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Hivelin, Céline. "Étude des mécanismes de libération du propeptide de la sortiline et de ses effets sur l’homéostasie glucidique". Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4109/document.
Pełny tekst źródłaIn France, approximately 15% of the population is obese and this number keeps rising up every year. Obesity is a major cause of diabetes, inducing an increase of the number of fat-filled cells, called the adipocytes, and a peripheral insulin resistance. This increase of the number of adipocytes is associated with a decrease of sortilin expression, a transmembrane protein which is involved in the release of a propeptide (PE) in the blood circulation. Spadin, a synthetic PE analog, is known to modulate the potassium TREK-1 channel activity. Since, this channel is expressed in pancreatic beta cells which secrete insulin, a hormone involved in blood glucose regulation, spadin may play a role in glucose homeostasis. Consistent with this hypothesis, spadin improves glucose tolerance in mice, by stimulating insulin release. Spadin is a natural peptide derived from sortilin, which is known to control the glucose transporter Glut4 trafficking to the plasma membrane of adipocytes. This suggests that spadin may regulate glucose storage in adipocytes by affecting the sortilin function. However, my results show that spadin has no effect on glucose storage. In summary, spadin is involved in insulin secretion and glucose homeostasis and may be an alternative treatment against obesity and diabetes
Hivelin, Céline. "Étude des mécanismes de libération du propeptide de la sortiline et de ses effets sur l’homéostasie glucidique". Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4109.
Pełny tekst źródłaIn France, approximately 15% of the population is obese and this number keeps rising up every year. Obesity is a major cause of diabetes, inducing an increase of the number of fat-filled cells, called the adipocytes, and a peripheral insulin resistance. This increase of the number of adipocytes is associated with a decrease of sortilin expression, a transmembrane protein which is involved in the release of a propeptide (PE) in the blood circulation. Spadin, a synthetic PE analog, is known to modulate the potassium TREK-1 channel activity. Since, this channel is expressed in pancreatic beta cells which secrete insulin, a hormone involved in blood glucose regulation, spadin may play a role in glucose homeostasis. Consistent with this hypothesis, spadin improves glucose tolerance in mice, by stimulating insulin release. Spadin is a natural peptide derived from sortilin, which is known to control the glucose transporter Glut4 trafficking to the plasma membrane of adipocytes. This suggests that spadin may regulate glucose storage in adipocytes by affecting the sortilin function. However, my results show that spadin has no effect on glucose storage. In summary, spadin is involved in insulin secretion and glucose homeostasis and may be an alternative treatment against obesity and diabetes
Daziano, Guillaume. "Rôle du propeptide de la sortiline et de ses dérivés dans les mécanismes de survie de la cellule bêta pancréatique". Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ6025.
Pełny tekst źródłaIn 2019, the International Diabetes Federation revealed that nearly 500 million people have diabetes worldwide. It is estimated that this incidence will reach 700 million people by 2045. In addition to the financial aspect of treatment, diabetes is a real public health issue. Indeed, the deleterious hyperglycemic environment associated with diabetes is could induce serious complications, leading to a functional alteration of many organs such as the heart, the brain or the kidney. Insulin resistance associated with the deterioration of insulin secretion and the loss of pancreatic beta cell mass are the main characteristics of type 2 diabetes. Thus, in order to improve the management of diabetic patients, the identification of a controlled therapeutic approach to protect beta cell mass and promote insulin secretion only in response to glucose and without side effects, appears ideal.The laboratory has identified the endogenous PE and its synthetic derivatives Spadin and Mini-Spadin as selective inhibitors of TREK-1 potassium channels. By this mechanism, the peptides showed also a strong antidepressant potential by modulating serotonin secretion, neuronal proliferation and survival. At the peripheral level, Spadin has been described in vitro and in vivo as a peptide with an incretin effect comparable to that of exendin-4, an antidiabetic commonly used in the clinic. Thus, following this study and by analogy to the protective effects observed on the neuron, we hypothesized that PE and its derivatives may have a beneficial role in the survival mechanisms in the pancreatic beta-cell.In this thesis, we demonstrate that endogenous PE and its derivatives protect beta cells from apoptosis induced by the chronic presence of the pro-inflammatory and diabetogenic interleukin IL-1β, as well as from an acute toxic shock induced by staurosporine. Furthermore, analysis of intracellular mechanisms reveals that these peptides cause an increase in intracellular calcium concentration, activate the ERK and Akt proliferative and survival pathways, and maintain CREB transcriptional factor activity in a deleterious environment via a calmodulin kinase-dependent pathway.Thus, this work shows that PE and its synthetic derivatives protect the pancreatic beta-cell and initiate virtuous cellular processes through an original PKA-independent signaling pathway, where membrane potential and calcium play a crucial role. This suggests the sortilin-derived peptides as a new class of pancreatic beta-cell protective molecules
Moreno, Sébastien. "Le récepteur 3 de la neurotensine/Sortiline dans la régulation de l’état dépressif". Thesis, Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4136/document.
