa-se com alterações no perfil lipídico, inflamação crônica de baixo grau e aumento do tecido adiposo. Frente a essa questão, levantamos a hipótese de que alterações inflamatórias e metabólicas favorecem a instalação e progressão de diversas alterações metabólicas, e estão diretamente envolvidas com aptidão cardiorrespiratória mensurada pelo consumo de oxigênio pico (baixo ou alto VO2pico). Sendo assim, o presente estudo buscou responder duas questões centrais divididas em duas etapas: ESTUDO I – avaliação das respostas metabólicas e inflamatórias periférica durante diferentes intensidades de esforço de acordo com o nível de condicionamento físico dos sujeitos; ESTUDO II – avaliação da resposta metabólica e inflamatória celular de acordo com o nível de condicionamento físico. Para o ESTUDO I foram recrutados 28 sujeitos saudáveis do sexo masculino (idade: 28,8±8,6 anos; peso: 75,8±9,9 kg; VO2pico: 50,5±8,8 mL.kg-1.min-1) que realizaram por 60 minutos ou até a exaustão voluntária três protocolos de exercício agudo em baixa (<60% VO2pico), moderada (60-75% VO2pico) e alta intensidade (>90% VO2pico). Em todas as sessões foram coletadas amostras de sangue pré, imediatamente após e 60 minutos após o término da sessão para a determinação das concentrações de citocinas (TNF-α, IL-6, IL-10, IFN-γ, PAI-1, adiponectina), hormônios (leptina e insulina) e parâmetros lipídicos (colesterol total, triacilglicerol, HDL-c e ácidos graxos livres). No ESTUDO I, observou-se que a sessão de esforço propiciou significantes modulações sobre TNF-α, IL-6, razão IL-6/IL-10, lactato e ácidos graxos, principalmente em alta intensidade; além de significantes correlações entre a produção de IL-10 durante o exercício com o nível de condicionamento físico, no sangue periférico e estimulado. Interessantemente, o exercício de alta intensidade foi capaz de aumentar as concentrações sistêmicas de PAI-1 imediatamente após a sessão. Parao ESTUDO II foram recrutados 22 sujeitos (idade: 25,8±5,7 anos; peso: 76,5±14,4 kg; VO2pico: 47,8±12,3 mL.kg-1.min-1) para avaliar a produção de citocinas e expressão gênica de marcadores associados com a atividade do PPAR-γ e NF-κB em monócitos tratados por 24h sobre a presença de lipopolissacarideo (ativador da via inflamatória TLR-4/NF-kB), rosiglitazona e GW9662 (agonista e antagonista de PPAR- γ, respectivamente). Observou-se a nível molecular que maiores concentrações de IL-6 são produzidas por monócitos de sujeitos de alto VO2pico enquanto maiores concentrações de IL-10 são produzidas em sujeitos de baixo VO2pico. Quando avaliada a expressão gênica de proteínas das vias de sinalização do PPAR-γ e NF-κB observou-se maior expressão de AMPK, TLR-4, PGC-1 e PPAR-γ no grupo de alto VO2pico. Sendo assim, conclui-se que o exercício físico em intensidades altas impõe importantes alterações metabólicas que favorecem a instalação do quadro antiinflamatório, entretanto tais adaptações periféricas são dependentes do nível de condicionamento físico, dado que indivíduos de maior aptidão cardiorrespiratória apresentam maior expressão de proteínas e receptores celulares que modulam positivamente a ativação do PPAR-γ e inibem a via inflamatória do NF-kB. Desta forma, indivíduos de alto condicionamento físico apresentam adaptações benéficas nos mecanismos celulares e moleculares que refletem nas respostas metabólicas e inflamatórias periféricas frente à prática de exercício físico.
