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1
Dvořák, Pavel. „Biomedicínské aplikace polykaprolaktonových nanovlákenných membrán“. Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2021. http://www.nusl.cz/ntk/nusl-444549.
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The diploma thesis deals with the treatment of polycaprolactone (PCL) nanofibers. PCL fibers were subjected to the deposition of plasma amine polymers in a low pressure pulsed radiofrequency capacitively coupled discharge using cyclopropylamine monomer (CPA). Collagen as an extracellular matrix (ECM) protein was immobilized and cell proliferation on the modified nanofiber surface was monitored. Untreated PCL fibers were also subjected to the deposition of an antibacterial copper layer, and the fibers were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and energy dispersive spectroscopy (EDX).
2
Gründel, Anne. „Funktion glykolytischer Enzyme von Mycoplasma pneumoniae in der Wirt-Erreger-Interaktion“. Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-213500.
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Mycoplasma pneumoniae ist ein parasitär lebendes Bakterium, das eine atypische Pneumonie beim Menschen verursacht. Aufgrund seiner geringen Genomgröße besitzt dieser Organismus einen eingeschränkten Metabolismus sowie eine limitierte Zahl an Pathogenitätsfaktoren. Dennoch ist dieser Mikroorganismus perfekt an seinen Wirt angepasst und es war zu vermuten, dass neben dem komplexen Adhäsionsapparat von M. pneumoniae auch glykolytische Enzyme eine Rolle bei der Interaktion mit humanen Zellen spielen. Diese Enzyme sind maßgeblich bei intrazellulär ablaufenden Stoffwechselprozessen beteiligt. Es wurde jedoch bereits bei anderen Bakterien gezeigt, dass glykolytische Enzyme ebenfalls auf der Bakterienoberfläche zu finden sind und dort mit Komponenten der extrazellulären Matrix des Wirtes interagieren können. Dieser Vorgang trägt offensichtlich zur erfolgreichen Kolonisation des Wirtes bei. Ziel dieser Arbeit war es, alle glykolytischen Enzyme von M. pneumoniae hinsichtlich ihrer Lokalisierung zu beschreiben und Teilaspekte ihrer Funktion in der Interaktion mit Wirtskomponenten zu analysieren.
Die glykolytischen Enzyme wurden rekombinant produziert und für die Herstellung von monospezifischen polyklonalen Antikörpern verwendet. Die Lokalisation der Enzyme wurde durch Nachweis in der Membran- und Zytosolfraktion des M. pneumoniae Gesamtantigens untersucht. Mittels Immunfluoreszenz, Colony Blot und Protease-Verdau intakter Bakterienzellen wurde bestätigt, dass acht (Glycerinaldehyd-3-phosphat-Dehydrogenase, Lactatdehydrogenase, Transketolase, Pyruvatdehydrogenase, Phosphoglyceratmutase und Pyruvatdehydrogenase Untereinheiten A-C) der 19 glykolytischen Enzyme mit der Bakterienoberfläche assoziiert vorkommen.
Die Untersuchung von Mutanten ergab, dass die Lokalisation der Enzyme nicht an das Vorkommen der für die Anheftung der Bakterien an Zielstrukturen wesentlichen Adhäsine wie die Proteine P1, P40 und P90 sowie das Oberflächenprotein P01, gekoppelt ist. Jedoch sind sowohl intakte Zellen von M. pneumoniae als auch die oberflächenlokalisierten glykolytischen Enzyme in der Lage, an verschiedene humane Zellen zu binden. Eine Analyse der nachweisbaren Proteine auf der Oberfläche der Zellen führte zur Auswahl von sechs humanen Proteinen für weiterführende Studien: Plasminogen, Vitronektin, Fibronektin, Fibrinogen, Laminin und Laktoferrin. Mittels ELISA wurde eine konzentrationsabhängige Bindung der oberflächenassoziierten Enzyme von M. pneumoniae mit Wirtsproteinen festgestellt, die hinsichtlich der Intensität jedoch Unterschiede aufwies. So konnten ausgeprägte Interaktionen aller Enzyme mit humanem Plasminogen und Vitronektin nachgewiesen werden. Die Bindung von Fibronektin und Laktoferrin ist dagegen nur für einen Teil der glykolytischen Enzyme zu bestätigen. Die Untersuchung verschiedener Einflussfaktoren ergab, dass alle Bindungen zwischen glykolytischen Enzymen und humanen Proteinen spezifisch durch die entsprechenden Antiseren gehemmt werden und dass der Großteil der Interaktionen ionischen Wechselwirkungen unterliegt. Die Bindung zu Plasminogen basiert überwiegend auf Lysin-Resten. Untersuchungen, ob sich die glykolytischen Enzyme gegenseitig in der Bindung zu Wirtsfaktoren beeinflussen, ergab ein komplexes Muster, das hinsichtlich Plasminogen, Fibronektin und Laminin für eine Überlagerung der für die Interaktion maßgeblichen Proteinbereiche spricht.
Die Untersuchung einer möglichen Aktivierung von inaktivem Plasminogen zu proteolytisch aktivem Plasmin ergab, dass in Gegenwart aller oberflächenlokalisierten glykolytischen Enzyme von M. pneumoniae Plasmin gebildet wird. Es wurden jedoch Unterschiede im Aktivierungspotenzial nachgewiesen. Die Pyruvatdehydrogenase Untereinheit B zeigte die höchste, die Pyruvatdehydrogenase Untereinheit C die geringste Plasminproduktion. Die Verwendung des gewebespezifischen Plasminogenaktivators führte zu einer höheren Aktivierung als der Urokinase-Typ Plasminogenaktivator. Die Variabilität der Plasminproduktion kann mit der unterschiedlichen Bindungsaffinität der glykolytischen Enzyme zu Plasminogen begründet werden. So besitzt die Pyruvatdehydrogenase Untereinheit B im Vergleich mit der Pyruvatdehydrogenase Untereinheit C ein höheres Bindepotenzial, das sich in der gemessenen Aktivierung widerspiegelt. Die Bildung von Plasmin kann zum Abbau verschiedener extrazellulärer Matrix-Proteine führen. Diese Prozesse sind physiologisch, z. B. in der Fibrinolyse, von Bedeutung. Während in Gegenwart der glykolytischen Enzyme die humanen Proteine Laktoferrin, Laminin und Fibronektin nicht abgebaut wurde, konnte Fibrinogen in Gegenwart der Pyruvatdehydrogenase Untereinheit B bzw. der Phosphoglyceratmutase und Vitronektin durch alle glykolytischen Enzyme (bis auf die Pyruvatdehydrogenase Untereinheit C) degradiert werden.
Mit der erstmals durchgeführten Analyse aller glykolytischen Enzyme eines Mikroorganismus hinsichtlich ihrer Lokalisation und der Bindung zu Komponenten der humanen extrazellulären Matrix wurde ein komplexes Netzwerk an Wirt-Erreger-Interaktionen nachgewiesen.
3
Owen, Jo. „Structural and functional studies of fibulin-1 EGF domains“. Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270656.
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4
López, Ceballos Pablo. „Elucidating how protein turnover in cell-ECM adhesion stabilizes tissue structure during development“. Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/57622.
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Morphogenesis is the process by which cells rearrange to form complex three dimensional structures. Cell to extracellular matrix (ECM) adhesion, primarily mediated by Integrins, is essential for the formation and maintenance of tissue architecture. A critical way to regulate cell-ECM adhesion is by modulating the turnover of Integrins and their adhesion complex, and thereby modulating the stability of Integrin-based adhesions. We previously showed that mechanical force stabilizes Integrin-based adhesions during development by modulating Integrin turnover. Here, we extend our studies to understand how mechanical stress impacts the dynamics of the cytoplasmic adaptor protein Talin, a critical regulator of Integrin function. Using Fluorescence Recovery After Photobleaching (FRAP) analysis in combination with a newly developed mathematical model that encompasses the complexities of Talin turnover, we determined that mechanical force stabilizes cell-ECM adhesion by increasing the rate of assembly of Talin-mediated adhesion complexes. To dissect the mechanisms that regulate Talin turnover downstream of mechanical force, we used point mutations of Talin which abrogate specific functions of the Integrin adhesion complex and measured turnover kinetics. We found that the activation of Integrins, resulting in increased affinity for ECM ligands, is a crucial process to regulate adhesion complex turnover. To further investigate the role of Integrin activation in regulating adhesion stability, we introduced small molecules known to induce “outside-in activation” of Integrins in vitro into live, intact embryos. This approach revealed that outside-in activation stabilizes cell-ECM adhesion by decreasing Integrin endocytosis; similarly to what we have previously seen when mechanical force is increased. Based on this finding, we propose that mechanical force may induce changes in Integrin activation in order to stabilize cell-ECM adhesions. Overall, we show that Integrin activation is a key mechanism that regulates cell-ECM adhesion stabilization during embryogenesis.Medicine, Faculty of
Graduate
5
Osta, Muhammad Samir Ahmed. „Characterisation of ECM protein processing mechanisms underlying simple peritoneal sclerosis and encapsulating peritoneal sclerosis“. Thesis, University of Sheffield, 2015. http://etheses.whiterose.ac.uk/11406/.
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Introduction and hypothesis: Peritoneal dialysis (PD) is an important option for renal replacement therapy. Peritoneal sclerosis (PS) limits PD duration due to loss of ultrafiltration (UF) capacity, while about 3% of PD patients experience a condition termed encapsulating peritoneal sclerosis (EPS). In many fibrotic diseases reduced Extracellular matrix (ECM) breakdown due to lowered matrix metalloproteinase (MMP) activity occurs, often from over-expression of tissue inhibitors of MMP (TIMPs) that underlie fibrotic remodeling. Furthermore, recent application of 2D gel proteomics on peritoneal dialysis effluent (PDE) samples has identified several proteins that are elevated in patients with membrane damage. These observations have led to the hypothesis that: changes in proteins in PDE samples, in particular those associated with ECM breakdown have value as non-invasive biomarkers of PS and the switch to EPS. To test this hypothesis, PDE samples from 3 patient cohorts was analysed for ECM proteolytic activity. A range of ECM processing proteins and 3 proteins identified from previous proteomic studies of patients developing EPS (intellectin-1, dermatopontin and collagen α1 (I)) were analysed in PDE samples. Methods: Three patient cohorts were studied: two were from Sheffield Kidney Institute (SKI) that consisted of 32 spot PDE samples (SKI-1) that included 1 EPS patient & 51 PDE & plasma samples collected during a peritoneal equilibrium test (PET) with multiple dwell times in patients who did not have EPS (SKI-2). The third cohort consisted of 209 samples from the Global Fluid Study (GFS) including sequential samples from 12 EPS & 42 matched controls patients. MMP activity was assessed using the ENZchek assay system. Plasmin activity was assessed by using cleavage of the V0882 substrate. TIMPs, MMPs, intelectin-1, dermatopontin, and collagen (α1) I were quantified by commercial ELISA in PDE and plasma samples. PDE cytology (macrophages, leukocytes, fibroblasts and mesothelial cells) was performed to determine if changes in any protein could be associated with changes in cell types. Clinical data were recovered from either the peritoneal dialysis database (PDDB) at Sheffield or the GFS archives. The analysis was performed using Microsoft Excel 2010 software, SPSS, and Graphpad prism (prism 5.01 for windows). Results: Plasmin activity in PDE samples decreases with long duration of PD therapy. Minimal MMP activity was found in all PDE samples. In the SKI-1 cohort, MMP-1, -9, & -13 were almost undetectable with only MMP-2 & -3 being measurable with levels of ((mean±SD) 46±37 & 2.1±2.2 ng/mL respectively). In contrast TIMP-1 and TIMP-2 and to lesser extent TIMP-3 had significant levels in PDE samples from commencing PD (109±88, 17±12, and 0.28±0.33 ng/mL respectively). All TIMPs & MMP-2 were raised in the single patient who had a diagnosis of EPS. In samples from the GFS cohort, there was a rapid 6 fold increases in TIMP-1 within 100 days of the diagnosis of EPS, which when normalised to TIMP-2 levels was a good predictor of EPS. Calculation of the plasma to dialysate transfer rate by reference to that of circulating proteins with no peritoneal production and of known molecular weight (albumin, beta2microglobulin (B2M), transferrin, IgG, and creatinine) demonstrated that TIMPs & MMPs (especially TIMP-1 and MMP-2) have significant peritoneal production. Plasma levels for TIMP-1,-2, MMP-2,-3, and intelectin-1 (mean±SD) were 121±27, 85±16, 176±35, 11±5, and 374±136 ng/mL in healthy individuals respectively. Plasma levels in PD patients for TIMP-1,-2, MMP-2,-3, and intelectin-1 (mean±SD) were 297±78, 158±33, 309±112, 42±28, and 749 ±722 ng/mL respectively. None of the proteins identified by proteomics as predictors of EPS were able to be validated by ELISA. However TIMP-1,-2, MMP-2, intelectin-1, and collagen (α1) I in PDE samples had significant correlations with the loss of ultrafiltration and thus membrane damage. PDE cytology showed that peritoneal fibroblast and leukocyte numbers increase with time on PD, while peritoneal macrophage decreases with time on PD. There were no significant changes in mesothelial cells. Conclusions: Negligible MMP activity in PDE samples results from high TIMP levels which could underlie the development of PS. The rapid increase in TIMP-1 within 100 days of EPS development offers value as a diagnostic tool or a late biomarker. Plasma levels of TIMP-1,2, MMP-2,3, and intelectin-1 are higher in patients on PD compare to healthy individuals. The increase in peritoneal fibroblasts may be a source of TIMP-1.