Pełny tekst źródłaMajor depressive disorder is a condition that affects 20% of the population and is the leading cause of morbidity and disability worldwide. Recently, the TREK-1 potassium channel has been shown to be a potential target in the treatment of depression. The deletion of this channel or its blocking by a derived peptide resulting from the maturation of Sortilin, propeptide (PE), or its synthetic analogue Spadin, results in a phenotype of resistance to depression in mice. Sortilin is a protein able to bind with TREK-1 but also with the neurotrophic factor BDNF, an important factor for neuronal viability and depressive state regulation. Sortilin is therefore involved in regulating the intracellular addressing of TREK-1 and BDNF. Initially, my work focused on the consequences of the deletion of the Sortilin gene (sort1-/-) on the TREK-1 and BDNF addressing, and the neurotensinergic system. The results showed a decrease in TREK-1 membrane expression at the cerebral level and an increase in BDNF. All of these changes lead the Sort1-/- mice to develop a phenotype of resistance to depression. In addition, these mice show an increase in brain neurotensin concentration and its receptor 2, leading to increased resistance to pain perception. In a second phase, I was interested in whether PE, a potential antidepressant, showed serum variations in depressed patients and could be an indicator of depressive syndrome. We showed that the serum PE level is significantly reduced in depressed people, a level restored after treatment with antidepressants. In conclusion, Sortilin plays a major key in the regulation of depressive disorder and also in nociception
Moreno, Sébastien. "Le récepteur 3 de la neurotensine/Sortiline dans la régulation de l’état dépressif". Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2017. http://www.theses.fr/2017AZUR4136.
Pełny tekst źródłaMajor depressive disorder is a condition that affects 20% of the population and is the leading cause of morbidity and disability worldwide. Recently, the TREK-1 potassium channel has been shown to be a potential target in the treatment of depression. The deletion of this channel or its blocking by a derived peptide resulting from the maturation of Sortilin, propeptide (PE), or its synthetic analogue Spadin, results in a phenotype of resistance to depression in mice. Sortilin is a protein able to bind with TREK-1 but also with the neurotrophic factor BDNF, an important factor for neuronal viability and depressive state regulation. Sortilin is therefore involved in regulating the intracellular addressing of TREK-1 and BDNF. Initially, my work focused on the consequences of the deletion of the Sortilin gene (sort1-/-) on the TREK-1 and BDNF addressing, and the neurotensinergic system. The results showed a decrease in TREK-1 membrane expression at the cerebral level and an increase in BDNF. All of these changes lead the Sort1-/- mice to develop a phenotype of resistance to depression. In addition, these mice show an increase in brain neurotensin concentration and its receptor 2, leading to increased resistance to pain perception. In a second phase, I was interested in whether PE, a potential antidepressant, showed serum variations in depressed patients and could be an indicator of depressive syndrome. We showed that the serum PE level is significantly reduced in depressed people, a level restored after treatment with antidepressants. In conclusion, Sortilin plays a major key in the regulation of depressive disorder and also in nociception
Massa, Fabienne. "Rôle du système neurotensinergique dans la prolifération et l'adhésion des cellules cancéreuses de colon". Nice, 2011. http://www.theses.fr/2011NICE4055.
Pełny tekst źródłaNeurotensin (NT) can act in periphery and in the central nervous system. Two of this receptors are G protein coupled receptors (NTSR1 and NTSR2) and the third, is a type I receptor with one transmembrane domain (NTSR3 or sortilin). NT and NTSR1 are both implicated in tumoral progression and there are overexpressed in a lot of cancer. NT induces proliferation of cancerous cells which are mediated by NTSR1 which may transactivate the Epidermal Growth Factor Receptor (EGFR). We demonstrated that NT doesn’t transactivate the EGFR in HT29 cell line, a human adenocarcinoma of colon. NTSR3 is a multifunctional protein, is implicated in sorting of proteins, proliferation, differenciation… Moreover, once at the plasma membrane, NTSR3 can be hydrolysed and freed in a soluble form, in the extracellular medium (sNTSR3). During my PhD, I demonstrated that the sNTSR3 is an active molecule with a biological activity, as it induces the release of intracellular calcium. The sNTSR3 activates intracellular signaling like the complex FAK-Src, PKCα and Pi3K pathway, leading to an increase in cancerous cell adhesion. Furthermore, sNTSR3 increases E-Cadherin expression, space between cells and enhances the proliferation induced by EGF. Taken together, these results indicate that the soluble form of NTSR3 can be implicated in tumoral progression
Hassan, Noor. "Characterization and engineering of carbohydrate-active enzymes for biotechnological applications". Doctoral thesis, KTH, Industriell bioteknologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-165613.
Pełny tekst źródłaQC 20150429
Niemelä, Onni. "Aminoterminal propeptide of type III procollagen and basement related antigens in alcoholic liver disease". Oulu : University of Oulu, 1985. http://catalog.hathitrust.org/api/volumes/oclc/14472875.html.
Pełny tekst źródłaCacciatore, Angela [Verfasser], i Hans-Ruprecht [Akademischer Betreuer] Neuberger. "Prokollagen Propeptide : Marker für atriale Fibrose und Vorhofflimmern? / Angela Cacciatore. Betreuer: Hans-Ruprecht Neuberger". Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2013. http://d-nb.info/1052907148/34.
Pełny tekst źródłaIyappan, Saravanakumar. "The function of the beta6/Pre7 propeptide for 20S proteasome biogenesis in baker's yeast". [S.l. : s.n.], 2004. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB11612026.
Pełny tekst źródłaLarkin, Heidi. "Rôle de Calnuc dans le triage endosomial des récepteurs lysosomiaux et implication potentielle dans les maladies du lysosome". Thèse, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/8204.