Sedentary lifestyle is associated with changes on lipid profile, low-grade chronic inflammation and increased adipose tissue. In this line, we hypothesized that inflammatory and metabolic alterations favor the installation and progression of several metabolic disorders, and are directly involved with cardiorespiratory fitness (VO2peak uptake). Thus, the present study sought to answer two central questions divided into two steps: EXPERIMENT I - evaluation of the metabolic and inflammatory peripheral responses during different exercise intensities according to cardiorespiratory fitness; EXPERIMENT II - evaluation of cellular metabolic and inflammatory response according to the cardiorespiratory fitness. For EXPERIMENT I, 28 healthy male subjects were recruited (age: 28.8 ± 8.6 years, weight: 75.8 ± 9.9 kg, VO2peak: 50.5 ± 8.8 mL.kg-1.min-1) and performed for 60 minutes or until voluntary exhaustion three acute exercise protocols at low (<60% VO2peak), moderate (60-75% VO2peak) and high (> 90% VO2peak) intensities. In all sessions, blood sample was collected pre, immediately after exercise and 60 minutes after the end of each session to determine cytokine concentrations (TNF-α, IL-6, IL-10, IFN-γ, PAI-1, adiponectin), hormones (leptin and insulin) and lipid parameters (total cholesterol, triacylglycerol, HDL-c, and free fatty acids). In EXPERIMENT I, was observed that acute session provided significant modulations on TNF-α, IL-6, IL-6/IL-10 ratio, lactate and fatty free acids, mainly at high intensity; in addition, significant correlations was verified between IL-10 release during exercise and cardiorespiratory fitness in peripheral and stimulated-blood. Interestingly, high-intensity exercise was able to increase systemic concentrations of PAI-1 immediately after the session. For EXPERIMENT II, 22 subjects were recruited (age: 25.8 ± 5.7 years, weight: 76.5 ± 14.4 kg, VO2peak: 47.8 ± 12.3 mL.kg-1.min-1) to evaluate cytokine production and gene expression of markers associated with activation and/or inhibition of PPAR-γ and NF-κB in monocytes treated for 24h on the presence or absence of lipopolysaccharide (pro-inflammatory pathway activator by TLR-4/NF-κB), rosiglitazone and GW9662 (PPAR-γ agonist and antagonist, respectivetly). It was observed that higher concentrations of IL-6 are produced by monocytes of subjects with high VO2peak while higher concentrations of IL-10 are produced in subjects with low VO2peak. When the protein expression of PPAR-γ and NF-κB signaling pathways was evaluated, higher expression of AMPK, TLR-4, PGC-1 and PPAR-γ was observed in the high VO2peak group. Therefore, it is concluded that physical exercise at higher intensities imposes important metabolic changes that favor the installation of an antiinflammatory profile, however these peripheral adaptations are fitness-dependent, given that individuals with greater cardiorespiratory fitness have higher expression of proteins and cellular receptors that positively modulate the PPAR-γ activation and inhibit the NF-κB inflammatory pathway. In this sense, individuals with high physical fitness condition present beneficial adaptations in the cellular and molecular mechanisms that reflect in metabolic and inflammatory peripheral responses mediated by physical exercise practice.
FAPESP: 2014/08003-1
FAPESP (BEPE): 2016/12369-7
49
Fappi, Alan. "Efeitos do ácido graxo ômega-3 na prevenção da atrofia muscular induzida pela dexametasona." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-13012014-114428/.
Full textAbstract:
Várias condições podem estar associadas com a atrofia muscular, tais como inatividade, envelhecimento, septicemia, diabetes, câncer e uso de glicocorticoides. Todas estas condições levam a atrofia muscular através de mecanismos que incluem aumento da degradação proteica e/ou redução na síntese proteica, envolvendo pelo menos cinco sistemas: lisossomal, da calpaína, das caspases, metaloproteinases e o sistema ubiquitina-proteasoma (SUP). Glicocorticoides, tais como a dexametasona, acarretam atrofia muscular atuando em quase todos esses sistemas, com significante ativação do SUP e lisossomal, afetando uma importante via de trofismo muscular, a via do IGF-1/PI-3K/Akt/mTOR. Ácidos graxos poli-insaturados, como o Ômega-3 (ômega-3), têm sido utilizados de forma benéfica na atenuação da atrofia muscular que ocorre na septicemia e na caquexia associada ao câncer, no entanto, sua atuação sobre a atrofia muscular induzida por glicocorticoides ainda não foi avaliada. Objetivo: Avaliar se a suplementação do ácido graxo ômega-3 influenciaria o desenvolvimento da atrofia muscular induzida pela dexametasona em ratos. Metodologia: Vinte e quatro ratos Wistar suplementados e não suplementados com ômega-3 (40 dias) foram submetidos à administração de dexametasona subcutânea (5mg/Kg/dia) nos últimos 10 dias, formando assim quatro