6
Lundberg, Ida. „Fibroblasts and ECM in colorectal cancer : Analysis of subgroup specific protein expression and matrix arrangement“. Thesis, Umeå universitet, Patologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-85606.
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The tumor microenvironment is important for tumor growth and progression, where the cancer associated fibroblast (CAF) is one central cell type. The CpG island methylator phenotype (CIMP) divides colorectal cancer (CRC) into three subgroups and in this study we investigate how the different CIMP-groups and adjacent fibroblasts affect each other. This was done with the aim of finding CIMP-specific markers and to see if different tumor-fibroblast interactions result in differently invasive tumors. Here we report that CIMP-negative tumors have increased expression of fibronectin, while CIMP-high tumors have reduced expression of E-cadherin, findings that were seen in both tumor tissue samples and tumor cell lines. We also show that CIMP-negative and CIMP-high cancer cells induce an alignment of the fibronectin fibers produced by the fibroblasts and that CIMP-high cancer cells migrate with directionality on these matrices. These findings indicate that the different tumor subgroups in fact induce different phenotypes in CAFs, resulting in CIMP-specific markers. They also indicate that CIMP-negative and CIMP-high tumors may induce an alignment of fibronectin in order to promote cancer cell migration and thereby also tumor invasion.
7
Waters, Timothy Richard. „Studies on the Eco RV restriction endonuclease using oligodeoxynucleotides containing modified bases“. Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385336.
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8
Chan, Ien. „The role of extracellular matrix protein 1 (ECM1) in human skin“. Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423043.
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9
Tian, Wang, la Vega Montserrat Rojo de, Cody J. Schmidlin, Aikseng Ooi und Donna D. Zhang. „Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2–related factors 1 and 2 (NRF1 and NRF2)“. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2018. http://hdl.handle.net/10150/627124.
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Nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of NRF1 or NRF2 results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated. Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediates ubiquitylation and degradation of NRF2 through its NRF2-ECH homology-like domain 2 (Neh2). Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and stabilizes it. Consistently, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, whereas NRF2 is dramatically stabilized in KEAP1(-/-) cells. Replacing NRF1's Neh2L domain with NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino acids between the DLG and ETGE motifs, not just the motifs themselves, are essential for KEAP1-mediated degradation. Systematic site-directed mutagenesis identified the core amino acid residues required for KEAP1-mediated degradation and further indicated that the DLG and ETGE motifs with correct spacing are insufficient as a KEAP1 degron. Our results offer critical insights into our understanding of the differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles.
10
Thorogood, Harry. „The Eco RV restriction endonuclease : an investigation using resonance raman spectroscopy and oligonucleotide phosphorothioates“. Thesis, University of Newcastle Upon Tyne, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361576.
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11
Khaghani, Seyed Ali. „Cell and tissue engineering of articular cartilage via regulation and alignment of primary chondrocyte using manipulated transforming growth factors and ECM proteins : effect of transforming growth factor-beta (TGF-β1, 2 and 3) on the biological regulation and wound repair of chondrocyte monolayers with and without presence of ECM proteins“. Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/5371.
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Articular cartilage is an avascular and flexible connective tissue found in joints. It produces a cushioning effect at the joints and provides low friction to protect the ends of the bones from wear and tear/damage. It has poor repair capacity and any injury can result pain and loss of mobility. One of the common forms of articular cartilage disease which has a huge impact on patient's life is arthritis. Research on cartilage cell/tissue engineering will help patients to improve their physical activity by replacing or treating the diseased/damaged cartilage tissue. Cartilage cell, called chondrocyte is embedded in the matrix (Lacunae) and has round shape in vivo. The in vitro monolayer culture of primary chondrocyte causes morphological change characterized as dedifferentiation. Transforming growth factor-beta (TGF-β), a cytokine superfamily, regulates cell function, including differentiation and proliferation. The effect of TGF-β1, 2, 3, and their manipulated forms in biological regulation of primary chondrocyte was investigated in this work. A novel method was developed to isolate and purify the primary chondrocytes from knee joint of neonate Sprague-Dawley rat, and the effect of some supplementations such as hyaluronic acid and antibiotics were also investigated to provide the most appropriate condition for in vitro culture of chondrocyte cells. Addition of 0.1mg/ml hyaluronic acid in chondrocyte culture media resulted an increase in primary chondrocyte proliferation and helped the cells to maintain chondrocytic morphology. TGF-β1, 2 and 3 caused chondrocytes to obtain fibroblastic phenotype, alongside an increase in apoptosis. The healing process of the wound closure assay of chondrocyte monolayers were slowed down by all three isoforms of TGF-β. All three types of TGF-β negatively affected the strength of chondrocyte adhesion. TGF-β1, 2 and 3 up regulated the expression of collagen type-II, but decreased synthesis of collagen type-I, Chondroitin sulfate glycoprotein, and laminin. They did not show any significant change in production of S-100 protein and fibronectin. TGF-β2, and 3 did not change expression of integrin-β1 (CD29), but TGF-β1 decreased the secretion of this adhesion protein. Manipulated TGF-β showed huge impact on formation of fibroblast like morphology of chondrocytes with chondrocytic phenotype. These isoforms also decreased the expression of laminin, chondroitin sulfate glycoprotein, and collagen type-I, but they increased production of collagen type-II and did not induce synthesis of fibronectin and S-100 protein. In addition, the strength of cell adhesion on solid surface was reduced by manipulated TGF-β. Only manipulated form of TGF-β1 and 2 could increase the proliferation rate. Manipulation of TGF-β did not up regulate the expression of integrin-β1 in planar culture system. The implications of this R&D work are that the manipulation of TGF-β by combination of TGF-β1, 2, and 3 can be utilized in production of superficial zone of cartilage and perichondrium. The collagen, fibronectin and hyaluronic acid could be recruited for the fabrication of a biodegradable scaffold that promotes chondrocyte growth for autologous chondrocyte implantation or for formation of cartilage.
12
Khaghani, Seyed A. „Cell and tissue engineering of articular cartilage via regulation and alignment of primary chondrocyte using manipulated transforming growth factors and ECM proteins. Effect of transforming growth factor-beta (TGF-¿1, 2 and 3) on the biological regulation and wound repair of chondrocyte monolayers with and without presence of ECM proteins“. Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/5371.
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Articular cartilage is an avascular and flexible connective tissue found in joints. It produces a cushioning effect at the joints and provides low friction to protect the ends of the bones from wear and tear/damage. It has poor repair capacity and any injury can result pain and loss of mobility. One of the common forms of articular cartilage disease which has a huge impact on patient¿s life is arthritis. Research on cartilage cell/tissue engineering will help patients to improve their physical activity by replacing or treating the diseased/damaged cartilage tissue.
Cartilage cell, called chondrocyte is embedded in the matrix (Lacunae) and has round shape in vivo. The in vitro monolayer culture of primary chondrocyte causes morphological change characterized as dedifferentiation. Transforming growth factor-beta (TGF-¿), a cytokine superfamily, regulates cell function, including differentiation and proliferation. The effect of TGF-¿1, 2, 3, and their manipulated forms in biological regulation of primary chondrocyte was investigated in this work. A novel method was developed to isolate and purify the primary chondrocytes from knee joint of neonate Sprague-Dawley rat, and the effect of some supplementations such as hyaluronic acid and antibiotics were also investigated to provide the most appropriate condition for in vitro culture of chondrocyte cells.
Addition of 0.1mg/ml hyaluronic acid in chondrocyte culture media resulted an increase in primary chondrocyte proliferation and helped the cells to maintain chondrocytic morphology.
TGF-¿1, 2 and 3 caused chondrocytes to obtain fibroblastic phenotype, alongside an increase in apoptosis. The healing process of the wound closure assay of chondrocyte monolayers were slowed down by all three isoforms of TGF-¿. All three types of TGF-¿ negatively affected the strength of chondrocyte adhesion. TGF-¿1, 2 and 3 up regulated the expression of collagen type-II, but decreased synthesis of collagen type-I, Chondroitin sulfate glycoprotein, and laminin. They did not show any significant change in production of S-100 protein and fibronectin. TGF-¿2, and 3 did not change expression of integrin-¿1 (CD29), but TGF-¿1 decreased the secretion of this adhesion protein.
Manipulated TGF-¿ showed huge impact on formation of fibroblast like morphology of chondrocytes with chondrocytic phenotype. These isoforms also decreased the expression of laminin, chondroitin sulfate glycoprotein, and collagen type-I, but they increased production of collagen type-II and did not induce synthesis of fibronectin and S-100 protein. In addition, the strength of cell adhesion on solid surface was reduced by manipulated TGF-¿. Only manipulated form of TGF-¿1 and 2 could increase the proliferation rate. Manipulation of TGF-¿ did not up regulate the expression of integrin-¿1in planar culture system.
The implications of this R&D work are that the manipulation of TGF-¿ by combination of TGF-¿1, 2, and 3 can be utilized in production of superficial zone of cartilage and perichondrium. The collagen, fibronectin and hyaluronic acid could be recruited for the fabrication of a biodegradable scaffold that promotes chondrocyte growth for autologous chondrocyte implantation or for formation of cartilage.
13
Sefat, Farshid. „Cell engineering of human bone monolayers and the effect of growth factors and microcontact printed ECM proteins on wound healing. The role of ECM proteins, TGF¿-1, 2 and 3 and HCl/BSA in cellular adhesion, wound healing and imaging of the cell surface interface with the widefield surface plasmon microscope“. Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/5758.