Pełny tekst źródłaAbstract : Calnuc is a ubiquitous Ca2+-binding protein present on the trans-Golgi network (TGN) and endosomes. We previously highlighted the role of Calnuc in the transport of Low density lipoprotein receptor-related protein 9 (LRP9), a low density lipoprotein (LDL) receptor that cycles between the TGN and endosomes. Lysosomal receptors mannose-6-phosphate receptor (MPR) and Sortilin are well-characterized and also use the TGN-to-endosome trafficking pathway. Similarly to LPR9, we showed that Calnuc prevent their degradation in lysosomes by acting in their recycling from endosomes to the TGN. In fact, Calnuc is a important for the activation and the membrane association of Rab7, a small G protein which then recruit the Retromer complex known to be responsible for the retrograde transport of receptors. Lysosomal glycoprotein Ceroid lipofuscinosis neuronal 5 (CLN5) is also involved in this process. Because its structure and function have not yet been clearly defined, we established that it is synthesized as a type II transmembrane (TM) glycoprotein, but its cytoplasmic N-terminus and TM segment are rapidly removed following signal-peptide cleavage to generate mature CLN5 which is tightly associated to membrane through an amphipathic helix (AH). The understanding of the basic properties of CLN5 is particularly important given that CLN5 is involved in some variants of neuronal ceroid lipofuscinosis (NCL), a rare neurodegenerative disease caused by lysosomal overload. Moreover, our data indicate that CLN5 pathological mutants deprived of AH lose their membrane association, are retained in the endoplasmic reticulum, and are rapidly degraded. Based on the similarity featured by Calnuc and CLN5 in endosomal sorting, we explored the link between these two proteins. Cytosolic Calnuc and luminal CLN5 seem to form a complex, through the transmembrane protein CLN3, in order to influence the activity of Rab7. As CLN3 is also associated with NCL, we finally explored the potential involvement of Calnuc in this disease. Canuc depletion leads to typical NCL phenotypes such as lysosome enlargement, accumulation of autofluorescent material and of an increased of autophagy induction. Canuc's levels are decreased in all fibroblasts cell lines of NCL patients available indicating that Calnuc could be involved in some types of NCL. This thesis thus covers the discovery of the function of Calnuc in intracellular transport up to its potential involvement in the NCL, as well as a topological study CLN5.
Blondy, Sabrina. "Implication de la sortiline dans la résistance des cellules cancéreuses au 5-Fluorouracile. Cas du cancer colorectal". Thesis, Limoges, 2019. http://www.theses.fr/2019LIMO0020.
Pełny tekst źródłaWorldwide, colorectal cancer (CRC) is the second leading cause of cancer-related deaths. Colorectal adenocarcinomas are divided into low and high grades. More advanced tumor grade is associated with poorer global survival following 5-fluorouracil (5-FU)-based systemic chemotherapy. Even when 5-FU is used as the first-line molecule, responsiveness is only 20–30%, and drug resistance contributes to both poor patient prognosis and relapses, emphasizing the need to identify biomarkers involved in this process. In this study, we focused on sortilin, a multifunctional protein among VPS10P domain-related receptors with sorLA and sorCS1-3, that acts as a receptor and co-receptor as well as a regulator of intra- and extracellular protein sorting and trafficking. We obtained evidence that sortilin, but not sorLA, is a biomarker of CRC aggressiveness associated with poor clinical outcomes. In vivo and in vitro, in both 5-FU–resistant CRC cell lines and primary cultures, only sortilin was overexpressed at both protein and mRNA levels, indicating that it could serve as a biomarker of 5-FU resistance regardless of tumor grade and mutational status. Sortilin overexpression is especially localized in Golgi apparatus of 5-FU resistant cells and seems to be transcriptionally regulated through ATF-3 downregulation. Genetic (shRNA) and pharmacological (CADA) inhibition of sortilin potentiated 5-FU–induced cytotoxicity, resulting in a significant increase in cancer cell eradication, implying that sortilin is also actively involved in 5-FU resistance. Moreover, sorLA expression is unchanged upon sortilin inhibition. Our findings indicate that sortilin is a promising biomarker of 5-FU resistance in CRC, as well as a potential therapeutic target for overcoming 5-FU resistance
Fabre, Emmanuelle. "Roles du propeptide dans la secretion de la protease alcaline exocellulaire de la levure yarrowia lipolytica". Paris 6, 1992. http://www.theses.fr/1992PA066140.
Pełny tekst źródłaKawar, Susannah Louise. "Inhibition of myostatin (GDF-8) via myostatin propeptide minigenes : a potential gene therapy for Duchenne muscular dystrophy". Thesis, Royal Holloway, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497826.
Pełny tekst źródłaAl-Akhrass, Hussein. "Un rôle inédit de la sortiline dans le contrôle du transport rétrograde de l'EGFR pour limiter la croissance tumorale". Thesis, Limoges, 2017. http://www.theses.fr/2017LIMO0035/document.
Pełny tekst źródłaLung cancer is the third most common cancer in women and the second in men, it is the leading cause of cancer-related death worldwide, with an annual mortality of more than 1 million. Despite remarkable advances in targeted therapy, the majority of patients with lung cancer are diagnosed at an advanced stage where they do not experience a significant improvement in overall survival. Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signalling pathways. Internalisation and degradation of EGFR after ligand binding limits the intensity of its proliferative signalling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumour progression. Here, we report that sortilin is a key regulator of EGFR internalisation. Loss of sortilin in tumour cells promotes cell proliferation by sustaining EGFR signalling at the cell surface, ultimately accelerating tumour growth. In lung cancer patients, sortilin expression decreases with increased pathologic grade, and the expression of SORT1 (the gene encoding sortilin) is strongly correlated with a better survival, notably in patients with high EGFR expression. Thus, sortilin is a novel regulator of EGFR intracellular trafficking acting by controlling receptor internalisation and limiting tumour growth
Koclar, Gulden. "Pcr Cloning And Heterologous Expression Of Scytalidium Thermophilum Laccase Gene In Aspergillus Sojae". Master's thesis, METU, 2005. http://etd.lib.metu.edu.tr/upload/3/12607079/index.pdf.
Pełny tekst źródłaGäddnäs, F. (Fiia). "Insights into healing response in severe sepsis from a connective tissue perspective:a longitudinal case-control study on wound healing, collagen synthesis and degradation, and matrix metalloproteinases in patients with severe sepsis". Doctoral thesis, University of Oulu, 2010. http://urn.fi/urn:isbn:9789514262548.