grupos: Controle (CT), dexametasona (DX), ômega3 e dexametasona+ômega3 (DX+ômega3). Através de estudo de comportamento motor, histológico, PCR em tempo real e Western Blotting foram avaliados respectivamente, o número de grandes e pequenos movimentos em campo aberto; a área de secção transversa das fibras musculares (fibras I, IIA e IIB); a expressão dos genes MyoD, Miogenina, MuRF-1, Atrogina-1 e Miostatina; e a expressão de proteínas relacionadas com a via do IGF-1/PI-3K/Akt/mTOR: Akt, GSK3beta, FOXO3a e mTOR, totais e fosforiladas. Resultados: A dexametasona produziu diminuição na quantidade de pequenos movimentos, atrofia muscular em fibras do tipo IIB e diminuição na expressão de P-Akt, P-GSK3ômega e P-FOXO3a/FOXO3a total. A suplementação com Ômega-3 não se mostrou eficaz na atenuação de tais alterações. Por outro lado, o Ômega-3 associado à dexametasona (grupo DX+3) induziu a maior expressão de atrogenes (MuRF-1 e atrogina-1) causando, adicionalmente, maior atrofia muscular em fibras do tipo I e IIA, além de menor expressão gênica de Miogenina. O Ômega-3 de forma isolada conduziu de forma significativa a maior expressão de Miostatina e MyoD, e de forma não significante elevou a expressão proteica de mTOR total e induziu menor ganho de peso corporal dos animais ao fim do estudo. Conclusão: A suplementação de Ômega-3 não foi capaz de atenuar as alterações comportamentais, atrofia muscular e perda de peso corporal causadas pela administração de dexametasona, levando por outro lado a maior atrofia das fibras musculares e aumento na expressão de atrogenes. Desta forma, este estudo sugere que suplementos alimentares usualmente considerados benéficos para saúde, tal como o ácido graxo Ômega-3, podem agir em interação com alguns medicamentos, como os glicocorticoides, potencializando seus efeitos colateraisMany conditions can be related to muscle atrophy, such as inactivity, aging, sepsis, diabetes, cancer, as well as, glucocorticoid treatment. All these conditions lead to muscle atrophy through mechanisms that include increase of protein degradation and/or decrease of protein synthesis involving at least five systems: lysossomal, calpain, caspases, metaloproteinases and ubiquitin proteasome system (UPS). Glucocorticoids, such as dexamethasone cause muscle atrophy acting in almost all of these systems, with a significant UPS activation and affecting an important pathway related to muscular trophism, IGF-1/PI-3k/Akt/mTOR pathway. Poly-unsaturated fatty acids, such as Omega-3 (omega-3), have been used beneficially to attenuation of muscle atrophy that occur in sepsis and cachexia related to cancer, however, its action in the glucocorticoid-induced muscle atrophy, has never been evaluated. Objective: Assess whether the omega-3 supplementation would influence the development of dexamethasone-induced muscle atrophy in rats. Methods: Twenty four Wistar rats supplemented and non-supplemented with omega-3 (40 days) were submitted to dexamethasone administration (5mg/kg/day) during the last 10 days, thus establishing 4 groups: control (CT), dexamethasone (DX), omega-3 and dexamethasone+omega-3 (DX+ omega-3). The amount of large and small movements in open field; muscle fiber cross sectional areas (I, IIA and IIB); MyoD, Myogenin, MuRF-1, Atrogin-1 and Myostatin gene expression; and protein expression of Akt, GSK3omega, FOXO3a and mTOR, total and phosphorylated forms were assessed, respectively, by: motor behavior testing, histological reactions, Real-time PCR and Western Blotting analysis. Results: Dexamethasone administration induced significant decrease of small motor movements, atrophy in type IIB muscle fibers and decrease of P-Akt, P-GSK3omega and P-FOXO3a/total FOXO3a expression. Omega-3 supplementation was not able to attenuate these changes. Instead, omega-3 associated to dexamethasone (DX+ omega-3 group) additionally induced higher muscle atrophy in type I, IIA muscle fibers, and reduced expression of Myogenin. The isolated use of Omega-3 led to a significant higher expression of Myostatin and MyoD, and a non-significant increase of total mTOR protein expression and less body weight gain at end of study. Conclusion: Supplementation of omega-3 was not able to attenuate motor behavioral changes, muscle atrophy and loss of body weight caused by dexamethasone administration, leading on the other hand to higher muscle fibers atrophy and increase in atrogenes expression. Therefore, this study suggests that food supplements, usually considered benefic to the health, such as Omega-3 fatty acid, may interact with some medications, such as glucocorticoids, potentiating its side effects
50
Hollenhorst, Peter C. "Evolutionarily conserved forkhead transcription factors, Fkh1p and Fkh2p, in the yeast Saccharomyces cerevisiae." 2002. http://www.library.wisc.edu/databases/connect/dissertations.html.
Full text