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Bone repair is modulated by different stimuli. There is evidence that the Transforming Growth Factor-beta (TGF-¿) super-family of cytokines have significant effects on bone structure by regulating the replication and differentiation of chondrocytes, osteoblasts and osteoclasts. There is also significant evidence that interactions with extracellular matrix molecules also influence cell behaviour.
This study aimed at determining the role of the TGF-¿s, Collagen type I, Fibronectin and Laminin in bone cell behaviour. To do this MG63 bone cells were used to examine cell adhesion and alignment to different micro-contact printed ECM protein patterns of different widths. The study also aimed at examining how TGF-¿1, 2 and 3 and their solvent and carrier (HCl and BSA, respectively) effected cell surface interactions, cell morphology, cell proliferation and integrin expression. Finally, this study also aimed at examining how the TGF-¿s and their solvent and carrier influenced wound closure in an in vitro wound closure model and how TGF-¿s influence ECM secretion and integrin expression.
5, 10, 25, 50 and 100¿m wide repeat gratings of Collagen type I, Fibronectin and Laminin patterns were stamp patterned onto glass slides and plated with MG63 cells at 50,000 cells per coverslip. Cells on the fibronectin pattern attached and elongated soon after seeding, but did not adhere readily to collagen and laminin and appeared more rounded until 18hrs after seeding. Cells aligned significantly well on the 50¿m and 100¿m wide fibronectin patterned coverslips with mean angles of alignment ~7.87¿ ¿ 3.06SD and 6.45¿ ¿ 5.08SD, respectively, compared to those with smaller width (p<0.001). In comparison, cells aligned less readily to the other two ECM proteins, showing optimal alignments of 9.66¿ ¿ 4.18SD and 14.36¿ ¿ 1.57SD to the 50¿m wide collagen and laminin patterns, respectively. Differences in cell length mirrored those of alignment, with cells acquiring the greatest length when showing the greatest degree of alignment. The results indicate that MG63 cells responded significantly better to 50 and 100¿m wide fibronectin patterns compared to those with smaller width (p<0.001) indicating that the cells may attach mostly via fibronectin specific integrins.
Cell surface attachment was examined via a trypsinisation assay in which the time taken to trypsinise cells from the surface provided a means of assessing the strength of attachment. The results indicated that treatment with the solvent (HCl), TGF-¿1, 2 and 3 all decreased cell attachment, but this effect was significantly greater in the case of HCl and TGF-¿3 (p<0.001). However, there were significant differences in trypsinisation rates between HCl and TGF-¿3 (p<0.001). The wound healing response to the TGF-¿s and their solvent/carrier was also investigated in 300¿m ± 10-30¿m SD wide model wounds induced in fully confluent monolayers of MG63 bone cells. The results indicated that TGF-¿3 and HCl significantly enhance wound closure when compared against negative controls, TGF-¿1 and TGF-¿2 treatment (p<0.001). It was also found that TGF-¿1 and TGF-¿2 treatment significantly improved wound closure rate in comparison to the controls (p<0.001).
Experiments were performed to determine if the HCl effects on wound closure were dose dependent. Cells were incubated with 20¿M, 40¿M, 80¿M and 160¿M concentrations of HCl prior to wounding and wound closure rates were recorded. Wound closure was dependent on HCl dose with the 80¿M and 160¿M concentrations inducing increases in wound closure rates that were both significantly greater than those induced by 20¿M, 40¿M and control treatments (p<0.001). However, there were significant differences in wound closure between the 80¿M and 160¿M treatment groups after 30hrs of treatment (p<0.001).
The effect of different TGF-¿ isomers and their combinations on proliferation rate and cell length of human bone cells were also assessed. The results suggest that cell morphology changes were observed significantly more in cells treated with TGF-¿(2+3) and TGF-¿(1+3) (p<0.001). Any cell treated with TGF-¿1, TGF-¿(1+2) and TGF-¿(1+2+3) showed significantly less elongation compared to the control and other TGF-¿ isomers. In terms of proliferation rate, TGF-¿3 and TGF-¿(2+3) increased cell numbers more than TGF-¿1, TGF-¿2 and other combinations. TGF-¿1 and its combinations did not show significant proliferation and attachment compared to the control due to perhaps its inhibitory effect in contact with human bone cells.
Immunostaining indicated that treatment with TGF-¿3 significantly promoted the secretion of collagen type I and anti-human fibronectin in addition to integrin (¿3 and ¿1) expression. Statistically TGF-¿3 and their combinations showed significant differences in number of cells stained for collagen type I, anti-human fibronectin, ¿3 and ¿1integrin. Any cell treated with TGF-¿1 or any combination with TGF-¿1 showed significantly lower cell number stained with the same proteins and integrins (p<0.001). Imaging with WSPR allowed observation of the focal contacts without the need for immunostaining. WSPR images revealed guided cells with high contrast band like structures at the border of cells distal to the edge of guidance cue to which they aligned and with less concentrically formed band like features across the cell body. It is believed that the high contrast features are associated with the formation of focal contacts on the edge of the cells distal to the edge of fibronectin patterns, which suggests that cell guidance is aided by a decrease in cell attachment along a guidance feature. The WSPR experiments also indicated that TGF-¿s influenced the distribution of focal contacts. In the case of TGF-¿1 treated cells the bright high contrast regions were intense but only arranged around the periphery of the cell. In TGF-¿2 and TGF-¿3 cells the bright contrast regions were weaker but again mostly localised around the periphery. These findings supported the earlier trypsinisation results.
14
Sefat, Farshid. „Cell engineering of human bone monolayers and the effect of growth factors and microcontact printed ECM proteins on wound healing : the role of ECM proteins, TGFβ-1, 2 and 3 and HCl/BSA in cellular adhesion, wound healing and imaging of the cell surface interface with the widefield surface plasmon microscope“. Thesis, University of Bradford, 2013. http://hdl.handle.net/10454/5758.
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Bone repair is modulated by different stimuli. There is evidence that the Transforming Growth Factor-beta (TGF-β) super-family of cytokines have significant effects on bone structure by regulating the replication and differentiation of chondrocytes, osteoblasts and osteoclasts. There is also significant evidence that interactions with extracellular matrix molecules also influence cell behaviour. This study aimed at determining the role of the TGF-βs, Collagen type I, Fibronectin and Laminin in bone cell behaviour. To do this MG63 bone cells were used to examine cell adhesion and alignment to different micro-contact printed ECM protein patterns of different widths. The study also aimed at examining how TGF-β1, 2 and 3 and their solvent and carrier (HCl and BSA, respectively) effected cell surface interactions, cell morphology, cell proliferation and integrin expression. Finally, this study also aimed at examining how the TGF-βs and their solvent and carrier influenced wound closure in an in vitro wound closure model and how TGF-βs influence ECM secretion and integrin expression. 5, 10, 25, 50 and 100μm wide repeat gratings of Collagen type I, Fibronectin and Laminin patterns were stamp patterned onto glass slides and plated with MG63 cells at 50,000 cells per coverslip. Cells on the fibronectin pattern attached and elongated soon after seeding, but did not adhere readily to collagen and laminin and appeared more rounded until 18hrs after seeding. Cells aligned significantly well on the 50μm and 100μm wide fibronectin patterned coverslips with mean angles of alignment ~7.87° ± 3.06SD and 6.45° ± 5.08SD, respectively, compared to those with smaller width (p<0.001). In comparison, cells aligned less readily to the other two ECM proteins, showing optimal alignments of 9.66° ± 4.18SD and 14.36° ± 1.57SD to the 50μm wide collagen and laminin patterns, respectively. Differences in cell length mirrored those of alignment, with cells acquiring the greatest length when showing the greatest degree of alignment. The results indicate that MG63 cells responded significantly better to 50 and 100μm wide fibronectin patterns compared to those with smaller width (p<0.001) indicating that the cells may attach mostly via fibronectin specific integrins. Cell surface attachment was examined via a trypsinisation assay in which the time taken to trypsinise cells from the surface provided a means of assessing the strength of attachment. The results indicated that treatment with the solvent (HCl), TGF-β1, 2 and 3 all decreased cell attachment, but this effect was significantly greater in the case of HCl and TGF-β3 (p<0.001). However, there were significant differences in trypsinisation rates between HCl and TGF-β3 (p<0.001). The wound healing response to the TGF-βs and their solvent/carrier was also investigated in 300μm ± 10-30μm SD wide model wounds induced in fully confluent monolayers of MG63 bone cells. The results indicated that TGF-β3 and HCl significantly enhance wound closure when compared against negative controls, TGF-β1 and TGF-β2 treatment (p<0.001). It was also found that TGF-β1 and TGF-β2 treatment significantly improved wound closure rate in comparison to the controls (p<0.001). Experiments were performed to determine if the HCl effects on wound closure were dose dependent. Cells were incubated with 20μM, 40μM, 80μM and 160μM concentrations of HCl prior to wounding and wound closure rates were recorded. Wound closure was dependent on HCl dose with the 80μM and 160μM concentrations inducing increases in wound closure rates that were both significantly greater than those induced by 20μM, 40μM and control treatments (p<0.001). However, there were significant differences in wound closure between the 80μM and 160μM treatment groups after 30hrs of treatment (p<0.001). The effect of different TGF-β isomers and their combinations on proliferation rate and cell length of human bone cells were also assessed. The results suggest that cell morphology changes were observed significantly more in cells treated with TGF-β(2+3) and TGF-β(1+3) (p<0.001). Any cell treated with TGF-β1, TGF-β(1+2) and TGF-β(1+2+3) showed significantly less elongation compared to the control and other TGF-β isomers. In terms of proliferation rate, TGF-β3 and TGF-β(2+3) increased cell numbers more than TGF-β1, TGF-β2 and other combinations. TGF-β1 and its combinations did not show significant proliferation and attachment compared to the control due to perhaps its inhibitory effect in contact with human bone cells. Immunostaining indicated that treatment with TGF-β3 significantly promoted the secretion of collagen type I and anti-human fibronectin in addition to integrin (α3 and β1) expression. Statistically TGF-β3 and their combinations showed significant differences in number of cells stained for collagen type I, anti-human fibronectin, α3 and β1 integrin. Any cell treated with TGF-β1 or any combination with TGF-β1 showed significantly lower cell number stained with the same proteins and integrins (p<0.001). Imaging with WSPR allowed observation of the focal contacts without the need for immunostaining. WSPR images revealed guided cells with high contrast band like structures at the border of cells distal to the edge of guidance cue to which they aligned and with less concentrically formed band like features across the cell body. It is believed that the high contrast features are associated with the formation of focal contacts on the edge of the cells distal to the edge of fibronectin patterns, which suggests that cell guidance is aided by a decrease in cell attachment along a guidance feature. The WSPR experiments also indicated that TGF-βs influenced the distribution of focal contacts. In the case of TGF-β1 treated cells the bright high contrast regions were intense but only arranged around the periphery of the cell. In TGF-β2 and TGF-β3 cells the bright contrast regions were weaker but again mostly localised around the periphery. These findings supported the earlier trypsinisation results.
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Fátima, Luciana Alves de. „Análise diferencial da expressão gênica e proteica no corpo lúteo de bovinos submetidos a tratamentos com eCG“. Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-05082013-174714/.