Pełny tekst źródłaCioffi, U. "Effects of chronic inflammatory bowel diseases on left ventricular structure and function : dottorato di ricerca in fisiopatologia chirurgica". Doctoral thesis, Università degli Studi di Milano, 2003. http://hdl.handle.net/2434/69556.
Pełny tekst źródłaDemont, Yohann. "Le ProNGF dans le cancer du sein". Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10181/document.
Pełny tekst źródłaNerve growth factor (NGF), the prototypical neurotrophin, has extensively been studied for its role in the nervous system where it activates neuron survival and differentiation through the tyrosine kinase receptor TrkA and the neurotrophin receptor p75NTR. More recently, it was described that the precursor of NGF (proNGF) can be secreted and elicits neuronal apoptosis by engaging with p75NTR and sortilin receptors. Outside of the nervous system, several studies have indicated the implication of neurotrophins in tumors and in particular, our laboratory was pioneer in demonstrating the pro-survival and mitogenic effects of NGF for breast cancer cells. Nevertheless, nothing was reported about the role of the proNGF in breast cancer and this is what we have studied here. We demonstrated that proNGF was produced and secreted by breast cancer cells. Western blots analysis revealed a 25 kDa band that was decreased after transfection with siRNA against proNGF. Immunocytochemical observation showed proNGF localization in intracellular vesicles which were released upon treatment with the inducer of secretion ionomycin and proNGF was detected by mass spectrometry in conditioned medium of breast cancer cell. In addition, immunohistochemical analysis of 1423 normal vs human tumor biopsies showed proNGF overproduction in the epithelial compartment of malignant tumors when compared with benign and normal tissues, with a relationship to lymph node metastasis. Interestingly, in vitro, using Boyden chambers and RNA interference we showed that proNGF was a potent autocrine stimulator of breast cancer cell migration and invasion. Besides, impairment of its receptors revealed the essential role of sortilin in conducting proNGF pro-invasive effect whereas p75NTR was found not involved. In conclusion, our work demonstrates that proNGF is produced in breast tumors where it can stimulate cancer cell invasion, hence participating to metastasis. Further preclinical and clinical investigations will now have to be performed to determine the practical value of proNGF as a marker and/or therapeutic target
Boice, Emily. "The Role of the Propeptide and its Residues in Activation and Secretion of Elastase, an M4 Metalloprotease Secreted by Pseudomonas aeruginosa". VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/217.
Pełny tekst źródłaSloves, Pierre-Julien. "La sortiline et les voies endosomales apparentées sont les éléments clefs pour la biogenèse des organites apicaux et la virulence chez Toxoplasma gondii". Thesis, Lille 2, 2012. http://www.theses.fr/2012LIL2S020/document.
Pełny tekst źródłaToxoplasma gondii, the causative agent of toxoplasmosis belongs to the phylum named Apicomplexa that also contains Plasmodium falciparum, the causative agent of malaria and others parasites such as Cryptosporidium or Eimeria. Apicomplexan parasites are uniquely characterized by specific organelles, rhoptries and micronemes, which are located at the apical end of the parasite. These organelles are involved in the control of host-pathogen interactions. The proteins in these secretory organelles are trafficked through the endolysosomal system. However, the receptors that play key roles in protein sorting and biogenesis of these apical organelles remain to be identified. Sortilin is a type I transmembrane receptor known in humans for protein sorting and trafficking. Here, we report that the homologue of sortilin in T. gondii designated TgSORTLR for “Toxoplasma gondii SORTilin Like Receptor” is localized to Golgi and post-Golgi compartments and transports proteins into rhoptries and micronemes via their specific interactions with its luminal domain. We demonstrate that the C-terminus of TgSORTLR is also important for its subcellular localization through binding to cytosolic components of vesicular trafficking proteins known to be involved in anterograde and retrograde transports. The depletion of TgSORTLR using conditional knock-out strategy causes a complete rmis-localization of proteins of both rhoptries and micronemes, leading to the loss of these apical organelles. These mutants display a strong attenuation of the parasite virulence in mice with the absence of acute toxoplasmosis symptoms. Complementation of the strain lacking TgSORTLR showed that N-terminal region between 39-202 amino acids indicated that the N-terminus, similarly to the C-terminus is essential for its correct localization. We conclude that the full-length TgSORTLR protein is required for its biological functions as intracellular sorting receptor in T. gondii
Corbet, Cyril. "Etude de la signalisation du proNGF dans les cellules de cancer du sein". Thesis, Lille 1, 2012. http://www.theses.fr/2012LIL10120/document.
Pełny tekst źródłaNerve Growth Factor (NGF) induces the growth of breast cancer cells, whereas it has no effect on normal breast epithelial cells. NGF acts also on the tumor development in vivo and is considered as a potential therapeutic target in breast cancer. To exert its effects, NGF binds the receptors TrkA and p75NTR. More recently, proNGF, the NGF precursor, has been found to be secreted and to induce neuronal cell death by binding to a sortilin/p75NTR complex. Nevertheless, so far no data has been reported on the expression and the putative effects of proNGF in breast cancer cells. During my thesis, we have demonstrated that proNGF is produced and secreted by breast cancer cells. Moreover, we revealed an overproduction of proNGF in malignant breast tumors, in comparison to benign tumors and normal biopsies. Interestingly, a statistically significant association was obtained between the presence of proNGF and lymph node invasion by breast cancer cells. I confirmed that proNGF, but also NGF, induces in vitro breast cancer cell invasion. However, both proNGF and NGF induce their effects through distinct signaling pathways. I found that sortilin is essential for the proNGF pro-invasive effect while p75NTR is not necessary. Interestingly, proNGF, like NGF, is able to activate TrkA phosphorylation but this leads to different transduction cascades. TrkA interactome analysis allowed the identification of proteins differentially recruited on the receptor, depending on the ligand. Thus, our results demonstrate the first implication of proNGF in breast cancer. Deciphering of the pathways induced by proNGF and NGF would give the opportunity for new therapeutic modulations in breast cancer
López, Pelegrín Maria del Mar. "Mechanisms of proteolytic activity regulation exerted via a unique propeptide in matrix metalloproteinases and intra/intermolecular interactions in a novel family of minimal gluzincins". Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/347212.