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A gonadotrofina coriônica equina (eCG) tem sido utilizada em programas de sincronização para inseminação artificial em tempo fixo e normalmente promove o aumento do volume do corpo lúteo e a da produção de progesterona. Além disso, esta mesma gonadotrofina pode ser utilizada para superovulação. Desse modo, hipóteses relativas aos mecanismos pelos quais gonadotrofinas exógenas alteram as funções celulares nos corpos lúteos resultantes foram formuladas. Para testar tais hipóteses, 18 vacas (Bos indicus) foram divididas em grupos: controle (n=5), estimulado (n=6) e superovulado (n=7) e a ovulação das mesmas foi sincronizada usando um protocolo já estabelecido com dispositivo de progesterona. Os animais estimulados receberam 400 UI de eCG no dia de remoção do dispositivo de progesterona e os animais superovulados 4 dias antes. No dia 7 após injeção de GnRh, os animais foram abatidos para a coleta de CLL e sangue. Análises de peso e volume de CL, concentração de progesterona (P4), bem como da expressão gênica e proteica de fatores angiogênicos e de proteínas esteroidogênicas foram realizadas. Além disso, o transcriptoma foi analisado por microarranjo. Foi observado que o volume do CL foi maior nos animais do grupo estimulado (1177,37 ± 167,07 mm3) e ainda maior nos do superovulado (1495,18 ± 137,01 mm3) quando comparados ao grupo controle (830,33 ± 234,99 mm3; p = 0,03). A concentração média de progesterona por CL nos animais do grupo estimulado foi maior que nos animais do grupo controle (5,95 ± 0,17 vs 3,69 ± 0,72 ng/ml; p = 0,03) e que nos superovulados (4,11 ± 0.73; p = 0,01). Além disso, os tratamentos com eCG aumentaram a expressão do FGFR2 e também da STAR nos animais estimulados e superovulados (p < 0,05). Quanto aos resultados do microarranjo, no total 242 transcritos foram aumentados e 111 foram diminuídos nos animais estimulados e 111 foram aumentados e 113 diminuídos nos animais superovulados em relação aos animais controle (~1,5 vezes, p 0.05). Entre os genes diferencialmente expressos, muitos estavam envolvidos na síntese de lipídios e na produção de progesterona, tais como: PPARG, HMGCR, STAR, receptores de prolactina e folistatina. Estes achados demonstraram que os tratamentos com eCG modularam a expressão gênica diferencialmente, dependendo do tratamento, e que nossos dados contribuem para entender as vias relacionadas ao aumento do volume do CL e da produção de progesterona observada após os tratamentos. Em um segundo experimento, foi realizado análises da influência do FSH na expressão de VEGF no cultivo de células da granulosa. Neste experimento foi possível observar que o FSH aumentou a expressão gênica e proteica do VEGF, colaborando com a ideia de que as gonadotrofinas têm propriedades angiogênicas.Equine chorionic gonadotropin (eCG) has been widely used in synchronization protocol to artificial insemination program and usually promote corpus luteum (CL) volume increases and stimulates progesterone production. Furthermore the same gonadotropin can be used to superovulation protocols. Thus, hypotheses concerning the mechanisms by which exogenous gonadotropins alter cellular functions in resulting corpora lutea were formulated. To test that hypothesis, 18 (Bos indicus) cows were divided into control (n=5), stimulated (n=6) and superovulated groups (n=7). Ovulation was synchronized using a progesterone device-based protocol. Stimulated animals received 400 IU of eCG of device removal and superovulated animals received 2000 IU of eCG 4 days prior. Corpora lutea (CLL) and blood samples were collected seven days after GnRH administration. Analyses of CL weight and volume, progesterone (P4) concentration, as well as the gene and protein expression of angiogenic and steroidogenic proteins were performed. Furthermore, the transcriptome was evaluated by microarray. The CL volume was higher in superovulated (1495.18 ± 137.01) than in stimulated (1177.37 ± 167.07) cows and higher in stimulated than in the control (830.33 ± 234.99) cows, and the P4 concentration per CL was higher in stimulated (5.95 ± 0.17 ng/ml) animals than in the control (3.69 ± 0.72 ng/ml) and superovulated (4.11 ± 0.73 ng/ml; P = 0.01) animals. Overall, 242 transcripts were up-regulated and 111 transcripts were downregulated in stimulated cows (P 0.05) and 111 were up-regulated and 113 down-regulated in superovulated cows in relation to the control (1.5 fold, P 0.05). Among the differentially expressed genes, many were involved in lipid biosynthesis and progesterone production, as PPARG, HMGCR, STAR, prolactin receptors and follistatin. In conclusion, eCG modulates gene expression differently depending on the treatment. Our data contribute to the understanding of the pathways involved in increased CL volume and progesterone levels observed after eCG treatment. In a second experiment, analyzes were performed about the influence of FSH on the expression of VEGF in the culture of granulosa cells. In this experiment it was observed that FSH increases the expression of the VEGF gene and protein, these finding collaborate with the idea that gonadotrophins have angiogenic properties.
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Cruz, Juliana Nunes da. „Hidrolisado proteico da semente de cupuaçu como fonte de peptídeos inibidores da enzima conversora da angiotensina I“. Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/9/9131/tde-29042015-100916/.
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Peptídeos com ação inibitória da enzima conversora da angiotensina I (ECA) podem ser obtidos a partir de diversos alimentos e exercer efeito anti-hipertensivo. O cupuaçu (Theobroma grandiflorum S.), fruto nativo da Amazônia, possui sementes comestíveis contendo proteína de reserva similar à do cacau (Theobroma cacao L.), as quais parecem ser fonte de peptídeos inibidores da ECA. Desse modo, o objetivo deste trabalho foi investigar in vitro a ocorrência de peptídeos inibidores da ECA no hidrolisado proteico da semente de cupuaçu obtido por ação da Alcalase. O hidrolisado revelou o desaparecimento de proteínas entre 27 a 180 kDa, incluindo as globulinas, e o surgimento daquelas abaixo de 15 kDa após 2 h de hidrólise, indicando a formação de peptídeos menores. O ensaio de atividade utilizando o substrato Abz-FRK(Dnp)-P-OH revelou que o hidrolisado total promoveu 65% de inibição da ECA e esse pool peptídico foi fracionado em cinco frações (F1-F5) por cromatografia em fase reversa (RP-HPLC). Após a etapa de purificação, o monitoramento da inibição apontou, ao final, duas frações (3.2.8 e 3.4.10) com maior atividade inibitória. Oito peptídeos foram identificados por LC-MS/MS, sendo três deles já conhecidos como inibidores da ECA. Outros cinco novos peptídeos identificados (FLEK, GSGKHVSP, LDNK, MVVDKLF e MEKHS) foram sintetizados e tiveram sua ação inibitória validada por ensaios in vitro. O peptídeo GSGKHVSP apresentou a menor IC50 (3,11 µM) e Ki (0,74 µM), sendo um inibidor tipo misto quanto ao seu mecanismo de inibição revelado pelo gráfico de Lineweaver-Burk. Os resultados permitem concluir que o isolado proteico da semente de cupuaçu pode ser uma fonte para obtenção de peptídeos anti-hipertensivos, a despeito de serem necessárias investigações sobre a resistência desses peptídeos à digestão gastrointestinal e a eficácia da inibição in vivo.Peptides with angiotensin I-converting enzyme (ACE) inhibitory activity may be obtained from several foods and cause antihypertensive effect. Cupuassu (Theobroma grandiflorum S.), a native fruit from Amazon, has edible seeds with a storage protein similar to that of cocoa (Theobroma cacao L.) which seems to have incrypted ACE inhibitor peptides. Thus, the aim of this project was to investigate the in vitro formation of ACE inhibitory peptides in protein hydrolysate from cupuassu seeds using Alcalase enzyme. The hydrolysate revealed the disappearance of proteins between 27 and 181 kDa after 2h hydrolysis, including the globulin, and the increase of those below 15 kDa, indicating the formation of peptides. The ACE inhibitory activity assays using the substrate Abz-FRK(Dnp)P-OH revealed the hydrolysate had 65% ACE inhibition and the pool of peptides was fractionated into five fractions (F1-F5) by reversed phase high-performance liquid chromatography (RP-HPLC). After the purification step, two fractions (3.2.8 e 3.4.10) exhibited the highest ACE-inhibitory activity. Eight peptides had been identified by LC-MS/MS and three of them were ACE inhibitors. The other newly identified peptides (FLEK, GSGKHVSP, LDNK, MVVDKLF and MEKHS) were synthesized and in vitro assayed for ACE inhibitory activity. The peptide GSGKHVSP had the lower IC50 (3.11 µM) and Ki (0.74 µM). Lineweaver-Burk plots suggest this peptide is a mixed-type inhibitor according to the inhibition mechanism. The results indicate that protein isolate from cupuassu seeds may be a good protein source of antihypertensive peptides and further investigation is needed in order to evaluate the resistance of these peptides to gastrointestinal digestion and the inhibitory activity in vivo.
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Eriksson, Jenny. „Studies of Eosinophil Cationic Protein (ECP) in vivo and in vitro : Impact of Genetic and Posttranslational Modifications“. Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8261.
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Karawajczyk, Malgorzata. „Mechanisms of granule protein mobiliation in blood eosinophils“. Doctoral thesis, Uppsala University, Department of Medical Sciences, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-502.
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Serum levels of eosinophil granule proteins namely ECP, EPO and EPX, which are stored in the matrix of specific granules, were shown to correlate with the course of disease in disorders involving eosinophils. The concentration of eosinophil proteins in serum is the result of their release in vivo and ex vivo during the sampling procedure. Generally, eosinophils release the content of their specific granules in three ways: exocytosis, piecemeal degranulation (PM) or cytolysis. Which of them is operating in circulating eosinophils has not yet been defined. The aim of this thesis was to study the mechanisms of granule protein release from blood eosinophils in respect of protein subcellular localization and cell ultrastructure.
In patients with bacterial infections, serum levels of ECP but not EPO increased, while in patients with viral infections both proteins remained within the range of healthy controls. G-CSF is a cytokine involved in the response mechanism to bacterial but not viral infections. Administration of G-CSF to healthy subjects induced an elevation of eosinophil numbers and a preferential increase of serum EPX and ECP in comparison to EPO.
The model of PM consists of the stepwise transportation of specific granule contents from the granules towards the plasma membrane. We observed that administration of G-CSF to healthy subjects and the allergen exposure of allergic subjects during the pollen season, caused changes in the ultrastructure of eosinophil specific granules such as loosening of the matrix, granule matrix lucency and ragged losses of their core. Similar alterations of morphology had been previously described for eosinophils undergoing PM.
ECP, EPX and EPO were localized not only in the specific granules but also in extra-granular compartments as shown both by immuno electron microscopy and subcelular fractionations, An extra-granular EPX compartment was present in healthy as well as in allergic and in hypereosinophilic subjects, and there were no significant differences in its size between the groups. The size of the extra-granular compartments of ECP and EPO was increased in allergics during the season, and these compartments were clearly separate from that of EPX. Results of this show the differential mobilization ofgranule proteins in blood stream eosinophils serum and indicates PM as its mechanism.
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Silva, Daniel João Pires de Mendonça. „Crosslinking strategies to improve properties of protein-based nanofibrous membranes“. Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22780.
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Mestrado em BiotecnologiaO objetivo deste estudo foi desenvolver uma matriz nanofibrosa e ecológica de gliadina de trigo para ser submetida e testada a agentes de reticulação alternativos, calor, genipina, ácido cítrico e o convencional e tóxico glutaraldeído, de modo a que as conhecidas limitações estruturais e de resistência mecânica de fibras proteicas pudessem ser ultrapassadas, nomeadamente quando utilizadas em ambiente aquoso. Nanofibras lisas, bem definidas e sem grânulos de gliadina, com um diâmetro médio de 665 nm, foram produzidas por eletrofiação a uma concentração otimizada de 30% de gliadina (m/v), utilizando como solvente uma mistura de ácido acético/etanol. A maioria dos métodos de reticulação testados não conduziu a resultados satisfatórios, no que respeita à obtenção de membranas nanofibrosas de gliadina que preservassem a sua integridade estrutural e porosidade quando em contacto com a água. O procedimento de reticulação por calor não teve um impacto significativo nas propriedades das fibras, as quais continuaram solúveis em água. Em contraste, a capacidade resistência à água das membranas foi aumentada através de genipina, glutaraldeído e ácido cítrico, mas apenas a combinação de genipina e calor, a 120ºC, foi capaz de manter ligeiramente a estrutura porosa e fibrosa da matriz proteica. O tratamento com genipina a uma concentração de 5% (m/m) permitiu obter membranas com propriedades mecânicas melhoradas. O tempo de reação entre genipina e a proteína, assim como o tempo de maturação após eletrofiação, revelaram-se parâmetros importantes para o aumento da tolerância à água e melhoria das propriedades mecânicas. O tratamento a 120ºC tornou as fibras mecanicamente melhores, destacando-se aquelas tratadas com uma concentração de genipina de 5% após um tempo de armazenamento de um mês e aquelas tratadas com uma concentração de genipina de 10%. O tratamento tradicional com vapor de glutaraldeído resultou em fibras com uma capacidade de alongamento significativamente maior e com um aumento de força à rutura, embora o aumento do tempo de reação leve também a um significativo encolhimento da membrana e aumento da sua rigidez
The aim of this study was to develop an eco-friendly gliadin electrospun nanofibrous matrix and its appropriate crosslinking to improve mechanical properties and water resistance. Smooth, well-defined and beadless gliadin nanofibers, with an average diameter of 665 nm, were produced by electrospinning at an optimized concentration of 30% gliadin (w/v), using a mixture of acetic acid/ethanol as the solvent. Different crosslinking methods have been tested, such as heat, genipin, citric acid, and the conventional and toxic glutaraldehyde. Most of the crosslinking methods tested did not lead to satisfactory results in obtaining gliadin nanofibrous membranes that preserved their structural integrity and porosity when in contact with water. The heat-crosslinking procedure did not have a significant impact on the properties of the fibers, which remained soluble in water. In contrast, the water-resistance ability of the membranes was increased through the treatments with genipin, glutaraldehyde and citric acid, but only the combination of genipin and heat treatment at 120 °C was able to slightly maintain the porous and fibrous structure of the protein matrix. Treatment with genipin at a concentration of 5% (w/w) allowed obtaining membranes with improved mechanical properties. The reaction time between genipin and the protein, as well as the time of maturation after electrospinning, were important parameters for water tolerance increase and improvement of the mechanical properties. The treatment at 120 °C increased the fibers mechanical resistance, especially those treated with a concentration of 5% genipin after a storage time of one month and those treated with 10% genipin. The traditional treatment with glutaraldehyde vapor resulted in fibers having significantly greater elongation and increased strength at break, although the increase in reaction time also lead to significant membrane shrinkage and increased stiffness.
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Krauspenhar, Bruna. „Polimorfismos gen?tico e proteico da enzima conversora de angiotensina na s?ndrome de pr?-ecl?mpsia“. Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2015. http://tede2.pucrs.br/tede2/handle/tede/6064.
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Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES
Introduction: Preeclampsia is a disease characterized as high maternal and fetal morbidity and mortality, diagnosed only after 20th gestational week, its etiology is not completely understood and healing is placental removal. It has been looking for biomarkers that allow early diagnosis for a better outcome of the disease. The 90 kDa isoform of Angiotensin Converting Enzyme (ACE), proposed as a new biomarker for hypertension, has not been studied in the preeclampsia syndrome so far. Objective: To evaluate the gene and protein expression, as well as enzymatic activity of ACE in pregnancy induced hypertension. Material and methods: It were included 69 normotensive and preeclampsia syndrome pregnant women at S?o Lucas Hospital/PUCRS, Porto Alegre/ RS- Brazil. Blood sample was collected to perform ACE genetic polymorphism, and three urine samples (during pregnancy, after delivery and at least 3 months after delivery) were taken to perform ACE protein polymorphism and enzymatic activity. This study was conducted through a partnership between Nephrology Service from PUCRS and Kidneys and Hormones from UNIFESP Laboratories research. Results: Scientific paper was published in Medical Hypotheses journal, entitled ?Angiotensin Converting Enzyme 90 kDa isoform: Biomarker for diagnosis of preeclampsia?? that described the hypotheses of this research. Comparing the participants clinical data among the groups (Normal pregnant, pure preeclampsia, superimposed preeclampsia), statistical significancy was observed between obstetric gestational age, blood pressure, newborn weight (p< 0.001) and placental weight (p= 0.030). Hypertension familial history compared with ACE genotypes (p= 0.017) suggests allele I involvement. Enzymatic activity ZPhe and Hhl ratio was different during the gestational period (p< 0.025), and also in relation to the ACE genotypes (p< 0.001). ZPhe and HhL isolated enzymatic activity also, in relation to the ACE genotypes, was not statistically different (p = 0.83 e p = 0.16, respectively). The protein polymorphism was not performed due to some technique problems, but this activity will be finished as soon as possible. Conclusion: It seems that allele I is associated with the hypertension familial history, and the genotypes that have this allele (ID, II) are predominantly present in pregnant women with preeclampsia. Enzymatic activity of Zphe/Hhl shows different behavior during the gestational period, and it also change according to genotypes classification. The data suggest that the mechanism involved in essential hypertension can be different from those involved in transient and spontaneous hypertension triggered pregnancy induced hypertension.
Introdu??o: Pr?-ecl?mpsia ? uma doen?a de alta morbimortalidade materna e fetal, diagnosticada somente ap?s a 20? semana gestacional, de etiologia n?o totalmente esclarecida e a cura consiste na retirada da placenta. Segue-se na busca de biomarcadores que possibilitem um diagn?stico precoce para um melhor desfecho da doen?a. A isoforma 90 kDa da Enzima Conversora de Angiotensina (ECA), proposta como novo marcador de hipertens?o, ainda n?o foi estudada na s?ndrome de pr?-ecl?mpsia. Objetivos: Avaliar a express?o gen?tica, proteica e enzim?tica da ECA na Doen?a Hipertensiva Gestacional. Materiais e m?todos: Foram inclu?das 69 gestantes normotensas e com S?ndrome de Pr?-ecl?mpsia (Pr?-ecl?mpsia Pura ou Sobreposta) no Hospital S?o Lucas da PUCRS, Porto Alegre/ RS- Brasil. Foram coletadas uma amostra de sangue para realizar o polimorfismo gen?tico da ECA e 3 amostras de urina (durante a gesta??o, ap?s o parto e pelo 3 meses ap?s o parto) para realizar a an?lise do polimorfismo proteico e a atividade enzim?tica da ECA. Este estudo teve parceria entre os laborat?rios de pesquisa de Nefrologia da PUCRS e Rins e Horm?nios da UNIFESP. Resultados: Foi publicado um artigo cient?fico na revista Medical Hypotheses, intitulado em Angiotensin Converting Enzyme 90 kDa isoform: Biomarker for diagnosis of preeclampsia?, descrevendo a hip?tese desta pesquisa. Comparando os dados cl?nicos das participantes entre os grupos analisados (Gestante normal, Pr?- ecl?mpsia Pura e Pr?- eclampsia Sobreposta), houve signific?ncia estat?stica entre idade gestacional obst?trica, n?veis press?ricos, peso do rec?m-nascido (p<0,001) e peso da placenta (p= 0,030). A hist?ria familiar de hipertens?o comparada com os gen?tipos da ECA (p= 0,017) sugere envolvimento do alelo I. A raz?o da atividade enzim?tica de Zphe e Hhl foi diferente durante o per?odo gestacional (p<0,025) e tamb?m em rela??o aos gen?tipos da ECA (p<0,001). Enquanto que a atividade enzim?tica isolada de Zphe e Hhl em rela??o aos gen?tipos da ECA n?o foi significativa (p = 0,83 e p = 0,16, respectivamente). A an?lise do polimorfismo proteico n?o foi realizada devido a problemas na execu??o da t?cnica, mas essa atividade ser? conclu?da assim que poss?vel. Conclus?o: O alelo I parece estar associado com a hist?ria familiar de hipertens?o e os gen?tipos que possuem esse alelo (ID, II) est?o predominantemente mais presentes nas gestantes que apresentam pr?-ecl?mpsia. A atividade enzim?tica de ZPhe/Hhl apresenta comportamento diferente durante o per?odo gestacional e tamb?m se altera conforme a classifica??o genot?pica da gestante. Os dados sugerem que os mecanismos envolvidos na hipertens?o essencial possam ser diferentes dos envolvidos na hipertens?o transit?ria e espont?nea desencadeada nas Doen?as Hipertensivas Gestacionais.
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Xu, Xiaoyan. „Granulocyte Adhesion to Matrix Proteins and the Effect on the Release of Granule Proteins : Development of a Simple Method and its Application in Experimental and Clinical Studies“. Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5112-8/.
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Sánchez, Tatiana Marlene Galvez. „Avaliação comparativa das proteinas de fusão cmx e ecmx no teste de mantoux para o diagnóstico de tuberculose“. Universidade Federal de Goiás, 2017. http://repositorio.bc.ufg.br/tede/handle/tede/7004.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
Outro
Tuberculin skin test (TST) identifies a previous exposed to M. tuberculosis (Mtb) using an intradermal inoculation of purified protein derivates (PPD) that result in a delayed hypersensitivity reaction (DTH). Interferon-gamma release assay (IGRA) was suggested to replace TST. The IGRA uses antigens, ESAT-6 and CFP-10, absent in all BCG strains and some non tuberculous mycobacteria (NTM). However, reproducibility and high cost were limitations for endemic countries. For this reason, the development of new diagnose test for latent TB is necessary. Fusion proteins developed by our group has been recognized by the immune response generated by the infection with Mycobacterium tuberculosis. Thus the aim of this work was to evaluate the capacity of CMX or ECMX to be used in a Skin test for tuberculosis. BALB/c mice infected with Mtb were euthanized forty-five days after infection. Spleens, lungs and draining lymph nodes of infected mice were processed and evaluated by flow cytometry Both CD4 and CD8 IFN+ cells were able to recognize rCMX and rECMX. The skin test followed an evaluation of thickness/swelling ≥ PPD 2UT (positive control) to consider positive DTH. Based on thickness, at 24 h, rCMX 25μg (0.37±0.02) and rECMX 15-25μg (0.38±0.03/0,62±0,12) induced a positive DTH response. At 48h, rCMX 25μg (0.28±0.03) and rECMX 25μg (0.5±0.04) induced also a positive DTH reaction. In conclusion, fusion proteins rCMX and rECMX are recognized by infected mice with Mtb and skin test using rECMX 25μg induced better DTH response that of conventional PPD.