Pełny tekst źródłaLes metal·lopeptidases participen de manera decisiva en la fisiologia i patologia de tots els organismes vius. La seva estricta regulació és, per tant, essencial pel correcte funcionament d’aquestes i per a prevenir una activitat proteolítica inadequada en el temps i/o espai que podria causar malalties. Aquesta regulació s’aconsegueix mitjançant un ampli ventall de mecanismes, incloent la seva biosíntesis com a precursors inactius, també coneguts com a zimògens. En la present tesi s’han estudiat diversos mecanismes de regulació de metal·lopeptidases, tot combinant tècniques bioquímiques, biofísiques i estructurals. En el primer projecte, l’estructura cristal·lina d’un fragment zimogènic de la proteïna “karilysin” de Tannerella forsythia ha revelat el propèptid més curt descrit fins al moment per una metal·lopeptidasa. Assajos bioquímics i biofísics addicionals han permès determinar la importància del propèptid en l’expressió, plegament i estabilitat de la proteïna. En el segon projecte, s’ha descobert una nova família de metal·lopeptidases mínimes d’origen procariota, que s’han anomenat “minigluzincins”, les quals proporcionen un model estructural per a metal·lopeptidases pertanyents al clan de les gluzincines i per a d’altres integrals de membrana. Dues membres d’aquesta família, anomenades “proabylysin” i “projannalysin”, han exhibit formes úniques de manteniment de latència exercides, respectivament, de forma intra- i intermolecular mitjançant llurs segments C-terminals. En el tercer projecte, una altra membre d’aquesta nova família, anomenada “selecase”, ha presentat una activitat proteolítica selectiva i específica sobre caseïna. La conjunció d’estudis duts a terme, tant biofísics com estructurals, ha evidenciat que “selecase” transita de manera reversible entre diverses conformacions d’estructura tridimensional definida, associades amb una disminució d’activitat enzimàtica deguda a autoinhibició (és a dir, monòmers actius i dímers, tetràmers i octàmers inactius). En definitiva, aquesta tesi contribueix de manera substancial a ampliar el coneixement previ sobre metal·lopeptidases a nivell molecular i a entendre els mecanismes que en regulen l’activitat, facilitant així el disseny d’inhibidors específics com a part d’aproximacions terapèutiques.
Thurairaja, Ramesh. "The use of serum aminoterminal propeptide of type 1 procollagen (P1NP) and magnetic resonance imaging (MRI) in the management of patients with prostate cancer". Thesis, Queen Mary, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435933.
Pełny tekst źródłaJemel, Ikram. "La phospholipase A2 sécrétée de groupe X : maturation protéolytique et rôles fonctionnels". Nice, 2009. http://www.theses.fr/2009NICE4096.
Pełny tekst źródłaThe superfamily of phospholipase A2 currently consists of at least eleven secreted phospholipases A2 (sPLA2s) and twelve intracellular phospholipases A2. These proteins catalyze the hydrolysis of phospholipids at the sn-2 position, releasing free fatty acids and lysophospholipids. Furthermore, phospholipase A2 controls the production of a variety of lipid mediators which are important for multiple cellular functions in various physiological or physiopathological contexts such as inflammatory diseases and cancer. Group X sPLA2 was cloned in 1997 and have peculiar molecular properties. SPLA2-X has the most potent hydrolyzing activity toward phosphatidylcholine and is involved in arachidonic acid (AA) release. SPLA2-X is produced as a proenzyme and has a propeptide of 11 amino acids ending with a dibasic motif. The cellular location and the protease (s) involved in proenzyme conversion have remained unclear. The work of this thesis has allowed to better defining the way by which the maturation of group X sPLA2 can be made and how this sPLA2 functions at both physiological and physiopathological levels. Our in vitro studies with recombinant group X proenzymes and transfected cells (HEK293) have shown that furin-like protease plays a major role in the activation of the enzyme during its secretion. Our work also suggests that the removal of the propertied can also occur via other proteases and extracellularly as found when using the human colon cancer cell line LOVO as a cellular model. We also studied the maturation of sPLA2-X in mouse tissues in various physiological and physiopathological conditions. Of note, we found that sPLA2-X is stored in large amount and likely in an active form in the acrosome of mouse sperm cells. Finally, we discovered a human polymorphism in the propeptide sequence mutating Arg-38 into cysteine and leading to the secretion of an inactive protein that is rapidly degraded after synthesis. In the second part of this thesis, we have shown that the active form of sPLA2-X, but not its proenzyme is able i) to stimulate the proliferation of various mouse colon cell lines, including Colon-26 cancer cells, ii) to protect human red blood cells from infection by P. Falciparulmn the parasite of malaria, and iii) to control the acrosomal reaction of mouse sperm during capacitation with an important impact on the outcome of in vitro fertilization
Lebel, Carl. "Étude des effets d'un propeptide muté de la myostatine sur la greffe de myoblastes : dans le cadre du développement d'un traitement pour la dystrophie musculaire de Duchenne". Thesis, Université Laval, 2010. http://www.theses.ulaval.ca/2010/26882/26882.pdf.