A prova tuberculínica (PT) é um teste cutâneo que identifica a exposição prévia ao M. tuberculosis (Mtb), mediante a inoculação via intradérmica do derivado protéico purificado (PPD) de Mtb, o que resulta em uma reação de hipersensibilidade do tipo tardia (DTH). O ensaio de liberação de IFN-γ (IGRA) foi indicado para substituir a PT. O IGRA usa os antígenos ausentes na BCG e algumas micobactérias não causadoras de TB (MNT), ESAT-6 e CFP-10. Porém, apresenta falta de reprodutibilidade e alto custo quando usado em populações endêmicas para TB. Diante disso, o desenvolvimento de novos testes de diagnóstico é necessário. Nosso grupo desenvolveu proteínas de fusão que são reconhecidas por linfócitos gerados pela infecção com Mtb. Assim, o trabalho propõe avaliar a utilização das proteínas rCMX e rECMX no desenvolvimento de um teste cutâneo de diagnóstico para tuberculose. Camundongos BALB/c foram infectados com Mtb H37Rv. Após 45 dias, a infecção induziu linfócitos T CD4+ e CD8+ produtores de IFN-γ específicos para rCMX e rECMX no baço, pulmões e linfonodos drenantes. Enquanto ao teste cutâneo realizado 45 dias após a infecção, a leitura de espessura/inchaço ≥ PPD 2UT (controle positivo) indicou uma reação de DTH positiva. Avaliando a espessura 24h após o inóculo, rCMX 25μg (0.37±0.02) e rECMX 15-25μg (0.38±0.03/0,62±0,12) induziram reação de DTH positiva. As 48h, rCMX 25μg (0.28±0.03) e rECMX 25μg (0.5±0.04) também apresentaram reação positiva. Enquanto o inchaço as 24h, só a rECMX apresentou DTH positiva. Em conclusão, este trabalho mostra que as proteínas rCMX e rECMX são reconhecidas pela resposta celular de camundongos infectados com Mtb, e quando usadas no teste cutâneo induziram reação de DTH positiva comparável e até superior ao PPD convencional. Dessa forma, é recomendada a avaliação das proteínas de fusão em outros modelos animais e posteriormente em humanos.
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Grasman, Jonathan M. „Designing Fibrin Microthread Scaffolds for Skeletal Muscle Regeneration“. Digital WPI, 2015. https://digitalcommons.wpi.edu/etd-dissertations/18.
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Volumetric muscle loss (VML) typically results from traumatic incidents; such as those presented from combat missions, where soft-tissue extremity injuries account for approximately 63% of diagnoses. These injuries lead to a devastating loss of function due to the complete destruction of large amounts of tissue and its native basement membrane, removing important biochemical cues such as hepatocyte growth factor (HGF), which initiates endogenous muscle regeneration by recruiting progenitor cells. Clinical strategies to treat these injuries consist of autologous tissue transfer techniques, requiring large amounts of healthy donor tissue and extensive surgical procedures that can result in donor site morbidity and limited functional recovery. As such, there is a clinical need for an off-the-shelf, bioactive scaffold that directs patient’s cells to align and differentiate into muscle tissue in situ. In this thesis, we developed fibrin microthreads, scaffolds composed of aligned fibrin material that direct cell alignment along the longitudinal axis of the microthread structure, with specific structural and biochemical properties to recreate structural cues lost in VML injuries. We hypothesized that fibrin microthreads with an increased resistance to proteolytic degradation and loaded with HGF would enhance the functional, mechanical regeneration of skeletal muscle tissue in a VML injury. We developed a crosslinking strategy to increase fibrin microthread resistance to enzymatic degradation, and increased their tensile strength and stiffness two- to three-fold. This crosslinking strategy enhanced the adsorption of HGF, facilitated its rapid release from microthreads for 2 to 3 days, and increased the chemotactic response of myoblasts twofold in 2D and 3D assays. Finally, we implanted HGF-loaded, crosslinked (EDCn-HGF) microthreads into a mouse model of VML to evaluate tissue regeneration and functional recovery. Fourteen days post-injury, we observed more muscle ingrowth along EDCn-HGF microthreads than untreated controls, suggesting that released HGF recruited additional progenitor cells to the injury site. Sixty days post-injury, EDCn-HGF microthreads guided mature, organized muscle to replace the microthreads in the wound site. Further, EDCn-HGF microthreads restored the contractile mechanical strength of the tissue to pre-injured values. In summary, we designed fibrin microthreads that recapitulate regenerative cues lost in VML injuries and enhance the functional regeneration of skeletal muscle.
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Pozza, Roberta. „Acur?cia diagn?stica da raz?o protein?ria/creatinin?ria em pacientes com suspeita de s?ndrome de pr?-ecl?mpsia : revis?o sistem?tica e metan?lise de estudos diagn?sticos“. Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2010. http://tede2.pucrs.br/tede2/handle/tede/1649.
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Previous issue date: 2010-12-17Background: The laboratory gold standard test for identification of proteinuria in pregnant women is its measurement in a 24-hour urine sample. Urine protein-to-creatinine ratio in an isolated sample has been suggested as an option to a 24-hour urine collection. Proteinuria is a key feature of the preeclampsia syndrome. The current study aims at estimating the diagnostic accuracy of urine protein-to-creatinine ratio in comparison to 24 hours proteinuria determination in women with suspected preeclampsia syndrome. Methods: Systematic review and meta-analysis was used in comparing the accuracy of the protein-to-creatinine ratio in isolated urine samples with 24-hour urine protein excretion from Medline and LILACS electronic databases (to Feb/10) as data source. Results: The review included 14 studies with a total of 2,255 patients. Inclusion of a LILACS database search added one new paper to the sample. All the studies but two were cross-sectional in design. The method of urinary protein excretion evaluation differed among studies and was not mentioned in three. All the studies demonstrated significant correlation between protein-to-creatinine ratio and 24-hour proteinuria, with a coefficient greater than 0.500. Proteinuria-to-creatininuria ratio combined sensibility and specificity estimates were 86.6% (95% CI: 84.3-88.6) and 90.1% (95% CI: 88.2-91.7), respectively. Conclusion: The pooled estimate suggests that protein-to-creatinine ratio in isolated urine samples may be used for diagnosis and follow-up of patients with suspected preeclampsia syndrome.
INTRODU??O: O teste de laborat?rio padr?o-ouro para identifica??o de protein?ria em mulheres gr?vidas ? a sua medi??o em amostra de urina de 24 horas. A raz?o de prote?nas e creatinina na urina em amostra isolada tem sido sugerida como uma op??o para uma coleta de urina de 24 horas. Protein?ria ? uma caracter?stica diagn?stica da s?ndrome pr?-ecl?mpsia. O presente estudo visa estimar a precis?o do diagn?stico pela rela??o de prote?nas e creatinina na urina, em compara??o a determina??o de protein?ria em 24 horas de mulheres com suspeita de s?ndrome pr?-ecl?mpsia. M?TODOS: revis?o sistem?tica e meta-an?lise foram empregadas na compara??o da precis?o da rela??o prote?na-creatinina em amostras de urina isolada, com a prote?na urin?ria excretada em 24 horas. A consulta utilizou as bases de dados Medline e LILACS eletr?nico (a Fev/10) como fonte de dados. RESULTADOS: A revis?o incluiu 14 estudos com um total de 2.255 pacientes. A inclus?o do banco de dados LILACS adicionou um novo artigo ? amostra. O m?todo de avalia??o da excre??o urin?ria de prote?na diferiu entre os estudos e n?o foi mencionado em tr?s. Todos os estudos demonstraram correla??o significativa entre a prote?na e creatinina e protein?ria de 24 horas, com um coeficiente maior que 0,500. O ?ndice protein?ria-creatinin?ria apresentou sensibilidade e especificidade estimada de 86,6% (IC 95%: 84,3-88,6) e 90,1% (IC 95%: 88,2-91,7), respectivamente.CONCLUS?O: A estimativa combinada sugere que a raz?o de prote?na e creatinina em amostras de urina isolada pode ser usada para o diagn?stico e acompanhamento de pacientes com suspeita de s?ndrome pr?-ecl?mpsia.
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Cunha, Hilda Helena Souza da. „Protein?ria e ?cido ?rico s?rico maternos em pacientes com s?ndrome de HELLP“. Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2012. http://tede2.pucrs.br/tede2/handle/tede/1708.
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Previous issue date: 2012-08-28Objective: To evaluate the association of maternal serum uric acid (UA) and proteinuria with clinical and demographic data of pregnant women with preeclampsia syndrome (PES) complicated by HELLP syndrome. Methods: One hundred and nine pregnant women were divided into two groups: group 1 - HELLP pregnant women with PES complicated by HELLP syndrome (n=64); group 2 PES pregnant women with PES but no HELLP syndrome (n=105). Results: Age, ethnicity, parity, delivery mode and perinatal mortality were not statistically different between groups. Systolic and diastolic blood pressure, protein to creatinine (P/C) ratio, uric acid, creatinine and maternal complications were statistically different between groups; values were higher and events, more frequent among pregnant women with HELLP syndrome. The newborns of pregnant women with HELLP syndrome were more premature, had a lower birth weight and a lower APGAR score. Conclusion: Uric acid equal to or higher than 6.0 gm/dL and P/C ratio equal to or higher than 5 were more frequent in gestations with HELLP syndrome, which suggests that elevated proteinuria and uric acid levels in pregnant women with PES may increase the chances of developing HELLP syndrome
Objetivo: Avaliar a associa??o dos n?veis maternos de ?cido ?rico s?rico (AU) e protein?ria e os dados cl?nicos e demogr?ficos em gesta??es complicadas por s?ndrome de pr?-ecl?mpsia (SPE), com s?ndrome de HELLP. M?todos: Cento e sessenta e nove gestantes foram divididas em dois grupos: Grupo 1 - HELLP gestantes com SPE complicada pela s?ndrome de HELLP (n=64); Grupo 2 SPE gestantes com SPE sem s?ndrome de HELLP (n=105). Resultados: N?o ocorreram diferen?as estatisticamente significativas quanto ?s vari?veis idade, cor, paridade, via de parto e mortalidade perinatal entre os grupos. Press?o arterial sist?lica, press?o arterial diast?lica, ?ndice protein?ria/creatinin?ria (P/C), ?cido ?rico, creatinina e complica??es maternas apresentaram diferen?a estatisticamente significativa entre os dois grupos, sendo mais elevados e mais frequentes nas gestantes com s?ndrome de HELLP. Observou-se que os RN de gestantes com s?ndrome de HELLP foram mais prematuros, apresentaram menor peso ao nascimento e menor ?ndice de APGAR. Conclus?o: ?cido ?rico igual ou maior do que 6,0 mg/dL e ?ndice P/C igual ou maior do que 5 foram mais frequentes nas gesta??es com s?ndrome de HELLP, o que permite supor que maiores valores de ?cido ?rico e de protein?ria em gestantes com SPE aumentam a chance de desenvolvimento de s?ndrome de HELLP.
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Chan, Grace Lap-Yu. „Propafenone pharmacokinetics : GLC-ECD analysis, metabolic induction by phenobarbital in non-smoking and smoking healthy volunteers, protein binding, pharmacodynamics in patients“. Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/29064.
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Propafenone (PF) is a new class I antiarrhythmic agent used to treat supraventricular and ventricular tachyarrhythmias.
This thesis reports: a) an in vitro protein binding study of PF in normal and uremic sera; b) a drug-drug interaction study of PF and phenobarbital in healthy human subjects and c) a concentration-response relationship study of PF in patients. In order to conduct these studies, it was necessary to develop a sensitive and accurate assay method for the measurement of PF in biological fluids.
A capillary column electron-capture detection gas-liquid chromatographic (GLC-ECD) assay was developed for the quantitation of PF. The identity of the derivative formed with heptafluorobutyric anhydride was confirmed by GLC-mass spectrometry. The limit of determination of the assay method was 2.5 ng/mL using 1 mL of serum. The GLC-ECD method developed for the quantitation of PF was further modified to measure the major and active metabolite of PF, 5-hydroxy PF.