Pełny tekst źródłaOtite, Ugo. "Evaluation of serum and urinary human chorionic gonadotrophin beta, urinary beta core fragment and amino terminal propeptide of type 1 procollagen in the clinical management of prostate cancer". Thesis, Queen Mary, University of London, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406511.
Pełny tekst źródłaVulin, Adeline. "Restauration de la dystrophine par saut d'exons chez le modèle canin GRMD ; Augmentation de la masse musculaire par inhibition de la myostatine : rationnel thérapeutique pour DMD ?" Paris 12, 2005. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990003942550204611&vid=upec.
Pełny tekst źródłaDuchenne Muscular Dystrophy (DMD) is a progressive devastating disorder that remains incurable in spite of development of different therapeutic strategies. We decided to work on two original approaches. Our first aim was to setup molecular tools for post-transcriptional correction by targeting exon skipping of frequent out-of-frame deletions in the dystrophin gene and obtain a shorter but functional protein. We have achieved persistent exon skipping by a single administration of an AAV vector expressing antisense sequences linked to a modified U7 small nuclear RNA. Our results show the sustained production of functional dystrophin at physiological levels in injected muscles of GRMD dog model and the correction of the muscular dystrophy. Our second aim was to improve the DMD phenotype by increasing the skeletal muscle mass thanks to the down-regulation of myostatin and verify a possible improvement of the muscular regeneration. We have demonstrated that the propeptide of myostatin is an effective agent for increasing muscle mass and the functional benefit continue to be established in dystrophic mouse and dog models
Ikram, Jemel. "La phospholipase A2 sécrétée de groupe X : Maturation protéolytique et rôles fonctionnels". Phd thesis, Université de Nice Sophia-Antipolis, 2009. http://tel.archives-ouvertes.fr/tel-00496969.
Pełny tekst źródłaMilne, Trudy Jane. "Purification and characterisation of Tex31, a conotoxin precursor processing protease, isolated from the venom duct of Conus textile". Thesis, Queensland University of Technology, 2008. https://eprints.qut.edu.au/16960/1/Trudy_J_Milne_Thesis.pdf.
Pełny tekst źródłaMilne, Trudy Jane. "Purification and characterisation of Tex31, a conotoxin precursor processing protease, isolated from the venom duct of Conus textile". Queensland University of Technology, 2008. http://eprints.qut.edu.au/16960/.
Pełny tekst źródłaLindahl, Katarina. "Osteogenesis Imperfecta : Genetic and Therapeutic Studies". Doctoral thesis, Uppsala universitet, Metabola bensjukdomar, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-208942.
Pełny tekst źródłaHsu, Yi-Lin, i 許裔林. "Screening and Characterization of Streptomyces Transglutaminase Propeptide Mutants that Affect Mature Enzyme Activity". Thesis, 2016. http://ndltd.ncl.edu.tw/handle/54324008049819498920.
Pełny tekst źródła國立中興大學
分子生物學研究所
104
Transglutaminase is an acyl-transferase enzyme (amine γ-glutaminyltransferas, EC2.3.2.13; TGase) that catalyzes intra- or intermolecular crosslinking between glutamine and primary amines in proteins. TGase enzymes from microbial source have been widely used in food processing, textile, biomedical and pharmaceutical industries. The Streptomyces TGases are secreted as zymogen and stepwise processed into mature enzyme after cleavage of the pro-peptide by endogenous proteases. The pro-peptide of TGase has been demonstrated to play dual roles as having both molecular chaperone and inhibitor activities. In this study, random and site-directed mutagenesis in the propeptide regions of Streptomyces mobaraense (Sm) and Streptomyces netropsis (Sn) TGases were performed to identify mutants that maintain chaperone function and weaken their interactions with mature enzyme. The strategy of error-prone PCR and LIC (ligation-independent cloning) were applied to generate random mutations in the pro-peptide regions of Sm and Sn TGases. By coexpression of the plasmids containing mutated proTGase and TVMV protease genes in E. coli, mature TGases could be purified by one-step Ni2+-NTA affinity column. The purified Sm and Sn mature TGases that enhanced their enzymatic activities or have higher yields were identified. Preliminary screening revealed that 7 Sm and 50 Sn mature TGases have higher specific activities than that of the wild type after Ni2+-NTA affinity purification. DNA sequence analyses revealed that most of the mutants have one to two amino acids changes in the conserved domain of the TGase propeptide. Two of the Sn TGase propeptide mutants identified in the conserved domain, D22 and A13, were chosen for further site-directed mutagenesis. Results showed that replacement of D22 with G, A, L, K and Y facilitate high yield and produced mature enzymes with the same specific activities as wild type. Replacement of A13 with H, W, Y, F, E and T revealed that the Ni2+-NTA affinity purified mature TGases have higher specific activities but the yields were lower than that of the wild type.
Knobloch, James Edward. "Activation of vitamin K-dependent carboxylase by the propeptide from clotting factor X". 1987. http://catalog.hathitrust.org/api/volumes/oclc/17376038.html.
Pełny tekst źródłaTypescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 93-97).
Benedix, Yvonne. "Untersuchung zur Selektivität der Hemmung von Cathepsin L-ähnlichen Cysteinproteasen durch die dazugehörigen Propeptide /". 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015669108&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
Pełny tekst źródłaSchlabrakowski, Anne [Verfasser]. "Spezifität der Inhibition von Cathepsin-L-ähnlichen Cysteinproteasen durch ihre Propeptide / von Anne Schlabrakowski". 2003. http://d-nb.info/97008580X/34.