The serum protein binding of PF was examined and characterized in vitro in serum obtained from healthy human subjects using equilibrium dialysis. Two binding sites, one high-affinity, low-capacity and one low-affinity, high-capacity, were apparent. The serum protein binding of PF was found to be concentration-dependent, with PF free fraction increasing from 0.03 to 0.19 as PF concentration increased from 0.25 to 100 μg/mL. However, no evidence for significant concentration-dependent changes in binding were observed within the PF concentration range of 0.25-1.5 μg/ml, which covered a major portion of the therapeutic concentration range (0.5-2 μg/mL). In pooled uremic serum, the PF free fraction was approximately 50% of that of the PF free fraction in normal serum throughout the concentration range studied (1-5 μg/ml). In serum from patients with chronic renal failure, the increase in PF binding ratio was positively and significantly correlated with the increase in serum α₁-acid glycoprotein (AAG) concentration, suggesting that AAG is an important binding protein for PF in serum.
The effect of enzyme induction on the pharmacokinetics of PF and its major and active metabolite, 5-hydroxy PF, was studied in eight healthy non-smoking and eight healthy heavy cigarette smoking Caucasian males (age 20-45 y). Each subject received a single oral dose of PF (300 mg) on two occasions, separated by 23 days of phenobarbital treatment (100 mg daily at bedtime). Except for two smokers who were 'slow' metabolizers, all nonsmoking and smoking subjects were 'rapid' metabolizers (intrinsic clearance, CL[sub int] >0.5 L/min) Since there was great intersubject variability in most kinetic parameters calculated, each subject served as his own control. Phenobarbital induced hepatic microsomal enzymes and enhanced the extent of the first-pass metabolism of PF. There was a significant increase in CL[sub int] after phenobarbital treatment. The increase in CL[sub int] ranged from 10-831% in the non-smokers and 23-450% in the smokers, resulting in a substantial decrease in the systemic availability, as measured by a reduction in PF peak concentration (C[sub max]) and the area under the serum concentration-time curve (AUC). The decrease in C[sub max] ranged from 0-87% in the non-smokers and 8-85% in the smokers while the decrease in AUC ranged from 10-89% in the non-smokers and 19-82% in the smokers. Except for two smoking subjects, the percent decrease in serum AUC was similar to the percent decrease in salivary AUC noted after enzyme induction in the non-smoking and the smoking subjects.
Phenobarbital treatment did not lead to increases in the serum concentration, C[sub max] or the AUC of 5-hydroxy PF. Furthermore, there was no observed increase in the renal excretion of the conjugates of either 5-hydroxy PF or 5-hydroxy-4-methoxy PF, a subsequent metabolite of 5-hydroxy PF.
Twenty-three days of phenobarbital treatment did not cause any change in PF free fraction or serum AAG concentration in the non-smoking and the smoking subjects.
A wide range in the extent of metabolic induction of PF by phenobarbital, expressed as percent decrease in AUC, was observed in the non-smokers and the smokers, and in Vapid' and 'slow' metabolizers. Enzyme induction did not convert ‘slow' metabolizers of PF to 'rapid' metabolizers. Furthermore, the extent of metabolic induction of PF by phenobarbital was independent of the individual's polymorphic phenotype, serum phenobarbital concentration or the apparent initial ability of the individual's liver to metabolize drugs, i.e., CL[sub int] control.
When compared to the non-smokers, heavy cigarette smokers had a significantly larger CL[sub int], a lower C[sub max] and a smaller AUC. While smoking did appear to increase the clearance of PF, it is difficult to conclude that smoking induced the metabolism of PF, due to the small sample size and the lack of comparison of smokers (serving as their own experimental control) under a nonsmoking circumstance.
The concentration-response relationship of PF was studied in 10 patients (age 30-71 y) receiving PF (mean daily oral dose = 650 mg) for treatment of supraventricular arrhythmias. The QRS width measured from signal-averaged electrocardiograms (150 beats) was used as an indicator of the antiarrhythmic response of PF. The correlation between QRS width and several parameters such as PF serum concentration, 5-hydroxy PF serum concentration and serum AAG concentration was examined. Each of these parameters seemed to contribute to or influence the overall pharmacological effect of PF. It was possible to predict QRS width from the values of these parameters using an equation developed from multiple stepwise regression. The equation was described as Y = 0.5X₁ + 4.5X₂ + 347X₃ + 79 where Y was QRS width, X₁ was log PF serum concentration, X₂ was log 5-hydroxy PF serum concentration and X₃ was the reciprocal of serum AAG concentration.Pharmaceutical Sciences, Faculty of
Graduate
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Hebestreit, Johann Philipp. „Untersuchungen zum Synergismus von Saponinen und Toxinen bei in vitro kultivierten Säugetierzellen“. Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2005. http://dx.doi.org/10.18452/15180.
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Im Verlauf der Untersuchungen von Agrostemma githago L. var. githago, eines bekannten giftigen Vertreters der Caryophyllaceae, verwendeten wir neben Agrostemmasaponin das Saponinum album aus Gypsophila paniculata L., ebenfalls mit Gypsogenin (3b-Hydroxy-Olean-12-en-23-al-28-Säure) als Aglykon. Eine Kombination dieser Saponinderivate (3 µg/ml) mit einer Formylfunktion an Position C4 des Aglykons in Kombination mit RIPs und anderen natürlichen Toxinen zeigte eine kooperative Toxizität an ECV 304-Zellen. Ribosomen-inaktivierende Proteine (RIPs; EC Nr. 3.2.2.22) sind eine heterogene Familie von strukturell und evolutionsbedingt ähnlichen Proteinen mit einer katalytischen Domäne, die einen spezifischen Adeninrest enzymatisch von einer definierten Position der rRNA prokaryotischer und eukaryotischer Ribosomen zu entfernen vermag. Die kombinierte Verabreichung von subtoxischen Konzentrationen eines RIP-Typ 1 und des Saponins zeigte in dieser Studie einen spezifischen und zum ersten Mal größeren zytotoxischen Effekt auf Tumorzellen im Vergleich mit natürlichem Diphtheriatoxin. Es wird ein analoger, synergistischer Wirkungsmechanismus zwischen der durch Gypsophilasaponin induzierten Toxizität von Agrostin aus Agrostemma githago L. und von Saporin aus Saponaria officinalis L. bzw. dem rekombinant hergestellten his-Saporin diskutiert. Offensichtlich nutzen diese aus den Samen der Caryophyllaceae isolierten Proteine einen ähnlichen Weg, um die Zellmembran zu passieren, was auf den Abwehrmechanismus dieser Pflanzen gegen pathogene Organismen schließen lässt.In the course of our investigation of Agrostemma githago L. var. githago, a well-known toxic member of the Caryophyllaceae family, we tested Saponinum album from Gypsophila paniculata L., both saponins with gypsogenin (3b-hydroxy-olean-12-en-23-al-28-oic acid) as aglycone. A combination of these particular saponin derivatives with a formyl function in triterpene position 4 (3 µg/ml) together with RIPs and other natural toxins revealed a co-operative toxicity against ECV 304-cells. Ribosome-inactivating proteins (RIPs; EC No. 3.2.2.22) are a heterogeneous family of structurally and evolutionary related plant proteins. They share a common functional domain capable of catalytically removing a specific adenine residue from a highly conserved, surface-exposed stem-loop structure in the large rRNA of prokaryotic and eukaryotic ribosomes. The combined administration of individually non-toxic concentrations of a RIP type 1 and a saponin presented in this study leads to a potent and for the first time greater specifically cytotoxic effect on tumor cells in comparison with natural diphtheria toxin. An analogy could be drawn between the observed induction of RIP-toxicity of Agrostin and of Saporin/ genetically engineered his-Saporin from Saponaria officinalis L. in combination with Gypsophilasaponin. Obviously these proteins, both obtained from the seeds of Caryophyllaceae species, use a similar mechanism to penetrate through the cell membrane in vitro suggesting a similar defence mechanism of these plants against pathogenic organisms.
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Huang, Kai Ting, und 黃楷婷. „The Structure and Function of ECM Protein in Mitochondrial Enlargement and Clustering“. Thesis, 2015. http://ndltd.ncl.edu.tw/handle/17811912851655273254.
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碩士國立清華大學
生物科技研究所
103
Drosophila ECM is a CDGSH Ion-Sulfur binding domain containing protein that contains a CDGSH in C-terminal region. In this study, ECM is located on mitochondria at same direction. Overexpression of ECM dramatically causes Enlarged and Clustering Mitochondria in Drosophila S2 cell and mammalian HeLa cell so that we named it as ECM. We defined four regions in ECM, ECM-MH-1 and ECM-MH-2 from their similar and different region as N-terminal, transmembrane region, hinge region and CDGSH region. From the domain swap among ECM-MH-1, ECM-MH-2 and ECM, we found N-terminal of ECM is crucial for the mitochondrial enlargement and clustering in Drosophila and mammalian cell. ECM and ECM-MH-1 are located on mitochondria; the ECM-MH-2 is mainly located on ER in HeLa cell. We exchanged its transmembrane of ECM-MH-2 as the counter domain of ECM-MH-1 and ECM, this fusion ECM-MH-2 protein led to target to mitochondria and also trigger mitochondrial phenotype as same from ECM. We propose that N terminal domain of ECM-MH-2 and its Drosophila ortholog ECM has a critical function in the regulation of mitochondrial enlargement and clustering. In the live imaging, ECM promotes mitochondria to aggregate and cluster then cell divided in the end; it suggest this mitochondrial dynamics phenomenon might be regulated by cell cycle. Overexpression of ECM induced Drp1 to trans-locate on mitochondria and made mitochondria dull to dynamic. But this phenotype did not involve protein expression level of opa1 and drp1. We also found that anti-diabetes drug could reduce mitochondrial enlargement and clustering caused by ECM. However, which mechanism ECM is involved is not clear. By ECM-GFP fusion protein pull-down experiment, we found a protein, Hiw, is interacted with ECM by immunoprecipitation and LC/MS. Hiw, which is an ubiquitin E3 ligase, has been reported to be in the regulation of neuron growth. In this thesis, we evaluate which protein region of ECM that regulates the mitochondrial morphology change. With this clear understanding of ECM structure, function and genetic pathway, it might be possible to develop more therapeutic agents in ECM relative diseases, including aging and diabetes.
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Lu, Yung-Yu. „Functional Studies of a Stress Protein Family: Subcellular Localizations of AtHVA22a-e Proteins in Arabidopsis“. 2008. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2507200800293900.
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Leu, Jiann-Horng. „Cloning and characterization of apoptosis-related proteins from Penaeus monodon: Inhibitor of apoptosis protein (IAP) and caspase“. 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2405200713435400.
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Chen, Chung-Hong, und 陳俊宏. „The study of the effects of biodegradable polymers and ECM proteins on chondrocyte adhesion, proliferation and gene expression“. Thesis, 2004. http://ndltd.ncl.edu.tw/handle/27310293409062892297.
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碩士國立臺灣大學
化學工程學研究所
92
The goal of this study was to compare the performance of chondro- cytes in adhesion, proliferation and gene expression of chondrocytes when they were cultivated on different biodegradable polymers. Four kinds of biodegradable polymers was used in this study, including PDLLA, PLLA, PLGA, and PCL, which were made by using the solvent- casting method, and chondrocytes were cultured on the polymer films. Cell adhesion on day 1, cell proliferation and gene expression on day 4 and day 7 were investigated. The results show that chondrocytes prolife- rated better on PLGA and PDLLA films in 7 days, but there are no signi- ficant differences on each film for 14 days. The gene expression on diffe- rent polymer films showd difference. We suggest the PDLLA is most suitable for chondrocyte culture, since the gene expression of chondro- cytes is restored during 14 days culture period. As a result, PDLLA films was modified by adsorption of collagen type I, collagen type II, fibronectin, and polylysine. Cell adhesion on day 1, cell proliferation and gene expression on day 4,7,14 were investigated. The results showed that collagen type I, collagen type II, and fibronectin could enhance chondrocytes proliferation during culture. The gene expression was retained during 14 days on each surface. It seems that the adsorbed proteins would not effect the gene expression of chondrocytes.