Pełny tekst źródłaChen, I.-An, i 陳奕安. "The Effects of Recombinant Porcine Myostatin Propeptide on Myogenesis in C2C12 Myoblast and Mice Animal Model". Thesis, 2011. http://ndltd.ncl.edu.tw/handle/92924064777476895019.
Pełny tekst źródła國立中興大學
生命科學系所
99
Myostatin (MSTN) is a dominant negative regulator of skeletal muscle development and growth. Myostatin propeptide (MSPP) is a peptide fragment cutting from the N-terminal of myostatin precursor. MSPP is able to bind to MSTN and blocking its function. In previous studies, over-expressed MSPP in transgenic mice would dramatically promote muscle growth through myostatin inhibition. Therefore, we aimed to develop a convenient and effective method to increase the meat production of livestock by feeding or injecting them with MSPP. This procedure may reduce the production costs, provide a clinical potential application of human muscular dystrophies therapy, and moreover, prevent diet-induced metabolic syndrome like obesity. In this study, we used a pGAPZαA expression cassette harboring mspp cDNA and large-scale production of MSPP by yeast Pichia pastoris fermentation. The product was further purified as a 37 kDa recombinant protein by nickel cloumn, and the production rate of fermentation was 0.9 mg/L. In the in vitro functional study, treated C2C12 myoblasts with the purified MSPP (10 μg/ml) in the regular culture medium could dramatically promote cell proliferation by cell proliferation assay analysis. We further investigated the downstream cell proliferation signals of myostatin propeptide by monitoring the mRNA levels of some transcription factors and myogenic regulatory factors (MRFs) in grow medium (GM) and differentiation medium (DM). We found that Cdk2, p21, MyoD and Myf5 mRNA levels were upregulated after treated MSPP (10 μg/ml) in GM and DM. And Cdk2 was significant upregulated (p<0.05) in GM. In in vivo study, we fed mice with normal fat diet (NFD) or high fat diet (HFD), and gave them the crude extract MSPP by oral gavage or intraperitoneal injection (i.p). In the first experiment, mice treated with MSPP significantly increased both of body and muscle weight in HFD group, and the cross-section areas of myotube were increased. In the second experiment, commercialized HFD was highly palatability. Mouse body weight was more than control group after feeding HFD for 4 days and the glucose tolerance dramatically got worse after 21 days. The groups treated with MSPP could prevent HFD-induced glucose tolerance reduction. However, the MSPP concentration were insufficient in crude extract to increase the body and muscle weight by oral gavage and i.p manipulations significantly. In order to facilitate the meat production efficiency for livestock with the MSPP treatment, we will further apply the genetic engineering techniques to modify the gene sequence (D76 mutated into A). With this manipulation, we can further reduce the degradation rate of MSPP in animals and also increase the working half-life to promote the application for MSPP in the economic meat production in the future.
Benedix, Yvonne [Verfasser]. "Untersuchung zur Selektivität der Hemmung von Cathepsin-L-ähnlichen Cysteinproteasen durch die dazugehörigen Propeptide / von Yvonne Benedix". 2006. http://d-nb.info/989327485/34.
Pełny tekst źródłaKaulmann, Guido [Verfasser]. "The structure of human procathepsin S : crystallographic investigations on the functional role of the propeptide / von Guido Kaulmann". 2004. http://d-nb.info/976431319/34.
Pełny tekst źródłaTao, Wei-Yu, i 陶威宇. "Expression of PCSK and Proteolytic Processing of BMP Propeptide on Dorso-Ventral Patterning of Helobdella Neuroectoderm: a Preliminary Study". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/47271389432792250729.
Pełny tekst źródła國立臺灣大學
生命科學系
103
Bone morphogenetic protein (BMP) morphogen is known to play a vital role in body axis patterning during embryogenesis. Unlike BMP4/Dpp functions as a morphogen patterning embryo dorsoventral (DV) axis in vertebrate and fly, BMP5-8 in leech, the key BMP signaling ligand specifies DV patterning, acts in a “cell-cell contact” fashion. Evidences indicate that the ligand BMP proprotein’s differential proteolytic processing by proprotein convertases (PCs or PCSKs) influences its signaling range. Further, different signaling ranges were found between teloblast lineages (N/Q and O/P), above which make the proteolytic processing of BMP5-8 in leech embryo DV patterning an unsolved question. To characterize the role of PCSK-mediated cleavage in leech DV patterning, I carried out the following experiments. First, by reverse transcription-PCR and whole mount in situ hybridization, expressions of all 12 PCSK-related genes in leech have been confirmed and localized at embryogenesis stage 8. Second, a cell surface-linked indicator of proteolysis assay (CLIP) is prepared to test PC activity in vivo. Third, ectopic expression of cleavage site-mutated BMP5-8 in leech has been used. The above results indicate that the proteolytic processing of BMP5-8 is not required for development of normal neuroectodermal, which is also a key event of body axis formation.
Iyappan, Saravanakumar [Verfasser]. "The function of the β6-Pre7 [beta-6-Pre7] propeptide for 20S proteasome biogenesis in baker's yeast / vorgelegt von Saravanakumar Iyappan". 2005. http://d-nb.info/973920521/34.
Pełny tekst źródłaWu, Hsin-Shan, i 吳欣珊. "The Effect of Recombinant Wild-type Porcine Myostatin Propeptide and Its Mutant Form on Growth and Differentiation Gene Expression in C2C12 Myoblast". Thesis, 2015. http://ndltd.ncl.edu.tw/handle/ukhc98.