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Hsieh, Hui-Min, und 謝惠泯. „The Influence of ECM Protein by Adding High Concentration Glucose and Vitamin C、E in Culture Endothelial Cell Study“. Thesis, 1999. http://ndltd.ncl.edu.tw/handle/97997969237905290639.
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碩士中山醫學院
營養科學研究所
87
Abstract In this study is to explore the influence of adding high concentrated glucose and antioxidant C、E to Fibronectin(FN) a ECM protein and Quantitative changed of total cellular protein. Furthermore to examine the relationship of TGF-s and AGE to biosynthesis of FN in culture study. Methodology of experiment: 105/well cells were incubated in 24 well plate. Each well contains M-199+10%FCS. M-199+10%FCS+30mM glucose (high physiological conc.) M-199+10%FCS+5mM glucose (normal physiological conc.) vitamin C (0.01mM.、0.05mM) and vitamin E(0.01mM、0.05mM) were added individually and in combination plus, included TGF-s and AGE antibody (0.5ug/ml) incubation were washed three times after 72hours, cell suspensions was obtained with lysis buffer. Cell lysis under Ultrasonic vibration. ELISA determinate quantitative Analysis of total cellular protein and FN concentration. The results of experiment shows that indeed the FN was significantly increase in high glucose concentration compare to normal glucose concentration Either 5%or10%FCS were present in the culture medium. Although the total quantitative of protein did not change, but adding vitamin C or E respective can cause significantly decrease of cellular FN concentration under the situation of high glucose concentration. In Addition providing vitamin C or E (0.05mM) respective were not significantly change the FN biosynthesis but add both vitamin C and E together shows additive effect on decrease fibronection biosynthesis within high glucose concentration. Furthermore TGF-s and AGE antibody can indeed reduce the Fibronectin biosynthesis. For the data of results, we know that under the high glucose concentration can increase Fibronectin biosynthesis. Together with certain amount of antioxidant vitamin C and E can suppress the high oxidant pressures of TGF-s induction or AGE- production which cause increase fibronectin concentration production. And lead to affect the smoothness of ECM endothelium cell surface, decrease progression of cellularization of blood vessel eventually prevent the occurrence of diabetic angiopathy.
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佐藤, 好隆, und Yoshitaka Sato. „Degradation of Phosphorylated p53 by Viral Protein-ECS E3 Ligase Complex“. Thesis, 2013. http://hdl.handle.net/2237/18598.
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Kai-Fa, Huang. „Post-Translationally Pyroglutamate Formation on Proteins: Studies on protein production, crystal structures, catalysis mechanism, inhibition and pathophysiology of human glutaminyl cyclase“. 2006. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2501200613275100.
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Chung, Amy S. „Macrophage matrix metalloproteinase-2/-9 and interleukin-1[beta] gene and protein expression following adhesion to ECM-derived multifunctional matrices via integrin complexation“. 2006. http://catalog.hathitrust.org/api/volumes/oclc/71354916.html.
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Thesis (M.S.)--University of Wisconsin--Madison, 2006.Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 59-63).
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Li, Chia-Feng, und 李嘉峰. „The Mechanism of Kelch-Like ECH-Associated Protein 1( Keap1) in Lung Adenocarcinoma Migration“. Thesis, 2011. http://ndltd.ncl.edu.tw/handle/54783667330135466675.
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碩士國立臺灣大學
毒理學研究所
99
Kelch-loke ECH-associated protein 1(KEAP1) is a redox-dependent substrate adaptor protein which interact with cul3 ubiquitin ligase complex to degradate NRF2(NF-E2-related factor 2). The decreased expression of KEAP1 will enhance NRF2 expression and accumulate in the nucleus, where binding with antioxidant responsive element(ARE) and activate the antioxidative enzyme expression. Here we observed the KEAP1 expression had inversely correlation with cell migration ability. So we suggesting that the NRF2 target gene may provide advantage for cancer cell progression and may control by KEAP1. In this study, KEAP1 and NRF2 protein expression in 238 and 167 lung cancer specimens was investigated immunohiistochemically and was significantly coorelated with survival and stage. We found KEAP1 high expression in early stage whether NRF2 is high expression in late stage. Also, KEAP1 had ability to inhibit many cancer cells migration and NRF2 had inversely correlation with KEAP1 in migration ability. Further we confirm the degradation interaction between KEAP1 and NRF2 in lung cancer cells and confirm the KEAP1 inhibit cancer cell migration is caused by degradation of NRF2. By microarray analysis, we first found KEAP1-NRF2 signaling pathway to connect with S100P protein which facilitate cancer metastasis in many cancer type. Moreover, the NRF2 protein may combine with TBPA which a binding protein of S100P promoter region. In conclusion, our data suggested that KEAP1 may mediate lung cancer migration ability through degradation of NRF2 which transcriptional control the S100P expression.
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Hsu, Chia-Ming. „Mining Dense Overlapping Subgraphs in Weighted Protein-Protein Interaction Networks“. 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-1807200716394500.
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Tsai, Meng-Jia. „Protein-Protein Interaction Prediction with Identification of Putative Interaction Patterns“. 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2208200715581500.
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Huang, Tao-Wei. „Prediction of Human Protein-Protein Interactions Using Support Vector Machines“. 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-0910200714331600.
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Chen, Chiuan-Jung. „Protein Loop Modeling“. 2004. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-1507200400502700.
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Fang, Chiung-Ying. „Characterization of post-translational modification and protein-protein interaction of RNA-binding protein 1, Rbp1p, in Saccharomyces cerevisiae“. 2007. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2307200711033800.
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Huang, Pei-Yi, und 黃珮儀. „Functional Association of SNP/InDel Variations in Human Reference Proteins by Evidence-Based Mining (EBM)“. Thesis, 2004. http://ndltd.ncl.edu.tw/handle/84502866398962494459.
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碩士國立陽明大學
衛生資訊與決策研究所
92
Identification of genes, whose products play a major role in human disease, is a major aim in the analysis of human genome. Genotypic variations have been proved to be the major cause of genetic disease and cancer. Recently, the common variations of gene sequence, such as SNP and InDel, have been proved to be related to phenotypical alterations or disorders as well. Proteins are the elements contributing to our physiology and molecular function. Their function might be altered if primary amino acid had changed. There are various techniques used to discover gene variations, but few of the variation located in coding sequence had been found. The biomedical literature has much to say about sequences, and all those published have been proved by clinical experiment. These literature references are the most powerful evidences for biomedical study or clinical research. OMIM is an integrated knowledge base of Mendelian Inheritance and MEDLINE is the most complete literature database, but to retrieve information from MEDLINE for the study of human genetic disease is not as convenient as biologist expect. We have implemented a web-based decision support system that combines biology knowledge with Evidence-Based Mining. It can assist experts in discovering potential SNP on coding sequences and to exploring their possible molecular function. This system is based on 15,291 human reference protein sequences which carry 512,803 potential cSNPs detected by out laboratory. In which 13,081 are associated with MEDLINE and 1,221(95.07%) are matched with OMIM.
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Peng, Chin-Lin. „ProtExt: a Web-based Protein-protein Interaction Extraction System for PubMed Abstracts“. 2004. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-1407200403401600.
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Wu, Tsung-Shung. „Functional characterization of Arf-like protein, ARL5 and its interacting protein EB1“. 2005. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-0908200521130700.
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Yan, Min-Zhe. „Web-Based Information Extraction System - A Case Study on Protein-Protein Interactions“. 2008. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0020-3107200808135500.
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46
Huang, Hsu-Sheng. „Small Protein Structure Prediction“. 2004. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-3007200409522000.
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47
Lin, Chien-Chieh. „Prediction of Paired Binding Regions in Protein-Protein Interactions by Sequential Pattern Mining“. 2008. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2907200800325600.
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Chang, Tse-Hao, und 張哲豪. „Analysis and Application of Human Eosinophil Cationic Protein and ECP-Derived Peptide to Negatively Charged Molecules“. Thesis, 2013. http://ndltd.ncl.edu.tw/handle/84379074838508600888.
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碩士國立清華大學
分子與細胞生物研究所
101
Human eosinophil cationic protein (hECP) is a basic and cytotoxic granular protein released from activated eosinophils. ECP interacts with cellular surface heparan sulfate proteoglycans (HSPGs) and internalizes into cells through lipid raft-associated macropinocytosis. Three heparin binding regions (HBRs) on ECP, 34RWRCK38 (HBR1), 75RSRFR79 (HBR2), and 101RPGRR105 (HBR3), have been recently identified. In this study, binding energy of amino acids interacting with haprin hexasaccharide was estimated by docking simulation, and Arg34, Gln40, His64 and Arg105 in ECP were predicted to contribute the most. To determine the roles of these residues in heparin binding to ECP, mutant ECPs with single alanine replacement were generated, and heparin binding affinities of wild type and mutant ECPs were measured and compared by isothermal titration calorimetry. Further, cell ELISA showed that Arg34, Arg36 and Lys38 within HBR1 acted as key residues for heparin binding in ECP. In addtion a novel cell penetrating peptide (CPPecp) spanning residues 32 to 41 in ECP was recently demonstrated to possess multiple biological functions. CPPecp was able to increase rhodamine-labeled liposome (RL) penetration into human cells. Moreover, cytotoxicity of liposomal formulated drug (LFD) significantly enhanced in the presence of CPPecp in the cells. Taken together, we have demonstrated key residues in HBRs of ECP for heparin binding. Membrane HSPGs and phospholipid binding drive CPPecp to enhance cellular uptake of liposomes, which in turn may facilitate novel design and application for LFD delivery.
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Hsieh, Feng-Koo, und 謝逢轂. „The Role of Kelch-Like ECH-Associated Protein 1 (KEAP1) in Lung Adenocarcinoma Migration and Invasion“. Thesis, 2008. http://ndltd.ncl.edu.tw/handle/31961946583141266157.
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碩士國立臺灣大學
毒理學研究所
96
Previous studies revealed that weakened KEAP1 (Kelch liked ECH-associated protein 1) expression enhanced NRF2 (NF-E2-related factor 2) nuclear accumulation and elevated antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes such as antioxidative and antixenobiotic stress enzymes and drug efflux pumps in non-small cell lung cancer, suggesting that gave lung cancer cells multiple advantages for proliferation. However, recent studies indicated that NRF2 was not correlated with reduced survival or overall survival of NSCLC. In this study, KEAP1 protein expression in 52 lung adenocarcinoma specimens was investigated immunohistochemically and was significantly correlated with overall survival. We found KEAP1 expressed higher in early stage lung adenocarcinoma than in late stage adenocarcinoma. Also, KEAP1 had ability to inhibit lung adenocarcinoma migration and invasion. At the mean time, we found that RhoA may be involved in this process. Moreover, in vivo animal study showed weakened KEAP1 expression promoted metastasis ability and primary tumorigenesis. In conclusion, our data suggested that KEAP1 may mediate lung adenocarcinoma migratory and invasive abilities through degradation of RhoA.
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Hsieh, Feng-Koo. „The Role of Kelch-Like ECH-Associated Protein 1 (KEAP1) in Lung Adenocarcinoma Migration and Invasion“. 2008. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-2907200817025900.
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