Pełny tekst źródła國立中興大學
生命科學系所
103
Myostatin (MSTN) is an extracellular autocrine produced by cardiac muscle, and circulates in the blood in an inactive form throughout the body to inhibit muscle proliferation and differentiation; it is not only restricted to skeletal muscle but also detected in other tissues (e.g. adipose tissue). Recent study indicated that myostatin can accelerated fatty acid oxidation to prevent diet-induced obesity and stimulated adipogenesis in bone mesenchymal stem cells to improved multipotent cell differentiation. Previous studies mostly using microinjection or transgenic expression of myostatin inhibitor or myostatin propeptide (MSPP) cDNA to animals ameliorate cachexia due to myostatin disequilibrium or high-fat diet induced metabolic syndrome but this technology is too expensive and not easy to do. Therefore, we aimed to develop an alternative low cost and effective method. We used a pPICZαA expression cassette harboring WT-MSPP cDNA and its mutant form designed to be resistant to BMP-1/TLD metalloproteinase (D75A-MSPP) by yeast Pichia pastoris fermentation, which can efficiently secret to the fermentation medium. The products was further purified as 35.4 kD recombinant protein by size exclusion column. In addition, C2C12 myoblasts treated with the crude extract WT-MSPP or D75A-MSPP (10 μg/mL) in the regular culture medium could dramatically promote cell proliferation. We further investigated the downstream cell proliferation signals of MSPP by monitoring the mRNA levels and protein levels of some transcription factors and myogenic regulatory factors (MRFs) in grow medium (GM) and differentiation medium (DM). We found that Cdk2, Pax7, MyoD and Smad3 mRNA levels were upregulated after treated WT-MSPP or D75A-MSPP (10 μg/mL) in GM and DM (p < 0.05). In addition, MyoD and Myogenin protein levels were significantly upregulated (p < 0.05), and Erk, p-Erk, Akt and p-Akt were obviously downregulated (p < 0.05) in GM. Moreover, Myogenin, Akt and p-Akt were significantly increased in DM. The myosin heavy chain immunofluorescence stain result indicated that WT-MSPP and D75A-MSPP can enhance the ability of C2C12 myoblasts differentiation to myotube, especially in D75A-MSPP. In vivo study, we will fed C57BL/6 mice with normal fat diet (NFD) or high fat diet (HFD), and give them the crude extract WT-MSPP or D75A-MSPP by intraperitoneal injection (i.p), measure their blood biochemistry values and sacrifice after 1 month to detect the body weight, muscle weight, organ weight and histochemical stains to determine that control MSTN whether or not a possible way to promote muscle growth, decrease fat accumulation and ameliorate obesity-induced type2 diabetes.
Suzuki, Shana T. N. "Effects of enhanced muscle growth by myostatin propeptide trangene and dietary fat content on gene expression of adiponectin, adiponectin receptors, PPAR-α and PPAR-γ". Thesis, 2007. http://hdl.handle.net/10125/20774.
Pełny tekst źródłaTsai, Sen-Wei, i 蔡森蔚. "Establishment a Muscle Atrophy Rat Animal Model Caused by Botulinum Toxin And Evaluation The Therapeutic Effects of Treadmill Exercise and Myostatin Propeptide in Neuromuscular Junction and Muscle Physiology after Intramuscular Botulinum Toxin Injection". Thesis, 2013. http://ndltd.ncl.edu.tw/handle/54746132896260361343.
Pełny tekst źródła國立中興大學
生命科學系所
101
Botulinum toxin type A (BoNT-A), a kind of botulinum toxin, is used for spasticity block recently. The mechanism of this drug is to block the secretion of pre-synaptic acetylcholine, thus makes muscle weakness. Botulinum toxin injection is usually performed in cerebral palsy to reduce spasticity. Treadmill training for cerebral palsy is a well-documented program. Although botulinum toxin injection and treadmill training have usually been used in combination, the effects of treadmill training in muscles after intramuscular botulinum toxin injection are not well established. We showed that after Botulinum toxin type A injection, treadmill training improved the sciatic functional index, the maximal contraction force of the gastrocnemius muscle, and the percentage of activated muscle fibers which was demonstrated by differences in amplitude and area of compound muscle action potential. Upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, AChR subunits α and β were also found following treadmill running which may have contributed to enhanced recovery of gastrocnemius strength. In clinical practice, when considering the therapeutic strategies of combining these two treatments, clinicians should take this potential counteraction effect into consideration. Muscle atrophy is a common symptom associated with reduced skeletal muscle activity following bone fracture, trauma, ligament tear, inflammatory disease and nerve injury. To date, there are no pharmacological strategies for preventing or treating muscle atrophy. Myostatin is a potent inhibitor of skeletal muscle growth. Myostatin propeptide (MPro) is showed to improve muscle growth. However, the underlying mechanism of muscle atrophy attenuation effects of myostatin propeptide in atrophied muscles is not well established. We constructed both wild type MPro (MSPP) and mutant MPro construct (MSPPD75A) with resistance to proteinase. Using the C2C12 in vitro cell model and BoNT-induced muscle atrophy model, we evaluated the effects of myostatin propeptide gene therapy. We also observed changes in gene activation associated with neuromuscular junction, muscle and nerve. We showed that through MSPPD75A gene delivery, gastrocnemius muscle atrophy caused by botulinum toxin was attenuated. Through the delivery of either MSPP or MSPPD75A, the expressions of downstream proteins in ubiquitine-proteosome pathway Smad3 and MuRF1 were decreased, and the expressions of the muscle regulatory factors, IGF-1, GAP43, and acetylcholine receptors were increased. The data suggested that gene therapy may be a promising treatment for muscle atrophy. And the results could be used as basic knowledge for clinical rehabilitation, as a basis for developing treatment strategy of gene therapy.
Verlan, Inna. "The Role of Cardiotrophin-Like Cytokine Factor 1 on the Development of Atherosclerosis". Thèse, 2017. http://hdl.handle.net/1866/21386.
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